IL327017A - Methods for treating lipid and cholesterol metabolism associated diseases and conditions - Google Patents

Description

WO 2025/054048 PCT / US2024 / 0440 METHODS AND USES OF MICROBIOME COMPOSITIONS , COMPONENTS , OR METABOLITES FOR TREATING LIPID AND CHOLESTEROL METABOLISM ASSOCIATED DISEASES , DISORDERS , AND CONDITIONS [ 0001 ] CROSS REFERENCE TO RELATED APPLICATIONS The present application claims priority to United States Provisional Patent Application No. 63 / 581,550 filed September 8 , 2023 , the entire contents of which are hereby incorporated by reference in their entirety . [ 0002 ] BACKGROUND Many diseases , disorders , or conditions including , but not limited to , lipid- induced metabolic syndrome , cerebral infarction / stroke , myocardial infarction / heart attack , Type II diabetes / diabetes mellitus , glucose intolerance , alcoholism , metabolic syndrome , kidney disease , cardiorenal syndrome , vascular diseases ( e.g. , hypertension , peripheral arterial disease ) , Alzheimer's disease , asthma ( e.g. , due to abdominal obesity or central / truncal obesity ) , atherosclerosis , hypothyroidism , liver disease , LDL- hypercholesterolemia , hypertriglyceridemia , mixed hyperlipoproteinemia , coronary heart disease , stroke , peripheral arterial disease , high blood pressure , hyperlipidemia , steatosis , non - alcoholic steatohepatitis ( NASH ) , fatty - liver disease , metabolic associated fatty liver disease ( MAFLD ) , non - alcoholic fatty liver disease ( NAFLD ) , liver fibrosis , cirrhosis , or hepatocellular carcinoma are suspected to be associated with improper metabolism ( e.g. improper lipid metabolism or improper cholesterol metabolism ) . Currently , there are no effective treatments to improve and / or treat the overall health and well - being of subjects ( e.g. patients ) , regain and maintain their proper metabolism levels , and by extension improve and / or treat metabolism associated diseases , disorders , and conditions ( e.g. including any diseases associated with lipid and / or cholesterol metabolism ) , and finding new drugs or treatment methods is a priority . [ 0003 ] SUMMARY The present disclosure provides an insight that compositions ( e.g. microbiome compositions ) and methods as described herein may be used to treat diseases , WO 2025/054048 PCT / US2024 / 0440 disorders , or conditions ( e.g. metabolism ( e.g. lipid and cholesterol metabolism ) associated diseases , disorders , and conditions ) in a subject ( e.g. a mammal ( e.g. human , mice , etc. ) ) . Furthermore , the present disclosure identifies that compositions ( e.g. microbiome compositions ) and methods as described herein may be used to treat and / or improve the metabolic health of a subject ( e.g. prevent , improve , and / or repair metabolism associated cell damage or organ damage ) , and improve overall functionality and health of a subject . Moreover , the present disclosure appreciates that compositions ( e.g. microbiome compositions ) and methods as described herein may be used to treat and / or improve the health and overall functionality of any organs , tissues , and / or other internal parts of a subject . Among other things , the present disclosure describes technologies that can be used to treat , prevent , and / or reduce the risk of a disease , disorder , or condition ( e.g. metabolism ( e.g. lipid and cholesterol metabolism ) associated diseases , disorders , and conditions ) . In some embodiments , the present disclosure describes compositions and methods to evaluate the effects of administering such compositions ( e.g. microbiome compositions as described herein ) to a subject and / or to identify or characterize effects and / or modulation of levels of metabolites or a metabolome in a subject upon administration of such compositions . In some embodiments , the metabolites that may be modulated may be associated with certain diseases , disorders , or conditions . In some embodiments , such technologies can be useful to discern metabolite - level differences in a particular subject ( e.g. , patient ) or population ( e.g. before and after administration of disclosed compositions ) . Accordingly , the present disclosure also provides technologies that can be useful to identify and / or assess the nature and effect of disclosed compositions in specific subjects ( e.g. , patients ) and / or populations and thus provide subject - specific information on how to treat a disease , disorder , or condition ( e.g. metabolism ( e.g. lipid and cholesterol metabolism ) associated diseases , disorders , and conditions ) in an individual subject or individual population . For example , in some embodiments , technologies provided herein can be useful to identify subject - specific compositions , based on the metabolome in subject - specific samples , and treat and / or prevent a disease , disorder , or condition ( e.g. metabolism ( e.g. lipid and cholesterol metabolism ) associated diseases , disorders , and conditions ) by administering disclosed compositions ( e.g. subject - specific compositions ) ( e.g. to modulate subject's metabolome ) . Thus , technologies described herein may be useful as therapeutics and tools for reducing the risk of certain diseases , disorders , or conditions ( e.g. metabolism associated ( e.g. lipid and cholesterol 2 WO 2025/054048 PCT / US2024 / 0440 metabolism ) diseases , disorders , and conditions ) , and for treating and / or preventing such diseases , disorders , or conditions . [ 0004 ] The present disclosure appreciates the insight that compositions described herein ( e.g. microbiome compositions ) directly influence metabolic activity and therefore influence the functioning of organs , organ systems , and overall health of a subject . Prior technologies have been limited to treating only a part of such systems , e.g. , dysfunctions associated with a particular organ . The present disclosure recognizes that such technologies , while beneficial , are triaging only a portion of the overall issues . The present disclosure , therefore , provides compositions and methods directed to improving function and overall health ( e.g. , metabolic health ) of cells , tissues , organs , organ systems , one or more connected organs , and / or a subject . [ 0005 ] Among other things , the present disclosure provides a method of treating or preventing a metabolism - associated disease , disorder , or condition ( e.g. lipid and cholesterol metabolism ) . In some embodiments , a method comprises administering to a subject a composition comprising one or more microbial strains or microbial components . In some embodiments , a method comprises administering to a subject a composition comprising one or more microbial metabolites . In some embodiments , a method comprises administering to a subject a composition comprising ( i ) one or more microbial strains or microbial components , or ( ii ) one or more microbial metabolites . [ 0006 ] In some embodiments , a metabolism - associated disease , disorder , or condition is or comprises one or more of body weight gain , lipid accumulation in liver , accumulation of visceral fat , elevated blood triglyceride levels , hypercholesterolemia , inflammation , and / or high blood - cholesterol levels ( e.g. Low Density Lipoprotein ( LDL ) levels ) . In some embodiments , a subject has been diagnosed with or is at high risk of a lipid disease , disorder , or condition . In some embodiments , a lipid disease , disorder , or condition is or comprises one or more of body weight gain , lipid accumulation in liver , accumulation of visceral fat , elevated blood triglyceride levels , hypercholesterolemia , inflammation , and / or high blood - cholesterol levels ( e.g. Low Density Lipoprotein ( LDL ) levels ) . [ 0007 ] In some embodiments , a subject has been diagnosed with or is at high risk of a metabolic disease , disorder , or condition . In some embodiments , a subject has been diagnosed with or is at high risk of lipid - induced metabolic syndrome , cerebral infarction / stroke , myocardial infarction / heart attack , Type II diabetes / diabetes mellitus , 3 WO 2025/054048 PCT / US2024 / 0440 glucose intolerance , alcoholism , metabolic syndrome , kidney disease , cardiorenal syndrome , vascular diseases ( e.g. , hypertension , peripheral arterial disease ) , Alzheimer's disease , asthma ( e.g. , due to abdominal obesity or central / truncal obesity ) , atherosclerosis , hypothyroidism , liver disease , LDL - hypercholesterolemia , hypertriglyceridemia , mixed hyperlipoproteinemia , coronary heart disease , stroke , peripheral arterial disease , high blood pressure , hyperlipidemia , steatosis , non - alcoholic steatohepatitis ( NASH ) , fatty - liver disease , metabolic associated fatty liver disease ( MAFLD ) , non - alcoholic fatty liver disease ( NAFLD ) , liver fibrosis , cirrhosis , or hepatocellular carcinoma . [ 0008 ] In some embodiments , a subject is animal . In some embodiments , a subject is a mammal , e.g. , a mammal that experiences or is susceptible to a disease , disorder , or condition as described herein . In some embodiments , an animal is a vertebrate , e.g. , a mammal , such as a non - human primate , ( particularly a higher primate ) , a sheep , a dog , a rodent ( e.g. a mouse or rat ) , a guinea pig , a goat , a pig , a cat , a rabbit , or a cow . In some embodiments , an animal is a non - mammal animal , such as a chicken , an amphibian , a reptile , or an invertebrate . In some embodiments , a subject is a human . [ 0009 ] In some embodiments , a subject is suffering from or susceptible to one or more metabolism - associated disease , disorder , or condition as described herein . In some embodiments , a subject displays one or more symptoms of one or more metabolism- associated disease , disorder , or condition as described herein . In some embodiments , a subject has been diagnosed with one or more metabolism - associated disease , disorder , or condition as described herein . In some embodiments , the subject is receiving or has received certain therapy to diagnose and / or to treat one or more metabolism - associated disease , disorder , or condition . [ 0010 ] In some embodiments , one or more microbial strains are from a mammalian microbiome . In some embodiments , one or more microbial strains are from a human microbiome . In some embodiments , a human microbiome is the microbiome of the subject . In some embodiments , a human microbiome is administered to maintain or modulate the microbiome of the subject . [ 0011 ] In some embodiments , one or more microbial components or microbial metabolites are selected from Appendix 1 , Appendix 3 , or Appendix 4. In some embodiments , metabolites can be from one or more microbial strains . In some embodiments , metabolites can be from a source that is not a microbial strain , e.g. , WO 2025/054048 PCT / US2024 / 0440 synthetically generated . In some embodiments , one or more microbial metabolites is or comprises a bile acid , Cholesterol , chenodeoxycholic acid , α61 - chenodeoxycholic acid ( CDCA ) , oxysterols , taurochenodeoxycholic acid , cholic acid , lithocholic acid , ursodeoxycholic acid , triglycerides , very - low density lipoprotein ( VLDL ) , VLDL - TG , cholesterol , eicosanoids , arachidonic acid , docosahexaenoic acid , eicosapentaenoic acid , trimethylamines ( TMA ) , trimethylamine - N - oxide ( TMAO ) , endogenous ethanol , acetone , acetaldehyde , butyrate , choline , or any combination thereof . In some embodiments , one or more microbial metabolites is or comprises Tauroursodeoxycholic acid , taurocholic acid , long - chain acyl - CoA dehydrogenase ( LCAD ) , deoxycholic acid ( DCA ) , lithocholic acid ( LCA ) , taurochenodeoxycholic acid , ursodeoxycholic acid , α7 - hydroxycholesterol , chenodeoxycholic acid , 27 - hydroxycholesterol , α7 - hydroxy - 4 - cholestene - 3 - one , or any combination thereof . In some embodiments , one or more microbial components or microbial metabolites is Butyrylcamitine , Theobromine , p - Hydroxyphenylpyruvic acid , Propionic acid , Picolinic acid , 2 - Hydroxy - 4methylvaleric acid , N6 - Acetylysine , Urocanic acid , N5 - Ethylglutamine , Trigonelline , Stachydrine , Ectoine , 5 - Hydroxylysine , Arginine ( arg ) , Cholic acid , 2- ( 4 - Hydroxyphenyl ) propionic acid , N - Acetyltryptophan , Hydroxyproline , Argininosuccinic acid , Glutamic acid ( Glu ) , Sarcosine , 5- Methoxyindoleacetic acid , Indole - 3 - lactic acid , Isovalerylalanine , N - Acetylleucine , 1- Methylhistidine , N - Acetylephenylalanine , Proline ( Pro ) , or any combination thereof . In some embodiments , one or more microbial components or microbial metabolites is 4- Hydroxyphenylpyruvic , Ectoine , Gramine , N - Acetyl - L - phenylalanine , Nepsilon - Acetyl - L- lysine , Stachydrine , Trigonelline , 3 - Ureidopropionic acid , Theobromine , Hippuric acid , Imidazolepropionic acid , NG - Methyl - L - arginine , trans - Urocanic Acid , N - Acetyl - L - leucine , Sarcosine , Isobutyrylcarnitine , b - Hydroxyisovaleric acid , L - Theanine / N5 - Ethylglutamine , 5- Hydroxylysine , Phenaceturic acid , betaine , hydroxyproline , Picolinic acid , 2 - Aminoadipic acid , Glycerophosphocholine , carnitine , Glycerol 3 - phosphate , Argininosuccinic acid , creatine , Terephthalic acid , Homocitrulline , Mucic acid , Homocysteinesulfinic acid . Trimethyllysine , Spermidine , Glyoxylic acid , XA0013 C6H604S , 3 - Indoxylsulfuric acid , Nicotinamide , N - Formylglycine , Ureidoglycolate , N - Methylproline , Glucaric acid , Butyrylcarnitine , Methionine sulfoxide , Carboxymethyllysine , Glycolic acid , Phenaceturic acid , Diethanolamine , Phosphorylcholine , Guanidinosuccinic acid , N - Acetylhistidine , Glyceric acid , S - Methylmethionine , Cysteine glutathione disulfide , Kynurenine , N- Acetylphenylalanine , Threonic acid , Malic acid , 7,8 - Dihydrobiopterin , Homovanillic acid , 5 WO 2025/054048 PCT / US2024 / 0440 Taurocholic acid , 5 - Methoxyindoleacetic acid , butyrate , b - Hydroxyisovaleric acid , 2- Oxoglutaric acid , N - Acetyltryptophan , Thiaproline , Hypotaurine , Cholic acid , Acetoacetic acid , Ethanolamine , Guanidoacetic acid , S - Sulfocysteine , Myristic acid C14 : 0 XA0027 , or any combination thereof . [ 0012 ] In some embodiments , one or more microbial strains are or comprise Gluconacetobacter sp . , Terrisporobacter sp . , Coprococcus sp . , Lactobacillus sp . , Clostridium sp . , Paenibacillus sp . , Veillonella sp . , Bifidobacterium sp . , Bacillus sp . , Acidaminococcus sp . , or a combination thereof . In some embodiments , one or more microbial strains are or comprise Gluconacetobacter hansenii , Terrisporobacter glycolicus , Coprococcus sp . , Lactobacillus plantarum , Clostridium butyricum , Paenibacillus sp . , Veillonella sp . , Bifidobacterium sp . , Bacillus subtilis , Acidaminococcus sp . , or a combination thereof . In some embodiments , one or more microbial strains are or comprise Gluconacetobacter hansenii , Terrisporobacter glycolicus , Coprococcus catus , Lactobacillus plantarum , Clostridium butyricum , Paenibacillus barengoltzii , Veillonella atypica , Bifidobacterium breve , Bacillus subtilis , Acidaminococcus sp . , or a combination thereof . In some embodiments , one or more microbial strains are or comprise Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus sp . , Lactobacillus plantarum , Veillonella sp . , Bifidobacterium sp . , or a combination thereof . In some embodiments , one or more microbial strains are or comprise Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus catus , Lactobacillus plantarum , Veillonella atypica , Bifidobacterium breve , or a combination thereof . In some embodiments , one or more microbial strains is or comprises Bacillus subtilis . [ 0013 ] In some embodiments , a composition comprises two or more microbial strains . In some embodiments , a composition comprises five or more microbial strains . In some embodiments , a composition comprises ten or more microbial strains . [ 0014 ] In some embodiments , a composition is administered topically , orally , subcutaneously , intravenously , intramuscularly , intracerebrally , intrathecally , rectally , opthalmically , intravitreally , or suprachoroidally . In some embodiments , a composition is administered orally . In some embodiments , a composition is administered intravenously . [ 0015 ] In some embodiments , a composition is formulated as a syrup , a liquid , a tablet , a troche , a gummy , a capsule , a powder , a gel , a film , an injection , or an eye drop . 6 WO 2025/054048 PCT / US2024 / 0440 [ 0016 ] In some embodiments , each microbial strain of the one or more microbial strains is present in the composition at a concentration from 10¹ to 10¹5 CFU . In some embodiments , each microbial strain of the one or more microbial strains is present in the composition at a concentration of at least 106 CFU . In some embodiments , each microbial strain of one or more microbial strains in a composition comprises 10¹ colony forming units ( CFUs ) to 1020 CFU . In some embodiments , each microbial strain of one or more microbial strains in a composition comprises 10¹ colony forming units ( CFUs ) to 1015 CFU . In some embodiments , each microbial strain of one or more microbial strains in a composition comprises 106 CFU to 1015 CFUs . In some embodiments , each microbial strain of one or more microbial strains in a composition comprises about 10¹ CFU to 10¹5 CFU , or about 10² CFU to 1014 CFU , or about 103 CFU to 10¹³ CFU , or about 10+ CFU to 1013 CFU , or about 105 CFU to 10¹² CFU , or about 106 CFU to 1011 CFU , or about 107 CFU to 1010 CFU , or about 108 CFU to º01 CFU , or about 105 CFU to 1010 CFU , or about 108 CFU to 10¹² CFU . In some embodiments , each microbial strain of one or more microbial strains in a composition comprises at least about 10¹ , 5 x 10¹ , 102 , 5 x 102 , 10³ , 5 x 10³ , 104 , 5 x 104 , 105 , 5 x 105 , 106 , 5 x 106 , 107 , 5 x 107 , 108 , 5 x 108 , 109 , 5 x 10 ° , º¹01 , 5 x 1010 , 10¹¹ , 5 x 1011 , 1012 , or more CFUs . In some embodiments , each of one or more microbial strains in a composition comprises at most about 1015 , 5 x 1014 , 1014 , 5 x 10¹³ , 1013 , 5 x 1012 , 1012 , 5 x 10¹¹ , 10¹¹ , 5 x º¹01 , º¹01 , 5 x º01 , 10 % , 5 x 108 , 108 , or less CFUs . In some embodiments , each microbial strain of one or more microbial strains in a composition comprises same number of CFUs . In some embodiments , some microbial strains of one or more microbial strains in a composition comprises a different number of CFUs . [ 0017 ] , The present disclosure provides , among other things , a composition for use in treating a metabolic disease , disorder , or condition comprising one or more microbial strains or microbial components . In some embodiments , a composition , as described herein , is for use in treating a metabolic disease , disorder , or condition comprises one or more microbial metabolites ( e.g. derived from sources other than microbial strains ( e.g. synthetically derived ) , derived from one or more microbial strains ) . [ 0018 ] The present disclosure provides a composition comprising one or more microbial strains selected from Gluconacetobacter sp . , Terrisporobacter sp . , Coprococcus sp . , Lactobacillus sp . , Clostridium sp . , Paenibacillus sp . , sp . , Bacillus sp . , Acidaminococcus sp . , or a combination thereof . In some embodiments , a composition comprises one or more microbial strains selected from Gluconacetobacter sp . , Veillonella sp . , Bifidobacterium 7 WO 2025/054048 PCT / US2024 / 0440 hansenii , Terrisporobacter glycolicus , Coprococcus sp . , Lactobacillus plantarum , Clostridium butyricum , Paenibacillus sp . , Veillonella sp . , Bifidobacterium sp . , Bacillus subtilis , Acidaminococcus sp . , or a combination thereof . In some embodiments , a composition comprises one or more microbial strains selected from Gluconacetobacter hansenii , Terrisporobacter glycolicus , Coprococcus catus , Lactobacillus plantarum , Clostridium butyricum , Paenibacillus barengoltzii , Veillonella atypica , Bifidobacterium breve , Bacillus subtilis , Acidaminococcus sp . , or a combination thereof . In some embodiments , a composition comprises one or more microbial strains selected from Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus sp . , Lactobacillus plantarum , Veillonella sp . , Bifidobacterium sp . , or a combination thereof . In some embodiments , a composition comprises one or more microbial strains selected from Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus catus , Lactobacillus plantarum , Veillonella atypica , Bifidobacterium breve , or a combination thereof . [ 0019 ] In some embodiments , a composition comprises a microbial strain . In some embodiments , a microbial strain is Bacillus subtilis . [ 0020 ] In some embodiments , a composition comprises at least two microbial strains selected from a group consisting of Gluconacetobacter sp . , Terrisporobacter sp . , Coprococcus sp . , Lactobacillus sp . , Clostridium sp . , Paenibacillus sp . , Veillonella sp . , Bifidobacterium sp . , Bacillus sp . , Acidaminococcus sp . , or a combination thereof . In some embodiments , a composition comprises at least two microbial strains selected from a group consisting of Gluconacetobacter hansenii , Terrisporobacter glycolicus , Coprococcus sp . , Lactobacillus plantarum , Clostridium butyricum , Paenibacillus sp . , Veillonella sp . , Bifidobacterium sp . , Bacillus subtilis , Acidaminococcus sp . , or a combination thereof . In some embodiments , a composition comprises at least two microbial strains selected from Gluconacetobacter hansenii , Terrisporobacter glycolicus , Coprococcus catus , Lactobacillus plantarum , Clostridium butyricum , Paenibacillus barengoltzii , Veillonella atypica , Bifidobacterium breve , Bacillus subtilis , Acidaminococcus sp . , or a combination thereof . In some embodiments , a composition comprises at least two microbial strains selected from Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus sp . , Lactobacillus plantarum , Veillonella sp . , Bifidobacterium sp . , or a combination thereof . In some embodiments , a composition comprises at least two microbial strains selected from a group consisting of Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus catus , 8 WO 2025/054048 PCT / US2024 / 0440 Lactobacillus plantarum , Veillonella atypica , Bifidobacterium breve , or a combination thereof . [ 0021 ] In some embodiments , a composition comprises at least five microbial strains selected from a group consisting of Gluconacetobacter sp . , Terrisporobacter sp . , Coprococcus sp . , Lactobacillus sp . , Clostridium sp . , Paenibacillus Veillonella sp . , sp . , Bifidobacterium sp . , Bacillus sp . , Acidaminococcus sp . , or a combination thereof . In some embodiments , a composition comprises at least five microbial strains selected from a group consisting of Gluconacetobacter hansenii , Terrisporobacter glycolicus , Coprococcus sp . , Lactobacillus plantarum , Clostridium butyricum , Paenibacillus sp . , Veillonella sp . , Bifidobacterium sp . , Bacillus subtilis , Acidaminococcus sp . , or a combination thereof . In some embodiments , a composition comprises at least five microbial strains selected from Gluconacetobacter hansenii , Terrisporobacter glycolicus , Coprococcus catus , Lactobacillus plantarum , Clostridium butyricum , Paenibacillus barengoltzii , Veillonella atypica , Bifidobacterium breve , Bacillus subtilis , Acidaminococcus sp . , or a combination thereof . In some embodiments , a composition comprises at least five microbial strains selected from Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus sp . , Lactobacillus plantarum , Veillonella sp . , Bifidobacterium sp . , or a combination thereof . In some embodiments , a composition comprises at least five microbial strains selected from a group consisting of Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus catus , Lactobacillus plantarum , Veillonella atypica , Bifidobacterium breve , or a combination thereof . [ 0022 ] In some embodiments , a composition comprises or consists of Gluconacetobacter sp . , Terrisporobacter sp . , Coprococcus sp . , Lactobacillus sp . , Clostridium sp . , Paenibacillus sp . , Veillonella sp . , Bifidobacterium sp . , Bacillus sp . , Acidaminococcus sp . , or a combination thereof . In some embodiments , a composition comprises or consists of Gluconacetobacter hansenii , Terrisporobacter glycolicus , Coprococcus sp . , Lactobacillus plantarum , Clostridium butyricum , Paenibacillus sp . , Veillonella sp . , Bifidobacterium sp . , Bacillus subtilis , Acidaminococcus sp . , or a combination thereof . In some embodiments , a composition comprises or consists of Gluconacetobacter hansenii , Terrisporobacter glycolicus , Coprococcus catus , Lactobacillus plantarum , Clostridium butyricum , Paenibacillus barengoltzii , Veillonella atypica , Bifidobacterium breve , Bacillus subtilis , Acidaminococcus sp . , or a combination thereof . In some embodiments , a composition comprises or consists of Gluconacetobacter hanseni , 9 WO 2025/054048 PCT / US2024 / 0440 Terrisporobacter glycolicus , Coprococcus sp . , Lactobacillus plantarum , Veillonella sp . , Bifidobacterium sp . , or a combination thereof . In some embodiments , a composition comprises or consists of Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus catus , Lactobacillus plantarum , Veillonella atypica , Bifidobacterium breve , or a combination thereof . [ 0023 ] In some embodiments , a composition as described herein comprises at least one , at least two , at least three , at least four , at least five , at least six , at least seven , at least eight , at least nine , or at least ten microbial strains ( e.g. microbial strains as disclosed herein ) . In some embodiments , a composition as described herein comprises at most one , at most two , at most three , at most four , at most five , at most six , at most seven , at most eight , at most nine , or at most ten microbial strains ( e.g. microbial strains as disclosed herein ) . In some embodiments , a composition as described herein comprises one , two , three , four , five , six , seven , eight , nine , ten , or more microbial strains ( e.g. microbial strains as disclosed herein ) . [ 0024 ] In some embodiments , a composition as described herein comprises at least one , at least two , at least three , at least four , at least five , at least six , at least seven , at least eight , at least nine , or at least ten microbial components ( e.g. microbial components as disclosed herein ) . In some embodiments , a composition as described herein comprises at most one , at most two , at most three , at most four , at most five , at most six , at most seven , at most eight , at most nine , or at most ten microbial components ( e.g. microbial components as disclosed herein ) . In some embodiments , a composition as described herein comprises one , two , three , four , five , six , seven , eight , nine , ten , or more microbial components ( e.g. microbial components as disclosed herein ) . [ 0025 ] In some embodiments , a composition , as described herein , comprises one or more microbial metabolites ( e.g. derived from sources other than microbial strains ( e.g. synthetically derived ) , derived from one or more microbial strains ) , wherein the composition is for treating an metabolism - associated disease , disorder , or condition . [ 0026 ] In some embodiments , a composition as described herein comprises at least one , at least two , at least three , at least four , at least five , at least six , at least seven , at least eight , at least nine , or at least ten microbial metabolites ( e.g. microbial metabolites as disclosed herein ) . In some embodiments , a composition as described herein comprises at most one , at most two , at most three , at most four , at most five , at most six , at most seven , at WO 2025/054048 PCT / US2024 / 0440 most eight , at most nine , or at most ten microbial metabolites ( e.g. microbial metabolites as disclosed herein ) . In some embodiments , a composition as described herein comprises one , two , three , four , five , six , seven , eight , nine , ten , or more microbial metabolites ( e.g. microbial metabolites as disclosed herein ) . [ 0027 ] In some embodiments , composition is for topical , oral , subcutaneous , intravenous , intramuscular , intracerebral , intrathecal , rectal , opthalmical , intravitreal , or suprachoroidal administration . In some embodiments , a composition is for oral administration . In some embodiments , a composition is for intravenous administration . [ 0028 ] The present disclosure provides , among other things , a composition for use in modulating one or more microbial metabolites in a subject . In some embodiments , a composition is for use in modulating one or more features in a subject . In some embodiments , one or more features is or comprises : ( i ) level of cell viability ; ( ii ) level or activity of a nucleic acid or protein , or form thereof ; ( iii ) body weight gain ; ( iv ) lipid accumulation in liver ; ( v ) accumulation of visceral fat ; ( vi ) elevated blood triglyceride levels ; ( vii ) blood - cholesterol levels ; ( viii ) oxidative stress ; ( ix ) hypercholesterolemia ; or ( x ) inflammation . [ 0029 ] In some embodiments , a composition is for use in characterizing ability of one more microbial strains to modulate one or more microbial metabolites in a subject . [ 0030 ] The present disclosure provides that a use of a composition as described herein is for treating or ameliorating a disease , disorder , or condition in a subject , wherein the disease , disorder , or condition is a metabolic disease , disorder , or condition associated with one or more microbial metabolites . In some embodiments , a use of a composition as described herein is for treating or ameliorating lipid - induced metabolic syndrome , cerebral infarction / stroke , myocardial infarction / heart attack , Type II diabetes / diabetes mellitus , glucose intolerance , alcoholism , metabolic syndrome , kidney disease , cardiorenal syndrome , vascular diseases ( e.g. , hypertension , peripheral arterial disease ) , Alzheimer's disease , asthma ( e.g. , due to abdominal obesity or central / truncal obesity ) , atherosclerosis , hypothyroidism , liver disease , LDL - hypercholesterolemia , hypertriglyceridemia , mixed hyperlipoproteinemia , coronary heart disease , stroke , peripheral arterial disease , high blood pressure , hyperlipidemia , steatosis , non - alcoholic steatohepatitis ( NASH ) , fatty - liver disease , metabolic associated fatty liver disease ( MAFLD ) , non - alcoholic fatty liver disease ( NAFLD ) , liver fibrosis , cirrhosis , or hepatocellular carcinoma . In some embodiments , a use 11 WO 2025/054048 PCT / US2024 / 0440 of a composition as described herein is for treating or ameliorating fatty - liver disease , metabolic associated fatty liver disease ( MAFLD ) , non - alcoholic fatty liver disease ( NAFLD ) , steatosis , non - alcoholic steatohepatitis ( NASH ) , liver fibrosis , cirrhosis , or hepatocellular carcinoma . [ 0031 ] The present disclosure provides a method of screening a microbial strain , comprising contacting the microbial strain to a culture comprising liver cells or liver cell lines that model a metabolic disease , disorder , or condition , and determining whether the microbial strain altered a feature of the culture , wherein the feature is associated with the metabolic disease , disorder , or condition . [ 0032 ] In some embodiments , a step of determining comprises comparing a feature before and after performance of the step of contacting . In some embodiments , a step of determining comprises comparing a feature after the step of contacting with a comparable reference . [ 0033 ] In some embodiments , a comparable reference is a historical reference . In some embodiments , a comparable reference is a negative control reference . In some embodiments , a comparable reference is a positive control reference . [ 0034 ] In some embodiments , a feature is a level of cell viability . In some embodiments , a feature is level or activity of a nucleic acid or protein , or form thereof . In some embodiments , a feature is or comprises weight gain . In some embodiments , a feature is or comprises lipid accumulation in liver cells . In some embodiments , a feature is or comprises accumulation of visceral fat . In some embodiments , a feature is or comprises triglyceride levels . In some embodiments , a feature is or comprises cholesterol levels . In some embodiments , a feature is or comprises inflammation . [ 0035 ] In some embodiments , a microbial strain may alter one or more features of a culture . In some embodiments , one or more features is associated with the metabolic disease , disorder , or condition . In some embodiments , one or more features is or comprises ( i ) level of cell viability ; ( ii ) level or activity of a nucleic acid or protein , or form thereof ; ( iii ) body weight gain ; ( iv ) lipid accumulation in liver ; ( v ) accumulation of visceral fat ; ( vi ) elevated blood triglyceride levels ; ( vii ) blood - cholesterol levels ; ( viii ) oxidative stress ; ( ix ) hypercholesterolemia ; or ( x ) inflammation . [ 0036 ] The present disclosure provides a method comprising administering to a subject a composition comprising one or more microbial strains or microbial components . 12 WO 2025/054048 PCT / US2024 / 0440 In some embodiments , the present disclosure provides a method comprising administering to a subject a composition comprising one or more microbial metabolites . In some embodiments , microbial metabolites can be from one or more microbial strains . In some embodiments , microbial metabolites can be from a source that is not a microbial strain , e.g. , synthetically generated . [ 0037 ] In some embodiments , a microbial strain or the microbial metabolite may alter a feature of the subject . In some embodiments , a microbial strain , a microbial component , or a microbial metabolite may alter one or more features of the subject . In some embodiments , a feature is a level of cell viability . In some embodiments , a feature is level or activity of a nucleic acid or protein , or form thereof . In some embodiments , a feature is or comprises body weight gain . In some embodiments , a feature is or comprises lipid accumulation in liver . In some embodiments , a feature is or comprises accumulation of visceral fat . In some embodiments , a feature is or comprises triglyceride levels . In some embodiments , a feature is or comprises cholesterol levels . In some embodiments , a feature is or comprises inflammation . [ 0038 ] In some embodiments , a feature is associated with a metabolism - associated disease , disorder , or condition . [ 0039 ] The present disclosure provides a method of characterizing a microbial strain , comprising adding the microbial strain to a culture comprising liver cells or liver cell lines that model a metabolic disease , disorder , or condition , and determining whether the microbial strain affects levels of one or more features of the liver cells or liver cell lines , wherein the one or more features are associated with the metabolic disease , disorder , or condition . [ 0040 ] The present disclosure provides a method of manufacturing a pharmaceutical treatment comprising characterizing one or more microbial strains , microbial components , or microbial metabolites comprising the steps of adding the one or more microbial strains to a culture comprising liver cells or liver cell lines that model a metabolic disease , disorder , or condition , and determining whether the one or more microbial strains affect levels of one or more features of the liver cells or liver cell lines , wherein the one or more features are associated with the metabolic disease , disorder , or condition . [ 0041 ] The present disclosure provides a method of manufacturing a pharmaceutical treatment comprising adding one or more microbial strains or microbial components , to a 13 WO 2025/054048 PCT / US2024 / 0440 syrup , a liquid , a tablet , a troche , a gummy , a capsule , a powder , a gel , a film , an injection , or an eye drop . The present disclosure provides a method of manufacturing a pharmaceutical treatment comprising adding one or more microbial metabolites , to a syrup , a liquid , a tablet , a troche , a gummy , a capsule , a powder , a gel , a film , an injection , or an eye drop . [ 0042 ] The present disclosure provides a method of assessing a microbial strain for ability to affect one or more features of a culture , comprising adding the microbial strain to the culture comprising liver cells or liver cell lines that model a metabolic disease , disorder , or condition , and determining whether the microbial strain affects levels of one or more features of the liver cells or liver cell lines , wherein the one or more features are associated with the metabolic disease , disorder , or condition . [ 0043 ] In some embodiments , a method further comprises before adding the microbial strain to the culture , determining levels of one or more features of the liver cells or liver cell lines in the culture , after adding the microbial strain to the culture , determining the levels of the same one or more features of the liver cells or liver cell lines in the culture , and comparing the levels of one or more features determined before adding the microbial strain with the levels of one or more features determined after adding the microbial strain . [ 0044 ] In some embodiments , one or more features includes : ( i ) level of cell viability ; ( ii ) level or activity of a nucleic acid or protein , or form thereof ; ( iii ) body weight gain ; ( iv ) lipid accumulation in liver ; ( v ) accumulation of visceral fat ; ( vi ) elevated blood triglyceride levels ; ( vii ) blood - cholesterol levels ; ( viii ) oxidative stress ; ( ix ) hypercholesterolemia ; ( x ) inflammation ; or ( xi ) a combination thereof . [ 0045 ] The present disclosure provides that a composition as described herein is for use in treating or preventing a metabolic disease , disorder , or condition , comprising one or more microbial strains or microbial components . The present disclosure further provides that a composition as described herein is for use in treating or preventing a metabolic disease , disorder , or condition , comprising one or more microbial metabolites . In some embodiments , one or more microbial components or microbial metabolites of a one or more microbial strains are selected from Appendix 1 , Appendix 3 , or Appendix 4 . [ 0046 ] In some embodiments , a composition as described herein is for use in treating or preventing a metabolism - associated disease , disorder , or condition . [ 0047 ] The present disclosure provides an injection comprising a composition of as described herein . 14 WO 2025/054048 PCT / US2024 / 0440 [ 0048 ] The present disclosure provides a food supplement comprising a composition as described herein . [ 0049 ] The present disclosure provides a kit comprising a composition as described herein , for example , for use in treating or preventing a metabolic disease , disorder , or condition . In some embodiments , a kit comprises a monitoring device . In some embodiments , a monitoring device is a cholesterol monitor . [ 0050 ] These , and other aspects encompassed by the present disclosure , are described in more detail below and in the claims . [ 0051 ] DEFINITIONS The scope of the present invention is defined by the claims appended hereto and is not limited by certain embodiments described herein . Those skilled in the art , reading the present specification , will be aware of various modifications that may be equivalent to such described embodiments , or otherwise within the scope of the claims . In general , terms used herein are in accordance with their understood meaning in the art , unless clearly indicated otherwise . Explicit definitions of certain terms are provided below ; meanings of these and other terms in particular instances throughout this specification will be clear to those skilled in the art from context . [ 0052 ] Use of ordinal terms such as " first , " " second , " " third , " etc. , in the claims to modify a claim element does not by itself connote any priority , precedence , or order of one claim element over another or the temporal order in which acts of a method are performed , but are used merely as labels to distinguish one claim element having a certain name from another element having a same name ( but for use of the ordinal term ) to distinguish the claim elements . [ 0053 ] The articles " a " and " an , " as used herein , should be understood to include the plural referents unless clearly indicated to the contrary . Claims or descriptions that include " or " between one or more members of a group are considered satisfied if one , more than one , or all of the group members are present in , employed in , or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context . In some embodiments , exactly one member of a group is present in , employed in , or otherwise relevant to a given product or process . In some embodiments , more than one , or WO 2025/054048 PCT / US2024 / 0440 all group members are present in , employed in , or otherwise relevant to a given product or process . It is to be understood that the invention encompasses all variations , combinations , and permutations in which one or more limitations , elements , clauses , descriptive terms , etc. , from one or more of the listed claims is introduced into another claim dependent on the same base claim ( or , as relevant , any other claim ) unless otherwise indicated or unless it would be evident to one of ordinary skill in the art that a contradiction or inconsistency would arise . Where elements are presented as lists ( e.g. , in Markush group or similar format ) , it is to be understood that each subgroup of the elements is also disclosed , and any element ( s ) can be removed from the group . It should be understood that , in general , where embodiments or aspects are referred to as " comprising " particular elements , features , etc. , certain embodiments or aspects " consist , " or " consist essentially of , " such elements , features , etc. For purposes of simplicity , those embodiments have not in every case been specifically set forth in so many words herein . It should also be understood that any embodiment or aspect can be explicitly excluded from the claims , regardless of whether the specific exclusion is recited in the specification . [ 0054 ] Administration : As used herein , the term " administration " typically refers to the administration of a composition to a subject or system to achieve delivery of an agent to the subject or system . In some embodiments , the agent is , or is included in , the composition ; in some embodiments , the agent is generated through metabolism of the composition or one or more components thereof . Those of ordinary skill in the art will be aware of a variety of routes that may , in appropriate circumstances , be utilized for administration to a subject , for example a human . For example , in some embodiments , administration may be ocular , oral , parenteral , topical , etc. In some particular embodiments , administration may be bronchial ( e.g. , by bronchial instillation ) , buccal , dermal ( which may be or comprise , for example , one or more of topical to the dermis , intradermal , interdermal , transdermal , etc. ) , enteral , intra - arterial , intradermal , intragastric , intramedullary , intramuscular , intranasal , intraperitoneal , intrathecal , intravenous , intraventricular , within a specific organ ( e . g . intrahepatic ) , mucosal , nasal , oral , rectal , subcutaneous , sublingual , topical , tracheal ( e.g. , by intratracheal instillation ) , vaginal , vitreal , etc. In many embodiments provided by the present disclosure , administration is oral administration . In some embodiments , administration may involve only a single dose . In some embodiments , administration may involve application of a fixed number of doses . In some embodiments , administration may involve dosing that is intermittent ( e.g. , a plurality of doses separated in 16 WO 2025/054048 PCT / US2024 / 0440 time ) and / or periodic ( e.g. , individual doses separated by a common period of time ) dosing . In some embodiments , administration may involve continuous dosing ( e.g. , perfusion ) for at least a selected period of time . Administration of cells can be by any appropriate route that results in delivery to a desired location in a subject where at least a portion of the delivered cells or components of the cells remain viable . A period of viability of cells after administration to a subject can be as short as a few hours , e.g. , twenty - four hours , to a few days , to as long as several years , i.e. , long - term engraftment . In some embodiments , administration comprises delivery of a bacterial extract or preparation comprising one or more bacterial metabolites and / or byproducts but lacking fully viable bacterial cells . [ 0055 ] Analog : As used herein , the term " analog " refers to a substance that shares one or more particular structural features , elements , components , or moieties with a reference substance . Typically , an " analog " shows significant structural similarity with the reference substance , for example sharing a core or consensus structure , but also differs in certain discrete ways . In some embodiments , an analog is a substance that can be generated from the reference substance , e.g. , by chemical manipulation of the reference substance . In some embodiments , an analog is a substance that can be generated through performance of a synthetic process substantially similar to ( e.g. , sharing a plurality of steps with ) one that generates the reference substance . In some embodiments , an analog is or can be generated through performance of a synthetic process different from that used to generate the reference substance . [ 0056 ] Approximately : As applied to one or more values of interest , includes to a value that is similar to a stated reference value . In certain embodiments , the term " approximately " or " about " refers to a range of values that fall within ± 10 % ( greater than or less than ) of the stated reference value unless otherwise stated or otherwise evident from the context ( except where such number would exceed 100 % of a possible value ) . [ 0057 ] Comparable : As used herein , the term " comparable " refers to two or more agents , entities , situations , sets of conditions , subjects , etc. , that may not be identical to one another but that are sufficiently similar to permit comparison therebetween so that one skilled in the art will appreciate that conclusions may reasonably be drawn based on differences or similarities observed . In some embodiments , comparable sets of conditions , circumstances , individuals , or populations are characterized by a plurality of substantially identical features and one or a small number of varied features . Those of ordinary skill in the 17 WO 2025/054048 PCT / US2024 / 0440 art will understand , in context , what degree of identity is required in any given circumstance for two or more such agents , entities , situations , sets of conditions , etc. to be considered comparable . For example , those of ordinary skill in the art will appreciate that sets of circumstances , individuals , or populations are comparable to one another when characterized by a sufficient number and type of substantially identical features to warrant a reasonable conclusion that differences in results obtained or phenomena observed under or with different sets of circumstances , individuals , or populations are caused by or indicative of the variation in those features that are varied . [ 0058 ] Conservative : As used herein , refers to instances when describing a conservative amino acid substitution , including a substitution of an amino acid residue by another amino acid residue having a side chain R group with similar chemical properties ( e.g. , charge or hydrophobicity ) . In general , a conservative amino acid substitution will not substantially change the functional properties of interest of a protein , for example , the ability of a receptor to bind to a ligand . Examples of groups of amino acids that have side chains with similar chemical properties include : aliphatic side chains such as glycine ( Gly , G ) , alanine ( Ala , A ) , valine ( Val , V ) , leucine ( Leu , L ) , and isoleucine ( Ile , I ) ; aliphatic - hydroxyl side chains such as serine ( Ser , S ) and threonine ( Thr , T ) ; amide - containing side chains such as asparagine ( Asn , N ) and glutamine ( Gln , Q ) ; aromatic side chains such as phenylalanine ( Phe , F ) , tyrosine ( Tyr , Y ) , and tryptophan ( Trp , W ) ; basic side chains such as lysine ( Lys , K ) , arginine ( Arg , R ) , and histidine ( His , H ) ; acidic side chains such as aspartic acid ( Asp , D ) and glutamic acid ( Glu , E ) ; and sulfur - containing side chains such as cysteine ( Cys , C ) and methionine ( Met , M ) . Conservative amino acids substitution groups include , for example , valine / leucine / isoleucine ( Val / Leu / Ile , V / L / I ) , phenylalanine / tyrosine ( Phe / Tyr , F / Y ) , lysine / arginine ( Lys / Arg , K / R ) , alanine / valine ( Ala / Val , A / V ) , glutamate / aspartate ( Glu / Asp , E / D ) , and asparagine / glutamine ( Asn / Gln , N / Q ) . In some embodiments , a conservative amino acid substitution can be a substitution of any native residue in a protein with alanine , as used in , for example , alanine scanning mutagenesis . In some embodiments , a conservative substitution is made that has a positive value in the PAM250 log - likelihood matrix disclosed in Gonnet , G.H. et al . , 1992 , Science 256 : 1443-1445 , which is incorporated herein by reference in its entirety . In some embodiments , a substitution is a moderately conservative substitution wherein the substitution has a nonnegative value in the PAM2log - likelihood matrix . 18 WO 2025/054048 PCT / US2024 / 0440 CONSERVATIVE AMINO ACID SUBSTITUTIONS For Amino Acid Code Replace With Alanine A D - ala , Gly , Aib , B - Ala , Acp , L - Cys , D - Cys Arginine R D - Arg , Lys , D - Lys , homo - Arg , D - homo - Arg , Met , Ile , D - Met , D - Ile , Orn , D - Om Asparagine N D - Asn , Asp , D - Asp , Glu , D - Glu , Gln , D - Gln Aspartic Acid D Cysteine C Glutamine Q D - Asp , D - Asn , Asn , Glu , D - Glu , Gln , D - Gln D - Cys , S - Me - Cys , Met , D - Met , Thr , D - Thr D - Gln , Asn , D - Asn , Glu , D - Glu , Asp , D - Asp Glutamic Acid E Glycine G D - Glu , D - Asp , Asp , Asn , D - Asn , Gln , D - Gln Ala , D - Ala , Pro , D - Pro , Aib , u0000 - Ala , Acp Isoleucine I D - Ile , Val , D - Val , AdaA , AdaG , Leu , D - Leu , Met , D - Met Leucine L Lysine K Methionine M Phenylalanine F Proline P Serine S D - Leu , Val , D - Val , AdaA , AdaG , Leu , D - Leu , Met , D - Met D - Lys , Arg , D - Arg , homo - Arg , D - homo - Arg , Met , D - Met , Ile , D - Ile , Orn , D - Orn D - Met , S - Me - Cys , Ile , D - Ile , Leu , D - Leu , Val , D- Val D - Phe , Tyr , D - Thr , L - Dopa , His , D - His , Trp , D - Trp , Trans - 3,4 or 5 - phenylproline , AdaA , AdaG , cis - 3,or 5 - phenylproline , Bpa , D - Bpa D - Pro , L - I - thioazolidine - 4 - carboxylic acid , D - or - L- - oxazolidine - 4 - carboxylic acid ( Kauer , U.S. Pat . No. ( 4,511,390 ) D - Ser , Thr , D - Thr , allo - Thr , Met , D - Met , Met ( O ) , D - Met ( O ) , L - Cys , D - Cys 19 Threonine T PCT / US2024 / 0440 D - Thr , Ser , D - Ser , allo - Thr , Met , D - Met , Met ( O ) , D - Met ( O ) , Val , D - Val Tyrosine Y D - Tyr , Phe , D - Phe , L - Dopa , His , D - His Valine V [ 0059 ] D - Val , Leu , D - Leu , Ile , D - Ile , Met , D - Met , AdaA , AdaG Control : As used herein , refers to the art - understood meaning of a " control " being a standard against which results are compared . Typically , controls are used to augment integrity in experiments by isolating variables in order to make a conclusion about such variables . In some embodiments , a control is a reaction or assay that is performed simultaneously with a test reaction or assay to provide a comparator . A " control " also includes a " control animal . " A " control animal " may have a modification as described herein , a modification that is different as described herein , or no modification ( i.e. , a wild- type animal ) . In one experiment , a " test " ( i.e. , a variable being tested ) is applied . In a second experiment , the " control , " the variable being tested is not applied . In some embodiments , a control is a historical control ( i.e. , of a test or assay performed previously , or an amount or result that is previously known ) . In some embodiments , a control is or comprises a printed or otherwise saved record . A control may be a positive control or a negative control . [ 0060 ] Determining , measuring , evaluating , assessing , assaying and analyzing : Determining , measuring , evaluating , assessing , assaying and analyzing are used interchangeably herein to refer to any form of measurement , and include determining if an element is present or not . These terms include both quantitative and / or qualitative determinations . Assaying may be relative or absolute . " Assaying for the presence of " can be determining the amount of something present and / or determining whether or not it is present or absent . [ 0061 ] Dosage form : Those skilled in the art will appreciate that the term " dosage form " may be used to refer to a physically discrete unit of an agent ( e.g. , a therapeutic agent ) for administration to a subject . Typically , each such unit contains a predetermined quantity of agent . In some embodiments , such quantity is a unit dosage amount ( or a whole fraction thereof ) appropriate for administration in accordance with a dosing regimen that has been determined to correlate with a desired or beneficial outcome when administered to a relevant population ( i.e. , with a therapeutic dosing regimen ) . Those of ordinary skill in the art appreciate that the total amount of a therapeutic composition or agent administered to a WO 2025/054048 PCT / US2024 / 0440 particular subject is determined by one or more attending physicians and may involve administration of multiple dosage forms . [ 0062 ] Dosing regimen : Those skilled in the art will appreciate that the term " dosing regimen " may be used to refer to a set of unit doses ( typically more than one ) that are administered individually to a subject , typically separated by periods of time . In some embodiments , a given agent has a recommended dosing regimen , which may involve one or more doses . In some embodiments , a dosing regimen comprises a plurality of doses each of which is separated in time from other doses . In some embodiments , individual doses are separated from one another by a time period of the same length ; in some embodiments , a dosing regimen comprises a plurality of doses and at least two different time periods separating individual doses . In some embodiments , all doses within a dosing regimen are of the same unit dose amount . In some embodiments , different doses within a dosing regimen are of different amounts . In some embodiments , a dosing regimen comprises a first dose in a first dose amount , followed by one or more additional doses in a second dose amount different from the first dose amount . In some embodiments , a dosing regimen comprises a first dose in a first dose amount , followed by one or more additional doses in a second dose amount same as the first dose amount . In some embodiments , a dosing regimen is correlated with a desired or beneficial outcome when administered across a relevant population . [ 0063 ] Engineered : In general , the term " engineered " refers to the aspect of having been manipulated by the hand of man . For example , a cell or organism is considered to be " engineered " if it has been manipulated so that its genetic information is altered ( e.g. , new genetic material not previously present has been introduced , for example by transformation , mating , somatic hybridization , transfection , transduction , or other mechanism , or previously present genetic material is altered or removed , for example by substitution or deletion mutation , or by mating protocols ) . As is common practice and is understood by those in the art , progeny of an engineered polynucleotide or cell are typically still referred to as " engineered " even though the actual manipulation was performed on a prior entity . [ 0064 ] Excipient : As used herein , refers to an inactive ( e.g. , non - therapeutic ) agent that may be included in a pharmaceutical composition , for example to provide or contribute to a desired consistency or stabilizing effect . In some embodiments , suitable pharmaceutical excipients may include , for example , starch , glucose , lactose , sucrose , gelatin , malt , rice , flour , chalk , silica gel , sodium stearate , glycerol monostearate , talc , sodium chloride , dried skim milk , glycerol , propylene , glycol , water , ethanol and the like . 21 WO 2025/054048 PCT / US2024 / 0440 [ 0065 ] Functional : As used herein , a " functional " biological molecule is a biological molecule in a form in which it exhibits a property and / or activity by which it is characterized . A biological molecule may have two functions ( i.e. , bifunctional ) or many functions ( i.e. , multifunctional ) . [ 0066 ] Gene : As used herein , refers to a DNA sequence in a chromosome that codes for a product ( e.g. , an RNA product and / or a polypeptide product ) . In some embodiments , a gene includes coding sequence ( i.e. , sequence that encodes a particular product ) . In some embodiments , a gene includes non - coding sequence . In some particular embodiments , a gene may include both coding ( e.g. , exonic ) and non - coding ( e.g. , intronic ) sequence . In some embodiments , a gene may include one or more regulatory sequences ( e.g. , promoters , enhancers , etc. ) and / or intron sequences that , for example , may control or impact one or more aspects of gene expression ( e.g. , cell - type - specific expression , inducible expression , etc. ) . For the purpose of clarity , we note that , as used in the present disclosure , the term " gene " generally refers to a portion of a nucleic acid that encodes a polypeptide or fragment thereof ; the term may optionally encompass regulatory sequences , as will be clear from context to those of ordinary skill in the art . This definition is not intended to exclude application of the term " gene " to non - protein - coding expression units but rather to clarify that , in most cases , the term as used in this document refers to a polypeptide - coding nucleic acid . [ 0067 ] Improve , increase , enhance , inhibit or reduce : As used herein , the terms " improve , " " increase , " " enhance , " " inhibit , " " reduce , " or grammatical equivalents thereof , indicate values that are relative to a baseline or other reference measurement . In some embodiments , a value is statistically significantly difference that a baseline or other reference measurement . In some embodiments , an appropriate reference measurement may be or comprise a measurement in a particular system ( e.g. , in a single individual ) under otherwise comparable conditions absent presence of ( e.g. , prior to and / or after ) a particular agent or treatment , or in presence of an appropriate comparable reference agent . In some embodiments , an appropriate reference measurement may be or comprise a measurement in comparable system known or expected to respond in a particular way , in presence of the relevant agent or treatment . In some embodiments , an appropriate reference is a negative reference ; in some embodiments , an appropriate reference is a positive reference . [ 0068 ] Isolated : As used herein , refers to a substance and / or entity that has been ( 1 ) separated from at least some of the components with which it was associated when initially 22 WO 2025/054048 PCT / US2024 / 0440 produced ( whether in nature and / or in an experimental setting ) , and / or ( 2 ) designed , produced , prepared , and / or manufactured by the hand of man . In some embodiments , an isolated substance or entity may be enriched ; in some embodiments , an isolated substance or entity may be pure . In some embodiments , isolated substances and / or entities may be separated from about 10 % , about 20 % , about 30 % , about 40 % , about 50 % , about 60 % , about 70 % , about 80 % , about 90 % , about 91 % , about 92 % , about 93 % , about 94 % , about % , about 96 % , about 97 % , about 98 % , about 99 % , or more than about 99 % of the other components with which they were initially associated . In some embodiments , isolated agents are about 80 % , about 85 % , about 90 % , about 91 % , about 92 % , about 93 % , about % , about 95 % , about 96 % , about 97 % , about 98 % , about 99 % , or more than about 99 % pure . As used herein , a substance is " pure " if it is substantially free of other components . In some embodiments , as will be understood by those skilled in the art , a substance may still be considered " enriched " , " isolated " or even " pure " , after having been combined with certain other components such as , for example , one or more carriers or excipients ( e.g. , buffer , solvent , water , etc. ) ; in such embodiments , percent isolation or purity of the substance is calculated without including such carriers or excipients . Those skilled in the art are aware of a variety of technologies for isolating ( e.g. , enriching or purifying ) substances or agents ( e.g. , using one or more of fractionation , extraction , precipitation , or other separation ) . [ 0069 ] Level : As used herein , the term " level " refers to a scale of amount or quantity of a substance ( e.g. , a metabolite ) . In some embodiments , a level can be simply the presence or absence of a substance . A level of a substance may be represented in multiple ways or formats . For example , in some embodiments , a level may be represented as a percentage ( % ) , a measure of weight ( e.g. , mg , gµ , ng , etc. ) , a measure of concentration ( e.g. , mg / mL , gµ / mL , ng / mL , etc. ) , a measure of volume ( e.g. , mL , Lµ , nL , etc. ) , in % change , etc. [ 0070 ] Metabolite : As used herein , the term " metabolite " refers to a substance ( e.g. , a small molecule , macromolecule , organic compound , or inorganic compound ) made or used during metabolism . Metabolism is generally understood as a process by which a substance ( e.g. , food , drug , chemical , cell , or tissue ) is chemically broken down . In some embodiments , a metabolite is an end product . In some embodiments , a metabolite is an intermediate . Exemplary metabolites are provided herein , e.g. , in Appendix 1-1 , 1-3 , 3 , and 4. Exemplary metabolic pathways are provided herein , e.g. , in Appendix 1-2 . In some embodiments , a metabolite may be produced or made by an organism . In some embodiments , a metabolite may be produced or made by a microorganism ( e.g. microbial 23 WO 2025/054048 PCT / US2024 / 0440 strain ) . In some embodiments , a microbial metabolite produced or made by a microbial strain . In some embodiments , a metabolite may be produced or made naturally ( e.g. by an organism ( e.g. microorganism ( e.g. microbial strain ) ) ) . In some embodiments , a metabolite may be produced or made synthetically ( e.g. from a source that is not a microbial strain ( e.g. , synthetically generated ) ) . [ 0071 ] Pharmaceutical composition : As used herein , the term " pharmaceutical composition " refers to a composition in which an active agent is formulated together with one or more pharmaceutically acceptable carriers . In some embodiments , the active agent is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population . In some embodiments , a pharmaceutical composition may be specially formulated for administration in solid or liquid form , including those adapted for the following : ophthalmic administration , intravitreal administration , suprachoroidal administration , oral administration , subcutaneous administration , intravenous administration , intramuscular administration , intracerebral administration , intrathecal administration , for example , drenches ( aqueous or non - aqueous solutions or suspensions ) , tablets , e.g. , those targeted for buccal , sublingual , and systemic absorption , boluses , powders , granules , pastes for application to the tongue , capsules , powders , etc. In some embodiments , an active agent may be or comprise a cell or population of cells ( e.g. , a culture , for example of an Ellagitannin - Enzyme - Synthesizing ( EES ) microbe ) ; in some embodiments , an active agent may be or comprise an extract or component of a cell or population ( e.g. , culture ) of cells . In some embodiments , an active agent may be or comprise an isolated , purified , or pure compound . In some embodiments , an active agent may have been synthesized in vitro ( e.g. , via chemical and / or enzymatic synthesis ) . In some embodiments , an active agent may be or comprise a natural product ( whether isolated from its natural source or synthesized in vitro ) . [ 0072 ] Pharmaceutically acceptable : As used herein , the term " pharmaceutically acceptable " which , for example , may be used in reference to a carrier , diluent , or excipient used to formulate a pharmaceutical composition as disclosed herein , means that the carrier , diluent , or excipient is compatible with the other ingredients of the composition and not deleterious to the recipient thereof . [ 0073 ] Pharmaceutically acceptable carrier : As used herein , the term " pharmaceutically acceptable carrier " means a pharmaceutically - acceptable material , 224 WO 2025/054048 PCT / US2024 / 0440 composition or vehicle , such as a liquid or solid filler , diluent , excipient , or solvent encapsulating material , involved in carrying or transporting the subject compound from one organ , or portion of the body , to another organ , or portion of the body . Each carrier must be is " acceptable " in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject ( e.g. , patient ) . Some examples of materials which can serve as pharmaceutically - acceptable carriers include : sugars , such as lactose , glucose and sucrose ; starches , such as corn starch and potato starch ; cellulose , and its derivatives , such as sodium carboxymethyl cellulose , ethyl cellulose and cellulose acetate ; powdered tragacanth ; malt ; gelatin ; talc ; excipients , such as cocoa butter and suppository waxes ; oils , such as peanut oil , cottonseed oil , safflower oil , sesame oil , olive oil , corn oil and soybean oil ; glycols , such as propylene glycol ; polyols , such as glycerin , sorbitol , mannitol and polyethylene glycol ; esters , such as ethyl oleate and ethyl laurate ; agar ; buffering agents , such as magnesium hydroxide and aluminum hydroxide ; alginic acid ; pyrogen - free water ; isotonic saline ; Ringer's solution ; ethyl alcohol ; pH buffered solutions ; polyesters , polycarbonates and / or poly anhydrides ; and other non - toxic compatible substances employed in pharmaceutical formulations . [ 0074 ] Prebiotic : As used herein , a " prebiotic " refers to an ingredient that allows or promotes specific changes , both in the composition and / or activity in the gastrointestinal microbiota that may ( or may not ) confer benefits upon the host . In some embodiments , a prebiotic can include one or more of the following : the prebiotic comprises a pome extract , berry extract and walnut extract . [ 0075 ] Prevention : The term " prevention " , as used herein , refers to a delay of onset , and / or reduction in frequency and / or severity of one or more symptoms of a particular disease , disorder or condition . In some embodiments , prevention is assessed on a population basis such that an agent is considered to " prevent " a particular disease , disorder or condition if a statistically significant decrease in the development , frequency , and / or intensity of one or more symptoms of the disease , disorder or condition is observed in a population susceptible to the disease , disorder , or condition . In some embodiments , prevention may be considered complete , for example , when onset of a disease , disorder or condition has been delayed for a predefined period of time . [ 0076 ] Reference : As used herein describes a standard or control relative to which a comparison is performed . For example , in some embodiments , an agent , animal , individual , population , sample , sequence or value of interest is compared with a reference or control WO 2025/054048 PCT / US2024 / 0440 agent , animal , individual , population , sample , sequence or value . In some embodiments , a reference or control is tested and / or determined substantially simultaneously with the testing or determination of interest . In some embodiments , a reference or control is a historical reference or control , optionally embodied in a tangible medium . Typically , as would be understood by those skilled in the art , a reference or control is determined or characterized under comparable conditions or circumstances to those under assessment . Those skilled in the art will appreciate when sufficient similarities are present to justify reliance on and / or comparison to a particular possible reference or control . In some embodiments , a reference is a negative control reference ; in some embodiments , a reference is a positive control reference . [ 0077 ] Risk : As will be understood from context , " risk " of a disease , disorder , and / or condition refers to a likelihood that a particular individual will develop the disease , disorder , and / or condition . In some embodiments , risk is expressed as a percentage . In some embodiments , risk is from 0 , 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 20 , 30 , 40 , 50 , 60 , 70 , 80 , 90 , or up to 100 % . In some embodiments risk is expressed as a risk relative to a risk associated with a reference sample or group of reference samples . In some embodiments , a reference sample or group of reference samples have a known risk of a disease , disorder , condition and / or event . In some embodiments a reference sample or group of reference samples are from individuals comparable to a particular individual . In some embodiments , relative risk is 0 , 1. 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , or more . [ 0078 ] Sample : As used herein , the term " sample " typically refers to an aliquot of material obtained or derived from a source of interest . In some embodiments , a source of interest is a biological or environmental source . In some embodiments , a source of interest may be or comprise a cell or an organism , such as a microbe , a plant , or an animal ( e.g. , a human ) . In some embodiments , a source of interest is or comprises biological tissue or fluid . In some embodiments , a biological tissue or fluid may be or comprise amniotic fluid , aqueous humor , ascites , bile , bone marrow , blood , breast milk , cerebrospinal fluid , cerumen , chyle , chime , ejaculate , endolymph , exudate , feces , gastric acid , gastric juice , lymph , mucus , pericardial fluid , perilymph , peritoneal fluid , pleural fluid , pus , rheum , saliva , sebum , semen , serum , smegma , sputum , synovial fluid , sweat , tears , urine , vaginal secretions , vitreous humour , vomit , plasma , mucous , digestive fluid , stool , and / or combinations or component ( s ) thereof . In some embodiments , a biological fluid may be or comprise an intracellular fluid , an extracellular fluid , an intravascular fluid ( blood plasma ) , an interstitial 26 WO 2025/054048 PCT / US2024 / 0440 fluid , a lymphatic fluid , and / or a transcellular fluid . In some embodiments , a biological fluid may be or comprise a plant exudate . In some embodiments , a biological tissue or sample may be obtained , for example , by aspirate , biopsy ( e.g. , fine needle or tissue biopsy ) , swab ( e.g. , oral , nasal , skin , or vaginal swab ) , scraping , surgery , washing or lavage ( e.g. , bronchioalveolar , ductal , nasal , ocular , oral , uterine , vaginal , or other washing or lavage ) . In some embodiments , a biological sample is or comprises cells obtained from an individual . In some embodiments , a sample is a " primary sample " obtained directly from a source of interest by any appropriate means . In some embodiments , as will be clear from context , the term " sample " refers to a preparation that is obtained by processing ( e.g. , by removing one or more components of and / or by adding one or more agents to ) a primary sample . For example , filtering using a semi - permeable membrane . Such a " processed sample " may comprise , for example nucleic acids or proteins extracted from a sample or obtained by subjecting a primary sample to one or more techniques such as amplification or reverse transcription of nucleic acid , isolation and / or purification of certain components , etc. [ 0079 ] Small molecule : As used herein , the term " small molecule " refers to small organic or inorganic molecules of molecular weight below about 3,000 Daltons . In general , small molecules may have a molecular weight of less than 3,000 Daltons ( Da ) . Small molecules can be , e.g. , from at least about 100 Da to about 3,000 Da ( e.g. , between about 100 to about 3,000 Da , about 100 to about 2500 Da , about 100 to about 2,000 Da , about 1to about 1,750 Da , about 100 to about 1,500 Da , about 100 to about 1,250 Da , about 100 to about 1,000 Da , about 100 to about 750 Da , about 100 to about 500 Da , about 200 to about 1500 , about 500 to about 1000 , about 300 to about 1000 Da , or about 100 to about 250 Da ) . [ 0080 ] Subject : As used herein , the term " subject " refers to an individual to which a provided treatment is administered . In some embodiments , a subject is animal . In some embodiments , a subject is a mammal , e.g. , a mammal that experiences or is susceptible to a disease , disorder , or condition as described herein . In some embodiments , an animal is a vertebrate , e.g. , a mammal , such as a non - human primate , ( particularly a higher primate ) , a sheep , a dog , a rodent ( e.g. a mouse or rat ) , a guinea pig , a goat , a pig , a cat , a rabbit , or a cow . In some embodiments , an animal is a non - mammal animal , such as a chicken , an amphibian , a reptile , or an invertebrate model C. elegans . In some embodiments , a subject is a human . In some embodiments , a subject is suffering from or susceptible to one or more diseases , disorders or conditions as described herein . In some embodiments , a subject displays one or more symptoms of a one or more diseases , disorders or conditions as 27 WO 2025/054048 PCT / US2024 / 0440 described herein . In some embodiments , a subject has been diagnosed with one or more diseases , disorders or conditions as described herein . In some embodiments , the subject is receiving or has received certain therapy to diagnose and / or to treat a disease , disorder , or condition . In another embodiment , the subject is an experimental animal or animal substitute as a disease model . [ 0081 ] Substantially : As used herein , refers to the qualitative condition of exhibiting total or near - total extent or degree of a characteristic or property of interest . One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely , if ever , go to completion and / or proceed to completeness or achieve or avoid an absolute result . The term " substantially " is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena . [ 0082 ] Therapeutic regimen : A " therapeutic regimen " , as that term is used herein , refers to a dosing regimen whose administration across a relevant population may be correlated with a desired or beneficial therapeutic outcome . [ 0083 ] Therapeutically effective amount : As used herein , is meant an amount that produces the desired effect for which it is administered . In some embodiments , the term refers to an amount that is sufficient , when administered to a population suffering from or susceptible to a disease , disorder , and / or condition in accordance with a therapeutic dosing regimen , to treat the disease , disorder , and / or condition . In some embodiments , a therapeutically effective amount is one that reduces the incidence and / or severity of , and / or delays onset of , one or more symptoms of the disease , disorder , and / or condition . Those of ordinary skill in the art will appreciate that the term " therapeutically effective amount " does not in fact require successful treatment be achieved in a particular individual . Rather , a therapeutically effective amount may be that amount that provides a particular desired pharmacological response in a significant number of subjects when administered to subjects ( e.g. , patients ) in need of such treatment . In some embodiments , reference to a therapeutically effective amount may be a reference to an amount as measured in one or more specific tissues ( e.g. , a tissue affected by the disease , disorder or condition ) or fluids ( e.g. , blood , saliva , serum , sweat , tears , urine , etc. ) . Those of ordinary skill in the art will appreciate that , in some embodiments , a therapeutically effective amount of a particular agent or therapy may be formulated and / or administered in a single dose . In some embodiments , a therapeutically effective agent may be formulated and / or administered in a plurality of doses , for example , as part of a dosing regimen . 28 WO 2025/054048 PCT / US2024 / 0440 [ 0084 ] Treatment : As used herein , the term " treatment " ( also " treat " or " treating " ) refers to any administration of a therapy that partially or completely alleviates , ameliorates , relives , inhibits , delays onset of , reduces severity of , and / or reduces incidence of one or more symptoms , features , and / or causes of a particular disease , disorder , and / or condition . In some embodiments , such treatment may be of a subject who does not exhibit signs of the relevant disease , disorder and / or condition and / or of a subject who exhibits only early signs of the disease , disorder , and / or condition . Alternatively , or additionally , such treatment may be of a subject who exhibits one or more established signs of the relevant disease , disorder and / or condition . In some embodiments , treatment may be of a subject who has been diagnosed as suffering from the relevant disease , disorder , and / or condition . In some embodiments , treatment may be of a subject known to have one or more susceptibility factors that are statistically correlated with increased risk of development of the relevant disease , disorder , and / or condition . [ 0085 ] BRIEF DESCRIPTION OF THE DRAWING Fig . 1 shows mice treated with CT6 or CT6m are significantly lighter than vehicle - treated animals . ( a ) All mice gained weight with aging . ( b ) TDP43 - Q331K transgenic animals are significantly ( p < 0.002 ) heavier than non - transgenic littermate control . ( c ) mice treated with CT6m exhibited a significant reduction ( p < 0.045 ) in body weight after 57 days of treatment . ( d ) Both CT6 and CT6m treatments had a significant impact on body weight after 163 days of treatment , ( e ) which became more pronounced for CT6m ( p < 0.0092 ) treatments at the end of the study . Statistics generated using one - way Anova with Dunnett's tests for multiple comparisons against group 2. * p < 0.05 ; ** p < 0.01 ; [ 0086 ] *** p < 0.001 ; **** p < 0.00 Fig . 2 shows treatment with CT6 or CT6m prevents accumulation of lipids and fat in livers of TDP43 transgenic mice . ( a ) macroscopic image of the whole liver of a vehicle - treated TDP43 - transgenic mouse displaying accumulation of lipid droplets in the liver . ( b ) macroscopic image of a CT6m - treated liver showing healthy color and morphology . ( c ) Liver samples from all four groups demonstrating treated - livers lack the appearance of lipid accumulation as seen in group 1 ( ntg , vehicle - treated ) & group ( TDP43 + vehicle ) . 29 WO 2025/054048 PCT / US2024 / 0440 [ 0087 ] Fig . 3 shows treatment with CT6 or CT6m prevents lipid accumulation in livers of TDP43 mice . H & E section of livers from TDP43 - transgenic & non - transgenic mice . Each panel represents different livers with n = 3 livers for each treatment group . TDPvehicle - treated animals ( 2nd column ) have the most pronounced lipid accumulation in livers while non - transgenic animals show some degree of fatty liver . Animals treated with CT6 or CT6m have the most normal liver , morphologically . [ 0088 ] Fig . 4 shows TDP43 - Q331K animals treated with CT6 or CT6m have significantly lower plasma cholesterol compared to control animals . ( a ) Plasma LDL cholesterol levels in ntg and TDP43 - Tg animals at the terminal end - of - study . A significant reduction in LDL levels can be seen in G3 animals treated with CT6 or G4 animals that were treated with CT6m compared to control animals in Gl & G2 . ( b ) Plasma HDL cholesterol levels in the same plasma sample set as in Fig . 4a demonstrate that CT6 & CT6m also has profound effects in positively modulating plasma HDL levels . ( c ) Cholesterol LDL / HDL ratio was calculated by dividing the LDL levels from Fig . 4a by the HDL levels from Fig . 4b . ( d ) To test the lipid - lowering effects of CT6 & CT6m more vigorously , we measured circulating triglyceride levels in the same plasma sample set used for measuring LDL & HDL cholesterol levels . Each data point represents a biological replicate with group having n = 19 plasma samples , group 2 with n = 16 plasma samples , group 3 with n = samples and n = 20 for group 4. Statistics generated using one - way Anova with Dunnett's tests for multiple comparisons against group 2 ( TDP43 + Vehicle ) . * p < 0.05 ; ** p < 0.01 ; *** p < 0.001 ; **** p < 0.0001 . [ 0089 ] Fig . 5 shows treatment - induced changes in cytokine and chemokine levels from TDP43 - Q331K Tg & ntg livers . Each data point represents a biological replicate with G1 ( ntg vehicle ) having n = 19 liver samples , G2 ( TDP43 + vehicle ) with n = 16 liver samples , G3 ( TDP43 + CT6 ) with n = 19 samples and n = 20 for G4 ( TDP43 + CT6m ) . Statistics generated using one - way Anova with Dunnett's tests for multiple comparisons against G2 ( TDP43 + Vehicle ) . * p < 0.05 ; ** p < 0.01 ; *** p < 0.001 . [ 0090 ] Conditions DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS Lipid and Cholesterol Metabolism Associated Diseases , Disorders , and WO 2025/054048 PCT / US2024 / 0440 [ 0091 ] Metabolism is the process by which a body ( e.g. , a human body ) changes food and drink that is consumed into energy . During this process , calories in food and drinks mix with oxygen to make the energy the body needs . Chemicals in the body's digestive system break the food down into sugars and acids . The body can use this fuel right away , or it can store the energy in the body's tissues , such as liver , muscles , and body fat . [ 0092 ] A metabolic disorder occurs when abnormal chemical reactions in a body disrupt this process . When this happens , one might have too much of some substances or too little of other ones that one needs to stay healthy . Accordingly , there are different groups of disorders some affect the breakdown of amino acids , carbohydrates , or lipids . Yet another group , mitochondrial diseases , affects the parts of the cells that produce the energy . [ 0093 ] One can also develop a metabolic disorder when some organs , such as the liver or pancreas , become diseased or do not function normally . For example , diabetes is a metabolic disorder caused by improper function of the pancreas . [ 0094 ] Lipid metabolism disorders involve lipids , which are fats or fat - like substances . They include oils , fatty acids , waxes , and cholesterol . If a person has one of these disorders , they do not have enough enzymes to break down lipids , or the enzymes may not work properly as a result of which a body cannot convert the fats into energy . This results in a build up of a harmful amount of lipids to in a person's body . Over time , such harmful levels of lipids may cause damage to cells and tissues , especially in the brain . peripheral nervous system , liver , spleen , and bone marrow . Many of these diseases , disorders , or conditions can be very serious , or sometimes even fatal . Some examples of metabolic diseases , disorders , or conditions ( e.g. improper lipid metabolism or improper cholesterol metabolism ) include but are not limited to lipid - induced metabolic syndrome , cerebral infarction / stroke , myocardial infarction / heart attack , Type II diabetes / diabetes mellitus , glucose intolerance , alcoholism , metabolic syndrome , kidney disease , cardiorenal syndrome , vascular diseases ( e.g. , hypertension , peripheral arterial disease ) , Alzheimer's disease , asthma ( e.g. , due to abdominal obesity or central / truncal obesity ) , atherosclerosis , hypothyroidism , liver disease , LDL - hypercholesterolemia , hypertriglyceridemia , mixed hyperlipoproteinemia , coronary heart disease , stroke , peripheral arterial disease , high blood pressure , hyperlipidemia , steatosis , non - alcoholic steatohepatitis ( NASH ) , fatty - liver disease , metabolic associated fatty liver disease ( MAFLD ) , non - alcoholic fatty liver disease ( NAFLD ) , liver fibrosis , cirrhosis , or hepatocellular carcinoma . 31 WO 2025/054048 PCT / US2024 / 0440 [ 0095 ] The present disclosure provides compositions ( e.g. microbiome compositions ) and methods that inhibit one or more of the events or processes that take place in metabolism - associated diseases , disorders , or conditions ( e.g. lipid and cholesterol metabolism associated diseases , disorders , and conditions ) . The present disclosure is based in part on the discovery that one or more microbial strains or compositions comprising one or more microbial strains are particularly suitable as therapeutic agents for metabolism- associated diseases , disorders , or conditions . [ 0096 ] [ 0097 ] Microbial Preparation ( s ) and / or Component ( s ) The present disclosure provides systems and methods for assessing , characterizing , and identifying one or more microbial strains of a microbiome ( e.g. to improve or treat or prevent a metabolism - associated disease , disorder , or condition as described herein ) . For example , the present disclosure provides systems and methods for assessing , characterizing , and identifying one or more microbial strains of a microbiome that have one or more abilities . Such systems and methods can be useful for assessing , characterizing , and identifying one or more microbial strains that affect the health of humans , livestock , and / or pets . In some embodiments , one or more microbial strains affect the health of humans , livestock , and / or pets by modulating their respective metabolomes , cell viability , ATP levels , one or more other parameters or features ( e.g. of an organ of a subject ) , or a combination thereof to prevent , treat , or reduce the risk of suffering from a disease , disorder , or condition ( e.g. metabolism ( e.g. lipid and cholesterol metabolism ) associated diseases , disorders , and conditions ) as disclosed herein . For example , technologies described herein may result in modulating the metabolome , improve cell viability , increase ATP levels , modulate one or more other parameters or features ( e.g. level of cell viability , level or activity of a nucleic acid or protein , or form thereof , body weight gain , lipid accumulation in liver , accumulation of visceral fat , elevated blood triglyceride levels , blood - cholesterol levels , oxidative stress , hypercholesterolemia , inflammation , etc. ) , or a combination thereof of the subject that results in a decrease in production of toxic components and / or components that suggest or are a marker for cellular damage ( e.g. liver cell damage ( e.g. lipid ( e.g. fat ) accumulation in liver ) in a subject ( e.g. in blood of a subject ) . 32 WO 2025/054048 PCT / US2024 / 0440 [ 0098 ] The present disclosure also provides systems and methods for manufacturing a pharmaceutical composition that comprise assessing , characterizing , and identifying one or more microbial strains of a microbiome . [ 0099 ] In some embodiments , assessing , characterizing , and identifying one or more microbial strains from a microbiome of a snake , lizard , fish , or bird . In some embodiments , assessing , characterizing , and identifying one or more microbial strains from a mammalian microbiome . A mammalian microbiome can be a canine , a feline , an equine , a bovine , an ovine , a caprine , or a porcine microbiome . In some embodiments , a microbiome used in a system or method described herein may prevent or treat a disease or condition . [ 0100 ] A microbiome can be isolated from any system or tissue of an organism that supports microbial growth . For example , a microbiome can be a cutaneous microbiome , an oral microbiome , a nasal microbiome , a gastrointestinal microbiome , a brain microbiome , a pulmonary microbiome , or a urogenital microbiome . A list of exemplary microbial strains found in a gastrointestinal microbiome is included below in Table 1. A microbiome sample can be obtained by various ways . For example , a cutaneous , oral , nasal , pulmonary , or urogenital microbiome sample could be obtained using a swab or tissue scrapping . In some embodiments , a gastrointestinal microbiome could be sampled from feces . A cutaneous microbiome , an oral microbiome , a nasal microbiome , a gastrointestinal microbiome , a brain microbiome , a pulmonary microbiome , or a urogenital microbiome sample could be obtained via a biopsy . [ 0101 ] In some embodiments , a microbiome is a microbiome of a healthy individual or an individual who does not suffer from or is not at risk of developing a particular disease or disorder . In some embodiments , a microbiome is a microbiome of an individual that suffers from or is at risk of developing a particular disease , disorder , or condition . In some embodiments , a microbiome is a microbiome of an individual who is known to suffer from a particular disease , disorder , or condition . In some embodiments , a human microbiome is a microbiome of a human with an unknown risk for one or more diseases , disorders , or conditions . [ 0102 ] In some embodiments , a microbiome is a reference microbiome . A reference microbiome can be a microbiome of a healthy individual or an individual who does not suffer from or is not at risk of developing a particular disease , disorder , or condition . In some instances , a reference microbiome may be from the same individual as a microbiome 33 WO 2025/054048 PCT / US2024 / 0440 to be assessed or characterized , but was obtained at a different time . In some instances , a reference microbiome may be from the same individual as a microbiome to be assessed or characterized , but was obtained from a different system or tissue . [ 0103 ] In some embodiments , an individual microbial strain or a combination of microbial strains may be assessed , characterized , or identified in a different relative amount than such strain or strains are found in a microbiome . For example , the effect of modulation of a cell or organism in response to a single strain may be assessed , characterized , or identified using in vitro methods ( e.g. mammalian cells ) or in vivo methods using mammals ( e.g. mice , humans , etc. ) as described herein . In some embodiments , for example , the effect of modulation of a cell or organism to treat , prevent , or reduce the risk on a disease , disorder , or condition ( e.g. a metabolism - associated disease , disorder , or condition as described herein ) may be assessed , characterized , or identified using in vitro methods ( e.g. mammalian cells ) or in vivo methods using mammals ( e.g. mice , humans , etc. ) as described herein . In some embodiments , for example , the effect of modulation of a cell or organism to treat , prevent , or reduce the risk on a disease , disorder , or condition ( e.g. a metabolism- associated disease , disorder , or condition as described herein ) by modulating one or more metabolites of the cell or organism , one or features or parameters ( e.g. level of cell viability , level or activity of a nucleic acid or protein , or form thereof , body weight gain , lipid accumulation in liver , accumulation of visceral fat , elevated blood triglyceride levels , blood- cholesterol levels , oxidative stress , hypercholesterolemia , inflammation , etc. ) of the cell or organism , or a combination thereof may be assessed , characterized , or identified using in vitro methods ( e.g. mammalian cells ) or in vivo methods using mammals ( e.g. mice , humans , etc. ) as described herein . As another example , the effect of modulation ( e.g. of levels of one or more metabolites ) of a cell or organism to treat , prevent , or reduce the risk on a disease , disorder , or condition , as described herein , in response to two microbial strains may be assessed , characterized , or identified together using methods described herein . [ 0104 ] An extract , component , or compound of a microbial strain may also be assessed , characterized , or identified using methods described herein . In some cases , an extract , component , or compound of a microbial strain that has been determined to treat . prevent , or reduce the risk on a disease , disorder , or condition , as described herein , in an organism ( e.g. mammal ) may be assessed , characterized , or identified . Assessing , characterizing or identifying an extract , component , or compound of a microbial strain that treats , prevents , or reduces the risk on a disease , disorder , or condition in an organism ( e.g. 34 WO 2025/054048 PCT / US2024 / 0440 mammal ) may provide additional information about potential biomarkers , targets , or protective agents in a microbiome . [ 0105 ] A variety of technologies can be used to prepare extracts of microbial strains , and / or to isolate extracts , components , or compounds therefrom , or to process ( e.g. , to isolate and / or purify one or more components or compounds from ) . To give but a few examples , such technologies may include , for example , one or more of organic extraction , vacuum concentration , chromatography , and so on .

Assessing Biological Impact [ 0106 ] [ 0107 ] The present disclosure provides the insight that compositions ( e.g. microbiome compositions ) as described herein can be used to treat , prevent , and / or reduce the risk of a disease , disorder , or condition of an organism ( e.g. a mammal ( e.g. a human ) ) by contacting the composition ( s ) ( e.g. , feeding the compositions to , administering to ) with an organism . In some embodiments , an organism may suffer from or be at risk of suffering from a disease , disorder , or condition ( e.g. mammalian disease , disorder , or condition ) . To determine whether one or more compositions treats , prevents , or reduces the risk of a disease , disorder , or condition ( e.g. a metabolism - associated disease , disorder , or condition ) , levels of one or more metabolites can be observed , measured , or assessed in samples that have been contacted with the one or more compositions . For example , levels of the one or more metabolites can be observed , measured , or assessed in samples at different times ( e.g. before administration of composition , after administration of composition , during administration of composition , etc. ) . To determine whether one or more compositions treats , prevents , or reduces the risk of a disease , disorder , or condition ( e.g. a metabolism- associated disease , disorder , or condition ) , one or more features or parameters may be observed , measured , or assessed in samples that have been contacted with the one or more compositions . For example , one or more features or parameters may be observed , measured , or assessed in samples at different times ( e.g. before administration of composition , after administration of composition , during administration of composition , etc. ) . [ 0108 ] In some embodiments , methods described herein utilize a first sample and a second sample . In some embodiments , a first sample is a reference sample . In some embodiments , a reference sample can be a sample obtained from a subject who is contacted with ( e.g. , administered or fed ) a composition , e.g. , CT10 composition , CT6 composition , or WO 2025/054048 PCT / US2024 / 0440 CT6m composition . In some embodiments , a reference sample can be a sample obtained from a subject who is contacted with ( e.g. , administered or fed ) a composition , e.g. , CTcomposition , CT6 composition , or CT6m composition , at a first time point . In some embodiments , a reference sample can be a sample obtained from a subject prior to being contacted with ( e.g. , administered or fed ) a composition , e.g. , CT10 composition , CTcomposition , or CT6m composition . In some embodiments , a reference sample can be a sample obtained from a healthy individual . In some embodiments , a reference sample can be a sample obtained from an individual who is suffering from or may have a risk for a disease , disorder , or condition ( e.g. metabolism - associated disease , disorder , or condition ) . In some embodiments , a reference sample is a control sample . In some embodiments , a reference sample is a negative control sample . In some embodiments , a reference sample is a positive control sample . In some embodiments , a reference sample may be a historic reference ( e.g. value across control samples ) . In some embodiments , a reference sample may be from a printed publication ( e.g. a text book , a journal , etc. ) . [ 0109 ] In some embodiments , a second sample can be a test sample . In some embodiments , a test sample may be a sample obtained from a subject who is contacted with ( e.g. , administered or fed ) a composition , e.g. , CT10 composition , CT6 composition , or CT6m composition . In some instances , a subject ( e.g. patient or population ) may be suffering from or at risk of a disease , disorder , or condition ( e.g. a metabolism - associated disease , disorder , or condition ) . In some instances , a subject ( e.g. patient or population ) may have an unknown risk for one or more diseases , disorders , or conditions as described herein . In some embodiments , a test can be a sample obtained from a subject who is contacted with ( e.g. , administered or fed ) a composition , e.g. , CT10 composition , CT6 composition , or CT6m composition , at a second time point . [ 0110 ] In some embodiments , methods described herein comprise comparing one or more metabolite levels ( e.g. a metabolome ) , or one or more parameters or features ( e.g. level of cell viability , level or activity of a nucleic acid or protein , or form thereof , body weight gain , lipid accumulation in liver , accumulation of visceral fat , elevated blood triglyceride levels , blood - cholesterol levels . oxidative stress , hypercholesterolemia , inflammation , etc. ) obtained from a test sample with one or more metabolite levels ( e.g. a metabolome ) , or one or more parameters or features ( e.g. level of cell viability , level or activity of a nucleic acid or protein , or form thereof , body weight gain , lipid accumulation in liver , accumulation of visceral fat , elevated blood triglyceride levels , blood - cholesterol levels , oxidative stress , 36 WO 2025/054048 PCT / US2024 / 0440 hypercholesterolemia , inflammation , etc. ) obtained from a reference sample . In some embodiments , by comparing one or more metabolite levels , parameters , or features obtained from a test sample with one or more metabolite levels , parameters , or features obtained from a reference sample , a composition described herein can be assessed , characterized or identified as being useful for treating , preventing , or reducing the risk of suffering from a disease , disorder , or condition ( e.g. a metabolism - associated disease , disorder , or condition ) as described herein . In some embodiments , by comparing one or more metabolite levels , parameters , or features obtained from a test sample with one or more metabolite levels , parameters , or features obtained from a reference sample , it can be determined that a composition as disclosed herein increases the severity or incidence of a disease , disorder , or condition phenotype . In some embodiments , by comparing one or more metabolite levels , parameters , or features obtained from a test sample with one or more metabolite levels , parameters , or features obtained from a reference sample , it can be determined that a composition as disclosed herein decreases the severity or incidence of a disease , disorder , or condition phenotype . In some embodiments , by comparing one or more metabolite levels , parameters , or features obtained from a test sample with one or more metabolite levels , parameters , or features obtained from a reference sample , it can be determined that a composition as disclosed herein has no effect on the severity or incidence of a disease , disorder , or condition phenotype . In some embodiments , by comparing one or more metabolite levels , parameters , or features obtained from a test sample with one or more metabolite levels , parameters , or features obtained from a reference sample , it can be determined that a composition as disclosed herein prevents a disease , disorder , or condition phenotype . [ 0111 ] The present disclosure also provides the recognition that compositions and methods provided herein can be used to monitor progression of a disease , disorder , or condition ( e.g. a metabolism - associated disease , disorder , or condition ) in an individual . For example , if metabolite levels , parameters or features ( e.g. level of cell viability , level or activity of a nucleic acid or protein , or form thereof , body weight gain , lipid accumulation in liver , accumulation of visceral fat , elevated blood triglyceride levels , blood - cholesterol levels , oxidative stress , hypercholesterolemia , inflammation , etc. ) determined to increase the severity of a disease , disorder , or condition decrease in relative amount , it may indicate that the disease , disorder , or condition is being attenuated , e.g. , by treatment or immune response . 37 WO 2025/054048 PCT / US2024 / 0440 [ 0112 ] The present disclosure also provides the insight that compositions and methods provided herein can be used to tailor treatments ( e.g. , therapies , nutraceuticals , and / or probiotics ) to an individual patient . In some embodiments , compositions and methods provided herein can provide " personalized " therapy . In some cases , metabolite levels , features or parameters ( e.g. level of cell viability , level or activity of a nucleic acid or protein , or form thereof , body weight gain , lipid accumulation in liver , accumulation of visceral fat , elevated blood triglyceride levels , blood - cholesterol levels , oxidative stress , hypercholesterolemia , inflammation , etc. ) within an individual can be assessed , characterized , or identified to determine if they have a disease , disorder , or condition . Based on the results , the individual can be treated with one or more compositions to adjust the metabolite levels ( i.e. , their metabolome ) , features or parameters . In some instances , this will affect the disease , disorder , or condition the individual is suffering from or at risk of developing . For example , if an individual is determined to have a relatively low amount of one or more metabolite levels that have been determined to decrease the severity of a disease , disorder , or condition , administration of the one or more compositions that have been determined to decrease the severity of a disease , disorder , or condition to the individual ( or an extract , component , or compound thereof ) may attenuate the severity of the individual's disease or condition . [ 0113 ] The present disclosure provides the insight that compositions and methods provided herein can be used recursively to treat , prevent , or ameliorate a disease , disorder , or condition . In some embodiments , for example , one or more compositions disclosed herein may be administered ( e.g. fed , injected , etc. ) to a subject after determining the effect of one or more compositions on subject's metabolite levels , or after determining the effect of one or more compositions on subject's features or parameters ( e.g. level of cell viability , level or activity of a nucleic acid or protein , or form thereof , body weight gain , lipid accumulation in liver , accumulation of visceral fat , elevated blood triglyceride levels , blood - cholesterol levels , oxidative stress , hypercholesterolemia , inflammation , etc. ) . In some embodiments , a composition may be administered once . In some embodiments , a composition may be administered more than once . In some embodiments , a composition may be administered daily , weekly , biweekly , monthly , bimonthly , etc. In each of these instances , levels of one or more metabolites , or changes in features or parameters may be monitored . In some embodiments , levels of one or more metabolites ( e.g. metabolome ) or changes in features or parameters may be monitored before administration of a composition . In some 38 WO 2025/054048 PCT / US2024 / 0440 embodiments , levels of one or more metabolites ( e.g. metabolome ) or changes in features or parameters may be monitored after administration of a composition . [ 0114 ] Pharmaceutical Compositions [ 0115 ] Provided herein are compositions comprising individual microbial strains or combinations of microbial strains , metabolites thereof , extracts thereof , or components thereof . In some embodiments , a composition comprises individual microbial strains or combinations of microbial strains from a mammalian microbiome , metabolites thereof , extracts thereof , and / or components thereof , which have been assessed , identified , characterized or assayed using methods as described herein . In some embodiments , a composition provided herein comprises one or more , two or more , three or more , four or more , five or more , six or more , seven or more , eight or more , nine or more , or ten or more microbial strains from a mammalian microbiome , extracts thereof , metabolites thereof , and / or components thereof , which have been assessed , identified , characterized or assayed using methods as described herein . [ 0116 ] , Provided herein are also compositions comprising one or more components or metabolites . In some embodiments , components or metabolites in compositions herein are from a source that is not a microbial strain , e.g. , synthetically generated . In some embodiments , components or metabolites in a composition may have been identified from a microbial strain , but are independent from a microbial strain and are not produced by a microbial strain , e.g. , they can be synthetically generated . [ 0117 ] In some embodiments , a composition provided herein comprises two or more , three or more , four or more , five or more , six or more , seven or more , eight or more , nine or more , or ten or more microbial strains listed in Table 1 below .

Table 1 : Exemplary Microbial Strains Found in Human Gut Microbiome Bacteroides pectinophilus Acetobacter sp Acetobacterium tundrae Achromobacter aegrifaciens Achromobacter insuavis Achromobacter piechaudii TABLE Exiguobacterium mexicanum Faecalibacterium prausnitzii Faecalitalea cylindroides Finegoldia magna Flavonifractor plautii Flintibacter butyricus WO 2025/054048 PCT / US2024 / 0440 Achromobacter xylosoxidans Acidaminococcus fermentans Acidaminococcus intestini Acinetobacter baumannii Acinetobacter junii Actinomyces sp . Agathobacter rectalis Agathobaculum butyriciproducens Aggregatibacter segnis Akkermansia muciniphila Alistipes finegoldii Alistipes indistinctus Alistipes onderdonkii Alistipes putredinis Alistipes shahii Allisonella histaminiformans Anaerobaculum hydrogeniformans Anaerococcus hydrogenalis Anaerococcus octavius Anaerococcus prevotii Anaerococcus tetradius Anaerococcus vaginalis Anaerofilum agile Anaerofustis stercorihominis Anaerosporobacter mobilis Anaerostipes caccae Anaerostipes hadrus Anaerostipes rhamnosivorans Anaerotruncus colihominis Anaerovorax odorimutans Arcobacter butzleri Asaccharobacter celatus Atopobium parvulum Atopobium vaginae Bacillus cereus Bacillus coagulans Bacillus licheniformis Bacillus pseudomycoides Bacillus sonorensis Bacillus toyonensis Bacillus wiedmannii Bacteroides caccae Bacteroides cellulosilyticus Bacteroides clarus Bacteroides coprocola Bacteroides coprophilus Fusicatenibacter saccharivorans Fusobacterium gonidiaformans Fusobacterium mortiferum Fusobacterium nucleatum Fusobacterium ulcerans Fusobacterium varium Gardnerella vaginalis Gemella haemolysans Gemella sanguinis Gemmiger formicilis Gluconacetobacter sp Gluconobacter sp Gordonibacter pamelaeae Granulicatella adiacens Grimontia hollisae Haemophilus parainfluenzae Harryflintia acetispora Helicobacter bilis Helicobacter bizzozeronii Helicobacter canadensis Helicobacter cinaedi Helicobacter pullorum Helicobacter pylori Helicobacter winghamensis Holdemanella biformis Holdemania filiformis Holdemania massiliensis Hungatella effluvii Hungatella hathewayi Intestinimonas butyriciproducens Kineothrix alysoides Kingella oralis Klebsiella pneumoniae Klebsiella pneumoniae subsp . ozaenae Klebsiella pneumoniae subsp . pneumoniae Klebsiella pneumoniae subsp . rhinoscleromatis Klebsiella quasipneumoniae subsp . quasipneumoniae Klebsiella singaporensis Klebsiella variicola Lachnobacterium bovis Lachnospira multipara Lachnospira pectinoschiza Lactobacillus acidophilus Lactobacillus amylolyticus Lactobacillus amylovorus Lactobacillus antri 40 WO 2025/054048 PCT / US2024 / 0440 Bacteroides dorei Bacteroides eggerthii Bacteroides faecis Bacteroides finegoldii Bacteroides fluxus Bacteroides fragilis Bacteroides intestinalis Bacteroides massiliensis Bacteroides nordii Bacteroides oleiciplenus Bacteroides ovatus Bacteroides plebeius Bacteroides salanitronis Bacteroides salversiae Lactobacillus brevis subsp . Gravesensis Lactobacillus buchneri Lactobacillus casei Lactobacillus coryniformis subsp . Coryniformis Lactobacillus crispatus Lactobacillus delbrueckii subsp . Bulgaricus Lactobacillus delbrueckii subsp . indicus Lactobacillus delbrueckii subsp . Lactis Lactobacillus fermentum Lactobacillus fructivorans Lactobacillus gasseri Lactobacillus helveticus Lactobacillus hilgardii Lactobacillus iners Bacteroides stercoris Lactobacillus jensenii Bacteroides thetaiotaomicron Lactobacillus johnsonii Bacteroides uniformis Lactobacillus mucosae Lactobacillus oris Bacteroides vulgatus Bacteroides xylanisolvens Bacteroides xylanolyticus Barnesiella intestinihominis Bartonella clarridgeiae Bartonella quintana str . Toulouse Bifidobacterium adolescentis Bifidobacterium angulatum Lactobacillus paracasei Lactobacillus paracasei subsp . tolerans Lactobacillus pentosus Lactobacillus plantarum subsp . plantarum Lactobacillus reuteri Lactobacillus rhamnosus Lactobacillus rogosae Bifidobacterium animalis Bifidobacterium bifidum Bifidobacterium breve Lactobacillus ruminis Lactobacillus salivarius Lactobacillus ultunensis Bifidobacterium catenulatum Bifidobacterium coryneforme Bifidobacterium dentium Bifidobacterium faecale Bifidobacterium gallicum Bifidobacterium longum Bifidobacterium longum subsp . infantis Bifidobacterium longum subsp . longum Bifidobacterium longum subsp . suis Bifidobacterium pseudocatenulatum Bifidobacterium pseudolongum Bifidobacterium stercoris Bilophila wadsworthia Bittarella massiliensis Blautia coccoides Blautia faecis Blautia glucerasea Lactobacillus vaginalis Lactococcus formosensis Lactococcus garvieae Lactococcus lactis subsp . Cremoris Lactococcus lactis subsp . lactis Lactonifactor longoviformis Laribacter hongkongensis Lautropia mirabilis Leptotrichia buccalis Leptotrichia hofstadii Leuconostoc lactis Leuconostoc mesenteroides subsp . Cremoris Listeria grayi Listeria monocytogenes Longicatena caecimuris Marvinbryantia formatexigens Megamonas funiformis 41 WO 2025/054048 PCT / US2024 / 0440 Blautia hansenii Blautia hydrogenotrophica Blautia luti Blautia obeum Blautia producta Blautia schinkii Blautia stercoris Blautia wexlerae Bradyrhizobium japonicum Burkholderia ambifaria Burkholderia cenocepacia Burkholderia glumae Burkholderia multivorans Burkholderia plantarii Butyricicoccus faecihominis Butyricicoccus pullicaecorum Butyricimonas faecihominis Butyricimonas paravirosa Butyricimonas virosa Butyrivibrio crossotus Campylobacter coli Campylobacter concisus Campylobacter curvus Campylobacter gracilis Campylobacter hominis Campylobacter jejuni subsp . Jejuni Campylobacter showae Campylobacter upsaliensis Candidatus Dorea massiliensis Candidatus Stoquefichus massiliensis Capnocytophaga gingivalis Capnocytophaga sputigena Megamonas rupellensis Megasphaera elsdenii Megasphaera indica Megasphaera micronuciformis Megasphaera paucivorans Methanobrevibacter smithii Methanomassiliicoccus luminyensis Methanosphaera stadtmanae Methylobacterium radiotolerans Mitsuokella jalaludinii Mitsuokella multacida Mobiluncus mulieris Mogibacterium timidum Mogibacterium vescum Moraxella catarrhalis Morganella morganii subsp . morganii Murdochiella asaccharolytica Mycobacterium abscessus Mycobacterium tuberculosis Mycoplasma hominis Neisseria cinerea Neisseria flavescens Neisseria macacae Neisseria mucosa Neisseria sicca Neisseria subflava Nitrobacter hamburgensis Nitrobacter winogradskyi Odoribacter laneus Odoribacter splanchnicus Olsenella profusa Olsenella scatoligenes Olsenella uli Oribacterium sinus Cardiobacterium hominis Catenibacterium mitsuokai Catonella morbi Cedecea lapagei Citrobacter amalonaticus Citrobacter freundii Citrobacter koseri Citrobacter youngae Clostridium acetobutryicum Clostridium aerotolerans Clostridium aldenense Clostridium aminophilum Clostridium aminovalericum Clostridium amygdalinum Clostridium asparagiforme Clostridium baratii Oscillibacter ruminantium Oscillibacter valericigenes Oscillospira guilliermondii Oxalobacter formigenes Paenibacillus jamilae Paenibacillus kribbensis Paenibacillus riograndensis Paeniclostridium sordellii Parabacteroides distasonis Parabacteroides goldsteinii Parabacteroides gordonii Parabacteroides johnsonii Parabacteroides merdae Paraprevotella clara 42 WO 2025/054048 PCT / US2024 / 0440 Peptoniphilus grossensis Clostridium bartlettii Clostridium beijerinckii Clostridium bifermentans Clostridium boltege Clostridium butyricum Clostridium celerecrescens Paraprevotella xylaniphila Parasutterella excrementihominis Parasutterella secunda Parvimonas micra Pediococcus acidilactici Pediococcus pentosaceus Clostridium cf. saccharolyticum Peptoniphilus duerdenii Clostridium citroniae Clostridium clariflavum Clostridium clostridioforme Clostridium cocleatum Clostridium colinum Clostridium difficile Clostridium glycyrrhizinilyticum Clostridium hathewayi Clostridium herbivorans Clostridium hiranonis Clostridium hylemonae Clostridium innocuum Clostridium lactatifermentans Clostridium lavalense Clostridium leptum Clostridium methoxybenzovorans Clostridium methylpentosum Clostridium nexile Clostridium orbiscindens Clostridium oroticum Clostridium perfringens Clostridium polysaccharolyticum Clostridium propionicum Clostridium ramosum Clostridium rectum Clostridium saccharogumia Clostridium saccharolyticum Clostridium sardiniense Clostridium saudii Clostridium scindens Clostridium sordellii Clostridium sphenoides Clostridium spiroforme Clostridium sporogenes Clostridium sticklandii Clostridium straminisolvens Clostridium symbiosum Clostridium tertium Clostridium thermocellum Clostridium xylanolyticum Clostridium xylanovorans Peptoniphilus harei Peptoniphilus indolicus Peptostreptococcus anaerobius Phascolarctobacterium faecium Phascolarctobacterium succinatutens Porphyromonas asaccharolytica Porphyromonas endodontalis Porphyromonas gingivalis Prevotella bivia Prevotella buccae Prevotella copri Prevotella disiens Prevotella marshii Prevotella melaninogenica Prevotella nigrescens Prevotella pallens Prevotella salivae Prevotella stercorea Prevotella tannerae Prevotella timonensis Propionibacterium acnes Propionibacterium avidum Propionibacterium namnetense Proteus mirabilis Proteus penneri Providencia alcalifaciens Providencia rettgeri Providencia rustigianii Providencia stuartii Pseudoflavonifractor capillosus Ralstonia sp . Robinsoniella peoriensis Roseburia cecicola Roseburia faecis Roseburia hominis Roseburia intestinalis Roseburia inulinivorans Rothia dentocariosa Ruminococcus albus Ruminococcus bromii 43 WO 2025/054048 PCT / US2024 / 0440 Collinsella aerofaciens Collinsella intestinalis Collinsella stercoris Collinsella tanakaei Coprobacillus cateniformis Coprobacter fastidiosus Coprococcus catus Coprococcus comes Coprococcus eutactus Corynebacterium ammoniagenes Corynebacterium matruchotii Corynebacterium pseudogenitalium Corynebacterium tuberculostearicum Deinococcus radiodurans Dermabacter hominis Desulfotomaculum guttoideum Desulfovibrio legallis Desulfovibrio piger Dialister invisus Dialister microaerophilus Dialister succinatiphilus Dielma fastidiosa Dorea formicigenerans Dorea longicatena Dysgonomonas mossii Edwardsiella tarda Eggerthella lenta Eggerthella sinensis Eikenella corrodens Eisenbergiella tayi Enhydrobacter aerosaccus Enterobacter aerogenes Enterobacter asburiae Enterobacter cancerogenus Enterobacter cloacae Enterobacter hormaechei Enterobacter kobei Enterobacter ludwigii Enterococcus asini Enterobacter xiangfangensis Enterococcus avium Enterococcus casseliflavus Enterococcus durans Enterococcus faecalis Enterococcus faecium Ruminococcus callidus Ruminococcus faecis Ruminococcus gnavus Ruminococcus lactaris Ruminococcus obeum Ruminococcus torques Ruthenibacterium lactatiformans Sarcina ventriculi Sellimonas intestinalis Senegalimassilia anaerobia Shigella boydii Shigella dysenteriae Shigella flexneri Shigella sonnei Slackia faecicanis Slackia isoflavoniconvertens Slackia piriformis Solobacterium moorei Staphylococcus caprae Staphylococcus epidermidis Staphylococcus hominis subsp . Hominis Staphylococcus lugdunensis Staphylococcus warneri Streptococcus agalactiae Streptococcus anginosus Streptococcus anginosus subsp . whileyi Streptococcus australis Streptococcus bovis Streptococcus constellatus subsp . constellatus Streptococcus equinus Streptococcus gallolyticus subsp . pasteuri Streptococcus gallolyticus subsp . pasteurianus Streptococcus gordonii Streptococcus gordonii str . Challis Streptococcus infantarius Streptococcus infantarius subsp . coli Streptococcus infantarius subsp . Infantarius Streptococcus infantis Streptococcus lactarius Streptococcus lutetiensis Streptococcus mutans Streptococcus parasanguinis Streptococcus pasteurianus Streptococcus pleomorphus Streptococcus rubneri 44 WO 2025/054048 PCT / US2024 / 0440 Enterococcus gallinarum Enterococcus hirae Enterococcus mundtii Enterococcus raffinosus Enterococcus raffinosus Erysipelotrichaceae bacterium Escherichia albertii Escherichia coli Escherichia fergusonii Eubacterium biforme Eubacterium callanderi Eubacterium contortum Eubacterium cylindroides Eubacterium desmolans Eubacterium dolichum Eubacterium eligens Eubacterium hadrum Eubacterium hallii Eubacterium infirmum Streptococcus salivarius Streptococcus salivarius subsp . salivarius Streptococcus sanguinis Streptococcus thermophilus Streptococcus vestibularis Subdoligranulum variabile Succinatimonas hippei Sutterella parvirubra Sutterella stercoricanis Sutterella wadsworthensis Terrisporobacter glycolicus Turicibacter sanguinis Ureaplasma parvum Vagococcus penaei Varibaculum cambriense Veillonella sp . Veillonella dispar Veillonella parvula Veillonella rogosae Veillonella tobetsuensis Eubacterium limosum Eubacterium oxidoreducens Vibrio cholerae Eubacterium ramulus Vibrio furnissii Eubacterium rectale Eubacterium ruminantium Eubacterium saburreum Eubacterium siraeum Vibrio mimicus Victivallis vadensis Eubacterium sulci Eubacterium tortuosum Eubacterium ventriosum Eubacterium xylanophilum Eubacterium yurii subsp . Margaretiae [ 0118 ] Weissella cibaria Weissella confusa Weissella paramesenteroides Xenorhabdus nematophila Yersinia enterocolitica subsp . Palearctica Yersinia pseudotuberculosis In some embodiments , a composition provided herein comprises Gluconacetobacter sp . , Terrisporobacter sp . , Coprococcus sp . , Lactobacillus sp . , Clostridium sp . , Paenibacillus sp . , Veillonella sp . , Bifidobacterium sp . , Bacillus sp . , Acidaminococcus sp . , or a combination thereof . In some embodiments , a composition comprises at least two of , at least three of , at least four of , at least five of , at least six of , at least seven of , at least eight of , at least nine of , or all of Gluconacetobacter sp . , Terrisporobacter sp . , Coprococcus sp . , Lactobacillus sp . , Clostridium sp . , Paenibacillus sp . , Veillonella sp . , Bifidobacterium sp . , Bacillus sp . , and Acidaminococcus sp . In some embodiments , for example , a composition comprises all of Gluconacetobacter sp . , Terrisporobacter sp . , Coprococcus sp . , Lactobacillus sp . , Clostridium sp . , Paenibacillus sp . , Veillonella sp . , Bifidobacterium sp . , Bacillus sp . , and Acidaminococcus sp .. Such 45 WO 2025/054048 PCT / US2024 / 0440 compositions may be referred to by different names , including but not limited to , CTcomposition , CT10 cocktail , and so forth . [ 0119 ] In some embodiments , a composition provided herein comprises Gluconacetobacter hansenii , Terrisporobacter glycolicus , Coprococcus sp . , Lactobacillus plantarum , Clostridium butyricum , Paenibacillus sp . , Veillonella sp . , Bifidobacterium sp . , Bacillus subtilis , Acidaminococcus sp . , or a combination thereof . In some embodiments , a composition comprises at least two of , at least three of , at least four of , at least five of , at least six of , at least seven of , at least eight of , at least nine of , or all of Gluconacetobacter hansenii , Terrisporobacter glycolicus , Coprococcus sp . , Lactobacillus plantarum , Clostridium butyricum , Paenibacillus sp . , Veillonella sp . , Bifidobacterium sp . , Bacillus subtilis , and Acidaminococcus sp . In some embodiments , for example , a composition comprises all of Gluconacetobacter hansenii , Terrisporobacter glycolicus , Coprococcus sp . , Lactobacillus plantarum , Clostridium butyricum , Paenibacillus sp . , Veillonella sp . , Bifidobacterium sp . , Bacillus subtilis , and Acidaminococcus sp . , and may be referred to by different names , including but not limited to , CT10 composition , CT10 cocktail , and so forth . [ 0120 ] In some embodiments , a composition provided herein comprises Gluconacetobacter sp . , Terrisporobacter sp . , Coprococcus sp . , Lactobacillus Veillonella sp . , Bifidobacterium sp . , or a combination thereof . In some embodiments , a composition comprises at least two of , at least three of , at least four of , at least five of , or all of Gluconacetobacter sp . , Terrisporobacter sp . , Coprococcus sp . , Lactobacillus sp . , Veillonella sp . , and Bifidobacterium sp .. In some embodiments , for example , a composition comprises all of Gluconacetobacter sp . , Terrisporobacter sp . , Coprococcus sp . , Lactobacillus sp . , Veillonella sp . , and Bifidobacterium sp .. Such compositions may be referred to by different names , including but not limited to , CT6 composition , CT6 cocktail , and so forth . [ 0121 ] In some embodiments , a composition provided herein comprises Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus catus , Lactobacillus plantarum , Veillonella atypica , Bifidobacterium breve , or a combination thereof . In some embodiments , a composition comprises at least two of , at least three of , at least four of , at least five of , or all of Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus catus , Lactobacillus plantarum , Veillonella atypica , and Bifidobacterium breve . In some embodiments , for example , a composition comprises all of Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus catus , Lactobacillus plantarum , Veillonella 46 WO 2025/054048 PCT / US2024 / 0440 atypica , and Bifidobacterium breve and may be referred to by different names , including but not limited to , CT6 composition , CT6 cocktail , and so forth . [ 0122 ] In some embodiments , a composition provided herein comprises Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus sp . , Lactobacillus plantarum , Veillonella sp . , Bifidobacterium sp . , or a combination thereof . In some embodiments , a composition comprises at least two of , at least three of , at least four of , at least five of , or all of Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus sp . , Lactobacillus plantarum , Veillonella sp . , and Bifidobacterium sp .. In some embodiments , for example , a composition comprises all of Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus sp . , Lactobacillus plantarum , Veillonella sp . , and Bifidobacterium sp . and may be referred to by different names , including but not limited to , CT6 composition , CT6 cocktail , and so forth . In some embodiments , a composition provided herein comprises Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus catus , Lactobacillus plantarum , Veillonella atypica , Bifidobacterium breve , or a combination thereof . In some embodiments , a composition comprises at least two of , at least three of , at least four of , at least five of , or all of Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus catus , Lactobacillus plantarum , Veillonella atypica , and Bifidobacterium breve . In some embodiments , for example , a composition comprises all of Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus catus , Lactobacillus plantarum , Veillonella atypica , and Bifidobacterium breve and may be referred to by different names , including but not limited to , CT6 composition , CT6 cocktail , and so forth . [ 0123 ] Exemplary microbiome compositions ( e.g. CT10 , CT10m , CT10x , CT6 , CT6m ) , as described herein , and their composition details are listed in Tables 2-6 below . [ 0124 ] Table 2 : CT10 Composition # Microbiome Therapy ( MBT ) Concentration in CFU / ml 2 Bifidobacterium breve 1 x 10⁹ Gluconacetobacter hansenii 1 x 10⁹ Terrisporobacter glycolicus x 10⁹ Veillonella atypica x 10⁹ Lactobacillus plantarum x 10⁹ Coprococcus catus x 10⁹ Clostridium butyricum x 10⁹ Paenibacillus barengoltzii x 10 ° Bacillus subtilis 1 x 10⁹ 47 WO 2025/054048 PCT / US2024 / 0440 [ 0125 ] # Acidaminococcus sp .

Table 3 : CT10m Composition Microbiome Therapy ( MBT ) Bifidobacterium breve Gluconacetobacter hansenii Terrisporobacter glycolicus 1 x 10⁹ Concentration in CFU / ml x 10⁹ x 10 ' x 10 ° Veillonella atypica x 10 ° Lactobacillus plantarum x 10 ° Coprococcus catus 2 x Clostridium butyricum x 10 ' Paenibacillus barengoltzii x 19 Bacillus subtilis 2 x 10 ° Acidaminococcus sp . x 10 ° Table 4 : CT10x Composition [ 0126 ] # [ 0127 ] Microbiome Therapy ( MBT ) Bifidobacterium breve Gluconacetobacter hansenii Concentration in CFU / ml x 3 x 10 ° Terrisporobacter glycolicus x 10⁹ Veillonella atypica x 10 ° Lactobacillus plantarum x 10 ° Coprococcus catus x 10⁹ Clostridium butyricum 1 x 10⁹ Paenibacillus barengoltzii x 10 ° Bacillus subtilis 1 x 10 ° Acidaminococcus sp . x 10 ° Table 5 : CT6 Composition ++ # MBT Bifidobacterium breve Gluconacetobacter hansenii Terrisporobacter glycolicus 1 +Lactobacillus plantarum Coprococcus catus Veillonella atypica Concentration in CFU / ml x 10⁹ x 10⁹ x 10 ' x 10 ' x 10⁹ x 10 ° [ 0128 ] Table 6 : CT6m Composition # MBT Bifidobacterium breve Gluconacetobacter hansenii Concentration in CFU / ml x 10⁹ x 10 ° Terrisporobacter glycolicus Veillonella atypica Lactobacillus plantarum Coprococcus catus 1 x 10⁹ x 10 ° x 10⁹ x 10 ° PCT / US2024 / 0440 [ 0129 ] In some embodiments , a composition provided herein comprises one or more , two or more , three or more , four or more , five or more , six or more , seven or more , eight or more , nine or more , or ten or more metabolites . Metabolites which may be assessed , identified , characterized , or assayed and / or comprised in compositions as disclosed herein , include those listed for example in the Appendices submitted herewith ( e.g. Appendix 1-1 , 1-2 , 1-3 , 2 , 3 , or 4 ) . [ 0130 ] In some embodiments , a metabolite may be Butyrylcamitine , Theobromine , p - Hydroxyphenylpyruvic acid , Propionic acid , Picolinic acid , 2 - Hydroxy - 4methylvaleric acid , N6 - Acetylysine , Urocanic acid , N5 - Ethylglutamine , Trigonelline , Stachydrine , Ectoine , 5 - Hydroxylysine , Arginine ( arg ) , Cholic acid , 2- ( 4 - Hydroxyphenyl ) propionic acid , N - Acetyltryptophan , Hydroxyproline , Argininosuccinic acid , Glutamic acid ( Glu ) , Sarcosine , 5 - Methoxyindoleacetic acid , Indole - 3 - lactic acid , Isovalerylalanine , N- Acetylleucine , 1 - Methylhistidine , N - Acetylephenylalanine , Proline ( Pro ) , or any combination thereof . [ 0131 ] In some embodiments , a metabolite may be 4 - Hydroxyphenylpyruvic , Ectoine , Gramine , N - Acetyl - L - phenylalanine , Nepsilon - Acetyl - L - lysine , Stachydrine , Trigonelline , 3 - Ureidopropionic acid , Theobromine , Hippuric acid , Imidazolepropionic acid , NG - Methyl - L - arginine , trans - Urocanic Acid , N - Acetyl - L - leucine , Sarcosine , Isobutyrylcarnitine , b - Hydroxyisovaleric acid , L - Theanine / N5 - Ethylglutamine , 5- Hydroxylysine , Phenaceturic acid , betaine , hydroxyproline , Picolinic acid , 2 - Aminoadipic acid , Glycerophosphocholine , carnitine , Glycerol 3 - phosphate , Argininosuccinic acid , creatine , Terephthalic acid , Homocitrulline , Mucic acid , Homocysteinesulfinic acid , Trimethyllysine , Spermidine , Glyoxylic acid , XA0013 C6H604S , 3 - Indoxylsulfuric acid , Nicotinamide , N - Formylglycine , Ureidoglycolate , N - Methylproline , Glucaric acid , Butyrylcarnitine , Methionine sulfoxide , Carboxymethyllysine , Glycolic acid , Phenaceturic acid , Diethanolamine , Phosphorylcholine , Guanidinosuccinic acid , N - Acetylhistidine , Glyceric acid , S - Methylmethionine , Cysteine glutathione disulfide , Kynurenine , N- Acetylphenylalanine , Threonic acid , Malic acid , 7,8 - Dihydrobiopterin , Homovanillic acid , Taurocholic acid , 5 - Methoxyindoleacetic acid , butyrate , b - Hydroxyisovaleric acid , 2- 49 WO 2025/054048 PCT / US2024 / 0440 Oxoglutaric acid , N - Acetyltryptophan , Thiaproline , Hypotaurine , Cholic acid , Acetoacetic acid , Ethanolamine , Guanidoacetic acid , S - Sulfocysteine , Myristic acid C14 : 0 XA0027 , or any combination thereof . [ 0132 ] In some embodiments , an individual microbial strain or combinations of microbial strains from a mammalian microbiome that have been killed ( e.g. , heat killed ) . Alternatively , in some embodiments , an individual microbial strain or combinations of microbial strains from a mammalian microbiome may include cells that are viable or alive . [ 0133 ] In some embodiments , one or more microbial strains comprise a viable or living individual microbial strain or combinations of microbial strains , e.g. , from a mammalian microbiome . [ 0134 ] In some embodiments , one or more microbial strains comprise a viable or living individual microbial strain or combinations of microbial strains , e.g. , from a mammalian microbiome , as described herein comprises and / or is formulated through use of one or more cell cultures and / or supernatants or pellets thereof , and / or a powder formed therefrom . [ 0135 ] In some embodiments , compositions for use in accordance with the present disclosure are pharmaceutical compositions , e.g. , for administration ( e.g. , topical , oral , subcutaneous , intravenous , intramuscular , intracerebral , intrathecal , rectal ( e.g. rectal intubation ) , opthalmical , intravitreal , or suprachoroidal administration ) to a mammal ( e.g. , a human ) . Pharmaceutical compositions typically include an active agent ( e.g. , individual microbial strains or combinations of microbial strains from a mammalian microbiome , extracts thereof , and / or components thereof ) , and a pharmaceutically acceptable carrier . Certain exemplary pharmaceutically acceptable carriers include , for instance saline , solvents , dispersion media , coatings , antibacterial and antifungal agents , isotonic and absorption delaying agents , and the like , compatible with pharmaceutical administration . [ 0136 ] In some embodiments , a pharmaceutical composition for use in accordance with the present disclosure may include and / or may be administered in conjunction with , one or more supplementary active compounds ; in certain embodiments , such supplementary active agents can include ginger , curcumin , probiotics ( e.g. probiotic strains of one or more of the following genera : Lactobacillus , Bifidobacterium , Saccharomyces , Enterococcus . Streptococcus , Pediococcus , Leuconostoc , Bacillus , and / or Escherichia coli ( see Fijan , Int J Environ Res Public Health . 2014 May ; 11 ( 5 ) : 4745-4767 , which is incorporated herein by 50 WO 2025/054048 PCT / US2024 / 0440 reference in its entirety ) ; prebiotics ( non - digestible food ingredients that help support growth of probiotic bacteria , e.g. , fructans such as fructooligosaccharides ( FOS ) and inulins , galactans such as galactooligosaccharides ( GOS ) , dietary fibers such as resistant starch , pectin , beta - glucans , and xylooligosaccharides ( Hutkins et al . , Curr Opin Biotechnol . 20Feb ; 37 : 7–1 , which is incorporated herein by reference in its entirety ) and combinations thereof . [ 0137 ] In some embodiments , a prebiotic comprises a fructooligosaccharide , an inulin , an isomaltooligosaccharide , a lactilol , a lactosucrose , a lactulose , a soy oligosaccharide , a transgalactooligosaccharide , a xylooligosaccharide , seaweed , or a combination thereof . In some embodiments , a prebiotic comprises seaweed . In some embodiments , a prebiotic comprises a pome extract , berry extract and walnut extract . [ 0138 ] In some embodiments , a probiotic composition can be formulated for oral administration . In some embodiments , a probiotic composition can be a food , a beverage , a feed composition , or a nutritional supplement . In some embodiments , an ellagitannin composition , an enzymatic composition , or both can be a liquid , syrup , tablet , troche , gummy , capsule , powder , gel , or film . In some embodiments , a probiotic composition is an enteric - coated formulation . [ 0139 ] In some embodiments , a probiotic comprises a prebiotic . In some embodiments , a prebiotic comprises a fructooligosaccharide , an inulin , an isomaltooligosaccharide , a lactilol , a lactosucrose , a lactulose , a soy oligosaccharide , a transgalactooligosaccharide , a xylooligosaccharide , seaweed , a pome extract , berry extract and walnut extract . or a combination thereof . [ 0140 ] Pharmaceutical compositions are typically formulated to be compatible with its intended route of administration . Examples of routes of administration include topical , oral , subcutaneous , intravenous , intramuscular , intracerebral , intrathecal , rectal , ( e.g. rectal intubation ) , ophthalmic , intravitreal , or suprachoroidal administration . Methods of formulating suitable pharmaceutical compositions are known in the art , see , e.g. , Remington : The Science and Practice of Pharmacy , 21st ed . , 2005 ; and the books in the series Drugs and the Pharmaceutical Sciences : a Series of Textbooks and Monographs ( Dekker , NY ) , which is incorporated in its entirety by reference herein . Oral compositions generally include an inert diluent or an edible carrier ( e.g. pharmaceutically acceptable diluent , pharmaceutically acceptable carrier ) . To give but a few examples , in some embodiments , an 51 WO 2025/054048 PCT / US2024 / 0440 oral formulation may be or comprise a syrup , a liquid , a tablet , a troche , a gummy , a capsule , e.g. , gelatin capsules , a powder , a gel , a film , etc. Similarly , ocular compositions ( e.g. for ophthalmic , intravitreal , or suprachoroidal administration ) may include an inert diluent or carrier ( e.g. pharmaceutically acceptable diluent , pharmaceutically acceptable carrier ) , various additives such as viscosity enhancers , permeations enhancers , cyclodextrins , etc. Examples of viscosity enhancers include hydroxy methyl cellulose , hydroxy ethyl cellulose , sodium carboxy methyl cellulose , hydroxypropyl methyl cellulose and polyalcohol . Example of permeation enhancers include chelating agents , preservatives , surface active agents , bile salts , Benzalkonium chloride , polyoxyethylene glycol ethers ( lauryl , stearyl and oleyl ) , ethylenediaminetetra acetic acid sodium salt , sodium taurocholate , saponins and cremophor EL , etc. For example , in some embodiments ocular formulations may be or comprise suspensions , emulsions ( e.g. water - in - oil or oil - in water ) , nanocarriers , ( e.g. nanoparticles , nanosuspensions , liposomes , nanomicelles , dendrimers , etc. ) ointments , gels , eye drops , etc. Cerebral compositions ( e.g. for intracerebral or intrathecal administration ) may include an inert diluent or carrier , and / or additives . In some embodiments , cerebral compositions are free of preservatives . In some embodiments , cerebral compositions are sterile . [ 0141 ] In some embodiments , pharmaceutically compatible binding agents , and / or adjuvant materials can be included as part of a pharmaceutical composition . In some particular embodiments , a pharmaceutical composition can contain , e.g. , any one or more of the following inactive ingredients , or compounds of a similar nature : a binder such as microcrystalline cellulose , gum tragacanth or gelatin ; an excipient such as starch or lactose , a disintegrating agent such as alginic acid , Primogel , or corn starch ; a lubricant such as magnesium stearate or Sterotes ; a glidant such as colloidal silicon dioxide ; a sweetening agent such as sucrose or saccharin ; or a flavoring agent such as peppermint , methyl salicylate , or orange flavoring . In some embodiments , the compositions can be taken as - is or sprinkled onto or mixed into a food or liquid ( such as water ) . In some embodiments , a composition that may be administered to mammals as described herein may be or comprise an ingestible item ( e.g. , a food or drink ) that comprises ( e.g. , is supplemented ) with an individual microbial strain or combinations of microbial strains from a mammalian microbiome , extracts thereof , and / or components thereof . [ 0142 ] In some embodiments , a food can be or comprise one or more of bars , candies , baked goods , cereals , salty snacks , pastas , chocolates , and other solid foods , as well 52 WO 2025/054048 PCT / US2024 / 0440 as liquid or semi - solid foods including yogurt , soups and stews , and beverages such as smoothies , shakes , juices , and other carbonated or non - carbonated beverages . In some embodiments , foods are prepared by a subject by mixing in individual microbial strains or combinations of microbial strains from a mammalian microbiome , extracts thereof , and / or components thereof . [ 0143 ] Compositions can be included in a kit , container , pack , or dispenser , together with instructions for administration or for use in a method described herein . [ 0144 ] Those skilled in the art , reading the present disclosure , will appreciate that , in some embodiments , a composition ( e.g. , a pharmaceutical composition ) as described herein may be or comprise one or more cells , tissues , or organisms ( e.g. , plant or microbe cells , tissues , or organisms ) that produce ( e.g. , have produced , and / or are producing ) a relevant compound . [ 0145 ] Those skilled in the art will appreciate that , in some embodiments , technologies for preparing compositions and / or preparations , and / or for preparing ( and particularly for preparing pharmaceutical compositions ) may include one or more steps of assessing or characterizing a compound , preparation , or composition , e.g. , as part of quality control . In some embodiments , if an assayed material does not meet pre - determined specifications for the relevant assessment , it is discarded . In some embodiments , if such assayed material does meet the pre - determined specifications , then it continues to be processed as described herein . [ 0146 ] In some embodiments , a pharmaceutical composition provided herein can promote the colonization of an individual microbial strain or combinations of microbial strains from a mammalian microbiome , particularly microbial strain ( s ) that have been identified , characterized , or assessed as decreasing the severity or incidence of a mammalian disease , disorder , or condition , in a mammal suffering from or at risk of the mammalian disease , disorder , or condition . In some embodiments , a pharmaceutical composition provided herein can attenuate the colonization of an individual microbial strain or combinations of microbial strains from a mammalian microbiome , particularly microbial strain ( s ) that have been identified , characterized , or assessed as increasing the severity or incidence of a mammalian disease , disorder , or condition , in a mammal suffering from or at risk of the mammalian disease , disorder , or condition ( e.g. a metabolism - associated disease , disorder , or condition as described herein ) . In some embodiments , a pharmaceutical 53 WO 2025/054048 PCT / US2024 / 0440 composition provided herein can promote the colonization of an individual microbial strain or combinations of microbial strains from a mammalian microbiome , particularly microbial strain ( s ) that have been identified , characterized , or assessed as not affecting the severity or incidence of the mammalian disease , disorder , or condition but have been identified , characterized , or assessed as being capable of outcompeting one or more microbial strains that have been identified , characterized , or assessed as increasing the severity or incidence of a mammalian disease , disorder or condition , in a mammal suffering from or at risk of the mammalian disease , disorder , or condition . [ 0147 ] , " " > , In some embodiments , each of the one or more microbial strains in a composition comprises 10¹ colony forming units ( CFUs ) to 1020 CFU . In some embodiments , each of the one or more microbial strains in a composition comprises 10¹ colony forming units ( CFUs ) to 1015 CFU . In some embodiments , each of the one or more microbial strains in a composition comprises 106 CFU to 10 15 CFUs . In some embodiments , each of the one or more microbial strains in a composition comprises about 10¹ CFU to 10¹CFU , or about 102 CFU to 1014 CFU , or about 103 CFU to 1013 CFU , or about 10+ CFU to 1013 CFU , or about 105 CFU to 1012 CFU , or about 10 ° CFU to 10¹¹ CFU , or about 107 CFU to 1010 CFU , or about 108 CFU to 10 CFU , or about 105 CFU to 10 10 CFU , or about 1CFU to 1012 CFU . In some embodiments , each of the one or more microbial strains in a composition comprises at least about 10¹ , 5 x 10¹ , 10² , 5 x 10² , 10³ , 5 x 10³ , 104 , 5 x 104 , 105 , 5 x 105 , 106 , 5 x 106 , 107 , 5 x 107 , 108 , 5 x 108 , 109 , 5 x 10⁹ , 1010 , 5 x 1010 , 10¹¹ , 5 x 1011 , 1012 , or more CFUs . In some embodiments , each of the one or more microbial strains in a composition comprises at most about 10¹5 , 5 x 1014 , 1014 , 5 x 10¹³ , 10¹³ , 5 x 1012 , 1012 , x 10¹¹ , 10¹¹ , 5 x 10¹0 , º¹01 , 5 x º01 , º01 , 5 x 108 , 108 , or less CFUs . In some embodiments , each of the one or more microbial strains in a composition comprises the same number of CFUs . In some embodiments , some of the one or more microbial strains in a composition comprises a different number of CFUs . [ 0148 ] In some embodiments , a composition comprises a total of 10¹ CFU to 10CFUs . In some embodiments , a composition comprises a total of 106 CFU to 1015 of CFUs . In some embodiments , a composition can include about 10¹ CFU to 10 20 CFU , or about 1CFU to 1015 CFU , or about 105 CFU to 10¹² CFU , about 105 CFU to 1010 CFU , or about 1CFU to 1012 CFU of one or more microbial strains . In some embodiments , a composition can include about 10¹ CFU to 1015 CFU , or about 102 CFU to 1014 CFU , or about 10³ CFU to 1013 CFU , or about 104 CFU to 10¹³ CFU , or about 105 CFU to 1012 CFU , or about 1 54 WO 2025/054048 PCT / US2024 / 0440 CFU to 10¹¹ CFU , or about 107 CFU to º¹01 CFU , or about 108 CFU to º01 CFU , or about 105 CFU to 1010 CFU , or about 108 CFU to 10¹² CFU of one or more microbial strains . In some embodiments , a composition can include at least 10¹ , 5 x 10¹ , 10² , 5 x 10² , 10³ , 5 x 103 , 104 , 5 x 104 , 105 , 5 x 105 , 106 , 5 x 106 , 107 , 5 x 107 , 108 , 5 x 108 , 10⁹ , 5 x º01 , 1010 , 5 x 1010 , 10¹¹ , 5 x 1011 , 1012 , or more CFUs of one or more microbial strains . In some embodiments , a composition can include at most 1015 , 5 x 1014 , 1014 , 5 x 10¹³ , 10¹³ , 5 x 10¹² , 10¹² , 5 x 10¹¹ , 10¹¹ , 5 x º¹01 , º¹01 , 5 x 10 % , 10 % , 5 x 108 , 108 , or less CFUs of one or more microbial strains . [ 0149 ] In some embodiments , a pharmaceutical composition is tailored to a specific mammal ( e.g. , a specific human , e.g. , a patient ) based on that mammal's ( e.g. , human's ) microbiome . In some embodiments , a pharmaceutical composition is specific for a microbiome of an individual mammal ( e.g. , human ) . In some embodiments , a pharmaceutical composition is specific for microbiomes of a population of mammals ( e.g. , humans ) . Populations of mammals can include , but are not limited to : families , mammals in the same regional location ( e.g. , neighborhood , city , state , or country ) , mammals with the same disease or condition , mammals of a particular age or age range , mammals that consume a particular diet ( e.g. , food , food source , or caloric intake ) .

Methods of Treatment [ 0150 ] [ 0151 ] The present disclosure recognizes that compositions described herein can be useful in the treatment of subjects . Methods provided by the present disclosure include methods for the treatment of certain diseases , disorders and conditions . In some embodiments , relevant diseases , disorders and conditions may be or include a metabolism- associated disease , disorder , or condition . In some embodiments , a metabolism - associated disease , disorder , or condition may be , but not limited to , lipid - induced metabolic syndrome , cerebral infarction / stroke , myocardial infarction / heart attack , Type II diabetes / diabetes mellitus , glucose intolerance , alcoholism , metabolic syndrome , kidney disease , cardiorenal syndrome , vascular diseases ( e.g. , hypertension , peripheral arterial disease ) , Alzheimer's disease , asthma ( e.g. , due to abdominal obesity or central / truncal obesity ) , atherosclerosis , hypothyroidism , liver disease , LDL - hypercholesterolemia , hypertriglyceridemia , mixed hyperlipoproteinemia , coronary heart disease , stroke , peripheral arterial disease , high blood pressure , hyperlipidemia , steatosis , non - alcoholic steatohepatitis ( NASH ) , fatty - liver 55 WO 2025/054048 PCT / US2024 / 0440 disease , metabolic associated fatty liver disease ( MAFLD ) , non - alcoholic fatty liver disease ( NAFLD ) , liver fibrosis , cirrhosis , or hepatocellular carcinoma etc .. [ 0152 ] Generally , methods of treatment provided by the present disclosure involve administering a therapeutically effective amount of a composition as described herein alone or in combination with other compositions and / or treatments to a subject who is in need of , or who has been determined to be in need of , such treatment . [ 0153 ] In some embodiments , methods of treatment provided herein are prophylactic or preventative , e.g. , may be administered to subjects prior to display of significant symptoms and / or to exposure to a particular expected inducement that is associated with metabolism - associated diseases , disorders , or conditions described herein . In some embodiments , methods of treatment provided herein are therapeutic , e.g. , may be administered to subjects after development of significant symptoms associated with metabolism - associated diseases , disorders , or conditions . [ 0154 ] In some embodiments , provided methods of treatment are administered to a subject that is a mammal , e.g. , a mammal that experiences a disease , disorder , or condition as described herein ; in some embodiments , a subject is a human or non - human veterinary subject , e.g. , an ape , cat dog , monkey , or pig . [ 0155 ] In many embodiments , treatment involves ameliorating at least one symptom of a disease , disorder , or condition associated with metabolism - associated diseases , disorders , or conditions . In some embodiments , a method of treatment can be prophylactic . [ 0156 ] In some embodiments , the methods can include administration of a therapeutically effective amount of compositions disclosed herein before , during ( e.g. , concurrently with ) , or after administration of a treatment that is expected to be associated with metabolism - associated diseases , disorders , or conditions . [ 0157 ] In some embodiments , subjects who receive treatment as described herein may be receiving and / or may have received other treatment ( e.g. , pharmacological treatment / therapy , surgical , etc. ) , for example that may be intended to treat one or more symptoms or features of a disease disorder or condition as described herein ( e.g. metabolism - associated diseases , disorders , or conditions ) , so that provided compositions are administered in combination with such other therapy ( i.e. treatment ) to treat the relevant disease , disorder , or condition . 56 WO 2025/054048 PCT / US2024 / 0440 [ 0158 ] In some embodiments , the compositions described herein can be administered in a form containing one or more pharmaceutically acceptable carriers . Suitable carriers have been described previously and vary with the desired form and mode of administration of a composition . For example , pharmaceutically acceptable carriers can include diluents or excipients such as fillers , binders , wetting agents , disintegrators , surface- active agents , glidants , and lubricants . Typically , a carrier may be a solid ( including powder ) , liquid , or any combination thereof . Each carrier is preferably " acceptable " in the sense of being compatible with other ingredients in the composition and not injurious to a subject . A carrier can be biologically acceptable and inert ( e.g. , it permits the composition to maintain viability of the biological material until delivered to the appropriate site ) . [ 0159 ] Tablets , pills , capsules , troches and the like can contain any of the following ingredients , or compounds of a similar nature : a binder such as microcrystalline cellulose , gum tragacanth or gelatin ; an excipient such as starch or lactose , a disintegrating agent such as alginic acid , primogel , or corn starch ; a lubricant such as magnesium stearate or sterotes ; a glidant such as colloidal silicon dioxide ; a sweetening agent such as sucrose or saccharin ; or a flavoring agent such as peppermint , methyl salicylate , orange flavoring , or other suitable flavorings . These are for purposes of example only and are not intended to be limiting . [ 0160 ] Oral compositions can include an inert diluent or an edible carrier . For purposes of oral therapeutic administration , an active compound can be incorporated with excipients and used in the form of tablets , lozenges , pastilles , troches , or capsules , e.g. , gelatin capsules . Oral compositions can also be prepared by combining a composition of the present disclosure with a food . In some embodiments , microbes ( e.g. one or more microbial strains ) can be formulated in a food item . Some non - limiting examples of food items to be used with the methods and compositions described herein include : popsicles , cheeses , creams , chocolates , milk , meat , drinks , pickled vegetables , kefir , miso , sauerkraut , etc. In other embodiments , food items can be juices , refreshing beverages , tea beverages , drink preparations , jelly beverages , and functional beverages ; alcoholic beverages such as beers ; carbohydrate - containing foods such as rice food products , noodles , breads , and pastas ; paste products such as fish , hams , sausages , paste products of seafood ; retort pouch products such as curries , food dressed with a thick starchy sauce , and Chinese soups ; soups ; dairy products such as milk , dairy beverages , ice creams , and yogurts ; fermented products such as fermented soybean pastes , fermented beverages , and pickles ; bean products ; various 57 WO 2025/054048 PCT / US2024 / 0440 confectionery products including biscuits , cookies , and the like , candies , chewing gums , gummies , cold desserts including jellies , cream caramels , and frozen desserts ; instant foods such as instant soups and instant soy - bean soups ; and the like . It is preferred that food preparations not require cooking after admixture with microbial strain ( s ) to avoid killing any microbes . In one embodiment a food used for administration is chilled , for example , iced flavored water . In certain embodiments , the food item is not a potentially allergenic food item ( e.g. , not soy , wheat , peanut , tree nuts , dairy , eggs , shellfish or fish ) . Pharmaceutically compatible binding agents , and / or adjuvant materials can be included as part of the composition . [ 0161 ] Ocular formulations ( e.g. for ophthalmic , intravitreal , or suprachoroidal administration ) can include an inert diluent or a carrier . For purposes of ocular therapeutic administration , an active compound can be incorporated with excipients and used in the form of suspensions , emulsions ( e.g. water - in - oil or oil - in water ) , nanocarriers , ( e.g. nanoparticles , nanosuspensions , liposomes , nanomicelles , dendrimers , etc. ) ointments , gels , eye drops , etc. In some embodiments , administration of such formulations is topical ( e.g. eye drops ) . In some embodiments , administration of such formulations is via injection ( e.g. intravitreal , suprachoroidal , etc. ) . [ 0162 ] Cerebral formulations ( e.g. for intracerebral or intrathecal administration ) can include an inert diluent or a carrier . For purposes of cerebral therapeutic administration , an active compound can be incorporated with excipients and used in the form of suspensions , emulsions ( e.g. water - in - oil or oil - in water ) , nanocarriers , ( e.g. nanoparticles , nanosuspensions , liposomes , nanomicelles , dendrimers , etc. ) ointments , gels , etc. In some embodiments , administration of such formulations is topical ( e.g. ointments ) . In some embodiments , administration of such formulations is via injection ( e.g. intracerebral , intrathecal , etc. ) . [ 0163 ] In some such embodiments , a composition described herein is administered to a subject according to a dosing regimen that achieves population of the subject's microbiome with administered cells . In some embodiments , a composition is administered to a subject in a single dose . In some embodiments , a composition is administered to a subject in a plurality of doses . In some embodiments , a dose of a composition is administered to a subject twice a day , daily , weekly , or monthly . 58 WO 2025/054048 PCT / US2024 / 0440 [ 0164 ] In some embodiments , each of the one or more microbial strains in a dose comprises 10¹ to 1015 colony forming units ( CFUs ) . In some embodiments , each of the one or more microbial strains in a dose comprises 106 to 1015 CFUs . In some embodiments , each of the one or more microbial strains in a dose comprises the same number of CFUs . In some embodiments , some of the one or more microbial strains in a dose comprises a different number of CFUs . [ 0165 ] In some embodiments , a dose of one or more microbial strains comprises a total of 106 to 1015 CFUs . In some embodiments , a dose of one or more microbial strains comprises a total of 107 to 10¹5 CFUs . In some embodiments , a dose of one or more microbial strains comprises 5-200 billion CFUs . In some embodiments , a dose of one or more microbial strains comprises 5-50 billion CFUs . In some embodiments , a dose of one or more microbial strains comprises 5-20 billion CFUs . In some embodiments , a dose of one or more microbial strains comprises 50-100 billion CFUs . In some embodiments , a dose of one or more microbial strains comprises 100-200 billion CFUs . [ 0166 ] In some embodiments , efficacy can be assessed by measuring the degree of oxidative stress of cells in a biological sample prior to and following administration of a composition as described herein . The degree of oxidative stress of cells can be assessed by , for example , measuring the expression of oxidative stress biomarkers , such as reactive oxygen species ( ROS ) levels , or lipid , protein , and nucleic acid damage levels , or by determining the ratio of oxidized to reduced forms of one or more biomarkers . High levels of oxidative stress can be cytotoxic , so the degree of oxidative stress can be measured by assessing the concentration of intracellular proteins present in the systemic circulation from inflamed or lysed cells ( e.g. nerve cells ) . [ 0167 ] EXEMPLIFICATION Example 1 : Evaluation of efficacy of microbiome compositions in affecting body weight in mouse model [ 0168 ] This Example provides an evaluation of the efficacy of microbiome compositions , specifically CT6 and CT6m compositions , in affecting body weight in in vivo mouse model . 59 WO 2025/054048 PCT / US2024 / 0440 [ 0169 ] Mouse Model : TDP43 - Q331K male mice that were 8 weeks old were used for these experiments . Wild type mice were used as a control in all experiments . [ 0170 ] Study : TDP43 - Q331K mice were divided into three groups of 17-20 animals per group , and were provided mock ( DPBS ) or microbiome composition ( CT6 or CT6m ; composition details listed in Tables 2 , 3 , and 4 ) by daily oral gavage for approximately 2days . The groups were : ( i ) Gl : Wild type mice treated with DPBS ( n = 19 ) ; ( ii ) G2 : TDP43- Q331K transgenic mice treated with DPBS ( n = 17 ) ; ( iii ) G3 : TDP43 - Q331K transgenic mice treated with CT6 composition ( n = 19 ) ; and ( iv ) G4 : TDP43 - Q331K transgenic mice treated with CT6m composition ( n = 20 ) . The body weights of the animals were recorded twice a week until the end of study . [ 0171 ] Results : Fig . 1 shows the results of this experiment . Figs . 1a - e show average body weight at different timepoints during the study . At study start , TDP43 mice had significantly heavier body weights compared to non - transgenic ( ntg ) i.e. wild type littermates ( p < 0.002 ) . When mice were 8 weeks old all treatment groups exhibited weight gain with aging , regardless of genotype or treatment ( see Fig . 1a - b ) . After 57 days of dosing vehicle - treated ntg mice and CT6m treated mice were significantly lighter compared to vehicle - treated TDP43 mice ( p < 0.0002 & p < 0.045 , respectively ) ( Fig . 1c ) . After 1days , both CT6 & CT6m - treated animals showed significantly lower body weights ( p < 0.041 & p < 0.035 , respectively ) compared to vehicle - treated TDP43 mice , whereas body weights of vehicle - treated ntg mice were no longer significantly different to vehicle - treated TDP43 mice ( Fig . 1d ) . There were no differences between vehicle - treated ntg and vehicle- treated TDP43 mice at the end of study ( > 220 days of dosing ) . Conversely , CT6 or CT6m- treated mice had significantly lower body weights ( p < 0.028 & p < 0.0092 , respectively ) compared to vehicle - treated TDP43 mice ( Fig . 1e ) . Moreover , none of the treated animals presented body weight loss exceeding 10 % from baseline , demonstrating that daily treatments were well - tolerated , thus providing substantial evidence that these therapies are safe . [ 0172 ] Example 2 : Evaluation of efficacy of microbiome compositions in affecting fat accumulation in livers in mouse model 60 WO 2025/054048 PCT / US2024 / 0440 [ 0173 ] This Example provides an evaluation of the efficacy of microbiome compositions , specifically CT6 and CT6m compositions , in affecting fat accumulation in livers in in vivo mouse model . [ 0174 ] Mouse Model : TDP43 - Q331K male mice that were 8 weeks old were used for these experiments . Wild type mice were used as a control in all experiments . [ 0175 ] Study : TDP43 - Q331K mice were divided into three groups of 20 animals per group , and were provided mock ( DPBS ) or microbiome composition ( CT6 or CT6m ; composition details listed in Tables 2 , 3 , and 4 ) by daily oral gavage for 224 days . The groups were : ( i ) G1 : Wild type mice treated with DPBS ( n = 20 ) ; ( ii ) G2 : TDP43 - Q331K transgenic mice treated with DPBS ( n = 20 ) ; ( iii ) G3 : TDP43 - Q331K transgenic mice treated with CT6 composition ( n = 20 ) ; and ( iv ) G4 : TDP43 - Q331K transgenic mice treated with CT6m composition ( n = 20 ) . The animals were sacrificed at the end of the study . following which histological analyses were performed . [ 0176 ] Results : Fig . 2 shows the results of this experiment . During harvesting of tissues , it was observed that a large proportion of vehicle - treated TDP43 - trangenic and vehicle - ntg animals had grossly observable fatty livers ( Fig . 2a ) . On the contrary , less than % of animals treated with CT6 or CT6m exhibited grossly observable fatty livers ( Fig . 2b ) , demonstrating that treatments with CT6 and / or CT6m provides protection against non- alcoholic fatty liver disease in TDP43 - Q331K male animals . Fig . 2c shows photographs of liver samples from each of the four groups demonstrating microbiome composition treated- livers lack the appearance of lipid accumulation that is seen in G1 ( ntg , vehicle - treated ) & G2 ( TDP43 + vehicle ) mice . [ 0177 ] To examine the degree of fatty liver disease , hematoxylin & eosin ( H & E ) staining was performed on formalin - fixed paraffin - embedded livers sections by Horus Scientific , a histology CRO in Worcester , MA . Microscopic evaluation of the H & E sections showed that vehicle - treated animals , regardless of genotype , exhibited a more pronounced and severe degree of lipid deposition in the livers compared to animals treated with CT6 or CT6m ( see Fig . 3 ) . [ 0178 ] These observations that CT6 & CT6m treatment protects the liver from fat accumulation is in accordance with the significant difference in body weight between vehicle - treated and CT6 / CT6m - treated animals ( see Example 1 ) , indicating that CT6 & CT6m has utility and efficacy in treating metabolic disorders . 61 WO 2025/054048 PCT / US2024 / 0440 [ 0179 ] Example 3 : Evaluation of efficacy of microbiome compositions in affecting LDL- cholesterol , HDL cholesterol , and circulating triglyceride levels in mouse model [ 0180 ] This Example provides an evaluation of the efficacy of microbiome compositions , specifically CT6 and CT6m compositions , in affecting low - density lipoprotein ( LDL ) cholesterol , high - density lipoprotein ( HDL ) cholesterol , and circulating triglyceride levels in in vivo mouse model . [ 0181 ] Mouse Model : TDP43 - Q331K male mice that were 8 weeks old were used for these experiments . Wild type mice were used as a control in all experiments . [ 0182 ] Study : TDP43 - Q331K mice were divided into three groups of 16-20 animals per group , and were provided mock ( DPBS ) or microbiome composition ( CT6 or CT6m ; composition details listed in Tables 2 , 3 , and 4 ) by daily oral gavage for 224 days . The groups were : ( i ) G1 : Wild type mice treated with DPBS ( n = 19 ) ; ( ii ) G2 : TDP43 - Q331K transgenic mice treated with DPBS ( n = 16 ) : ( iii ) G3 : TDP43 - Q331K transgenic mice treated with CT6 composition ( n = 19 ) ; and ( iv ) G4 : TDP43 - Q331K transgenic mice treated with CT6m composition ( n = 20 ) . [ 0183 ] To evaluate the impact of CT6 and CT6m treatments on other aspects of metabolic disorders , a lipid panel using mouse - specific , plate - based colorimetric LDL & HDL assay kits to measure the levels of circulating cholesterol from plasma collected at the end - of - study under non - fasting conditions was performed . Plate - based enzymatic assays kits were purchased from Crystal Chem for measuring Mouse HDL - cholesterol ( Cat . # 79990 ) and Mouse LDL - cholesterol ( Cat . # 79980 ) in plasma samples collected at end of study . The assays were carried out in 96 - well plates following the assay kit protocol instructions . The optical density ( OD ) was measured at 600 nM twice with the Promega GloMax Explorer plate reader , per protocol instructions . The first OD reading was done after a 5 minute incubation of modified polyvinyl sulfonic acid and polyethylene - glycol methyl ether ( PVS / PEGME ) detergent with 3 Lµ of plasma samples in a 96 well plate [ 0184 ] Results : Fig . 4 shows the results of this experiment . Measurement & quantification of LDL cholesterol , which is also commonly referred to as ' bad ' cholesterol , revealed no significant differences between vehicle - treated transgenic & non - transgenic animals ( mean [ LDL ] = 42.6 +/- 15.1 mg / dL vs. 47.1 +/- 13.6 mg / dL , respectively ; see Fig . 62 WO 2025/054048 PCT / US2024 / 0440 4a ) . However , treatment with CT6 led to a significant reduction ( p = 0.03 ) in LDL levels compared to vehicle - treated transgenic mice ( 34.7 +/- 12.2 mg / dL vs 47.1 +/- 13.6 mg / dL , respectively ) . This reduction was even more robust and significant ( p = 0.0002 ) in animals treated with CT6m , which had a mean LDL concentration of 26.8 +/- 16.2 mg / dL ( see Fig . 4a ) . When LDL level is elevated or too high , the cholesterol can build up along the walls of blood vessels leading to a higher risk for heart disease and stroke . [ 0185 ] HDL cholesterol is known as the ' good ' cholesterol because it absorbs cholesterol and carries it back to the liver where it gets flushed from the body . Contrary to LDL levels , high levels of HDL cholesterol can lower risks for cardiovascular disease / heart attack and stroke . Therefore , it was determined if CT6 or CT6m treatments imparts any effect on raising HDL levels . Indeed , a significant increase in plasma HDL cholesterol levels was observed in animals treated with CT6 ( p = 0.021 ) or CT6m ( p = 0.008 ) compared to vehicle treated TDP43 transgenic animals ( mean [ HDL ] = 46.1mg / dL vs. 47.8 mg / dL vs. 31.1 mg / dL , respectively ) ( see Fig . 4b ) . Intriguingly , it was found that among the four treatment groups , vehicle - treated ntg animals in group 1 ( G1 ) had the highest and most significantly ( p < 0.0001 ) elevated HDL levels , with a mean of 58.6 mg / dL . [ 0186 ] Very often the total cholesterol to HDL ratio is used for assessing one's risk to developing heart disease or stroke . In fact , studies suggests that the total cholesterol to HDL ratio is a better marker and risk indicator for atherosclerosis ( commonly referred as heart disease ) or stroke compared to looking at LDL or total cholesterol alone . Higher ratio of LDL / HDL indicate a higher risk for developing heart disease or stroke whereas lower ratio of LDL / HDL indicate lower cardiovascular / stroke risk . Indeed , it was observed that animals in G2 ( TDP43 + vehicle ) had the highest ratio of LDL / HDL compared to animals in groups G1 , G3 and G4 ( see Fig . 4c ) . [ 0187 ] Furthermore , to test the lipid - lowering effects of CT6 & CT6m compositions , circulating triglyceride levels were measured in the same plasma sample set used for measuring LDL & HDL cholesterol levels ( see Fig . 4d ) . It was observed that animals in G( TDP43 + vehicle ) had the highest plasma triglyceride levels compared to animals in groups G1 , G3 and G4 ( see Fig . 4d ) . Furthermore , both CT6 and CT6m treated TDP43 mice showed the significantly lower plasma triglyceride levels compared to vehicle treated TDP43 mice . These results suggest microbiome compositions , for example CT6 and CT6m compositions , decrease bad cholesterol and fats in the body thereby reducing risks for cardiovascular disease and stroke . 63 WO 2025/054048 PCT / US2024 / 0440 [ 0188 ] Example 4 : Evaluation of efficacy of microbiome compositions in affecting inflammation in mouse model [ 0189 ] This Example provides an evaluation of the efficacy of microbiome compositions , specifically CT6 and CT6m compositions , in affecting inflammation , specifically pro - inflammatory cytokines and chemokines levels , in in vivo mouse model .

Mouse Model : TDP43 - Q331K male mice that were 8 weeks old were used for these experiments . Wild type mice were used as a control in all experiments . [ 0190 ] [ 0191 ] Study : TDP43 - Q331K mice were divided into three groups of 16-20 animals per group , and were provided mock ( DPBS ) or microbiome composition ( CT6 or CT6m ; composition details listed in Tables 2 , 3 , and 4 ) by daily oral gavage for 224 days . The groups were : ( i ) G1 : Wild type mice treated with DPBS ( n = 19 ) ; ( ii ) G2 : TDP43 - Q331K transgenic mice treated with DPBS ( n = 16 ) ; ( iii ) G3 : TDP43 - Q331K transgenic mice treated with CT6 composition ( n = 19 ) ; and ( iv ) G4 : TDP43 - Q331K transgenic mice treated with CT6m composition ( n = 20 ) . The animals were sacrificed at the end of the study , following which histological analyses were performed . To assess the effects of CT6 or CT6m treatment on inflammation , the levels of pro - inflammatory cytokines and chemokines in liver lysates of mice were assessed . [ 0192 ] Results : Fig . 5 shows the results of this experiment . The levels of pro- inflammatory cytokines and chemokines in liver lysates of mice were measured using the Mouse Cytokine / Chemokine 31 - Plex Discovery Assay , which was outsourced to and performed by Eve Technologies ( Calgary , AB , Canada ) . As seen from Fig . 5 , various pro- inflammatory cytokine and chemokines were found to be significantly lower in the CT6 and CT6m treated TDP43 mice compared to the control groups G1 and G2 . These results suggest microbiome compositions , for example CT6 and CT6m compositions , decrease pro- inflammatory cytokine and chemokine levels . [ 0193 ] OTHER EMBODIMENTS It is to be appreciated by those skilled in the art that various alterations , modifications , and improvements to the present disclosure will readily occur to those skilled in the art . Such alterations , modifications , and improvements are intended to be part of the 64 WO 2025/054048 PCT / US2024 / 0440 present disclosure , and are intended to be within the spirit and scope of the invention . Accordingly , the foregoing description and drawing are by way of example only and any invention described in the present disclosure if further described in detail by the claims that follow . [ 0194 ] Those skilled in the art will appreciate typical standards of deviation or error attributable to values obtained in assays or other processes as described herein . The publications , websites and other reference materials referenced herein to describe the background of the invention and to provide additional detail regarding its practice , including those listed in the above References section , are hereby incorporated by reference in their entireties . [ 0195 ] It is to be understood that while embodiments of the invention have been described in conjunction with the detailed description thereof , the foregoing description is intended to illustrate and not limit the scope of the invention , which is defined by the scope of the appended claims . Other aspects , advantages , and modifications are within the scope of the following claims . [ 0196 ] EQUIVALENTS Those skilled in the art will recognize , or be able to ascertain using no more than routine experimentation , many equivalents to the specific embodiments of the invention described herein . The scope of the present invention is not intended to be limited to the above Description , but rather is as set forth in the following claims : 65 Appendix 1-1 . Metabolite Abbreviations Attorney Docket No. 2013404-01 Pathway Label + Pathway Index $ 1,3 - Diaminopropane - Methyl - 4 - imidazoleacetic acid 1 - Methylhistamine 1 - Methylnicotinamide Urea cycle relating metaboloism Urea cycle relating metaboloism 1 - Methylhistamine 1 - Methylnicotinamide 1 - Pyrroline 5 - carboxylic acid 2,3 - Diphosphoglyceric acid 2,5 - Dihydroxybenzoic - Aminoadipic acid 2 ' - Deoxyadenosine 2 - Aminoadipic acid Urea cycle relating metaboloism Metabolism of coenzymes Urea cycle relating metaboloism Central carbon metabolism Pathway overview Lipid and amino acid metabolism Nucleotide metabolism 2 ' - Deoxycytidine Nucleotide metabolism 2 ' - Deoxyguanosine 2 ' - Deoxyuridine 2 - Hydroxybutyric acid 2 - HBA 2 - Oxoadipic acid - Oxobutyric acid 2 - Oxoglutaric acid 2 - Oxoisovaleric acid 2 - Phenylethylamine - Phosphoglyceric acid 2 - PG 3,3 ' , 5 - Triiodothyronine 3,5 - Diiodotyrosine 3,4 - Dihydroxyphenylglycol 3,5 - DI - Tyr - Oxoadipic acid 2 - Oxobutyric acid 2 - OG 2 - KIV Nucleotide metabolism Nucleotide metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism Central carbon metabolism / Urea cycle relating metaboloism BCAA & aromatic amino acids BCAA & aromatic amino acids Central carbon metabolism BCAA & aromatic amino acids Pathway overview BCAA & aromatic amino acids Page 66 of 159 Attorney Docket No. 2013404-01 3 - Aminoisobutyric acid 3 - Aminoisobutyric acid 3 ' - Dephospho CoA Dephospho CoA 3 - Hydroxyanthranilic acid 3 - OHAA 3 - Hydroxybutyric acid 3 - HBA 3 - Hydroxykynurenine 3 - OHKY 3 - Hydroxypropionic acid b - Lactate 3 - Iodotyrosine 3 - Methoxy - 4 - hydroxyphenylethyleneglycol MHPG 3 - Methoxyanthranilic acid 3 - Methoxytyramine 3 - Methyl - 2 - oxovaleric acid 3 - Methylcrotonyl CoA_divalent 3 - Methylhistidine 3 - Phosphoglyceric acid 3 - Ureidopropionic acid 4 - Acetamidobutanoic acid 4 - Guanidinobutyric acid 4 - Hydroxyphenylacetaldehyde 4 - Methyl - 2 - oxovaleric acid 3 - Methoxyanthranilic acid 3 - Methoxytyramine 3 - Methylcrotonyl CoA 3 - Methylhistidine 3 - PG - Acetamidobutanoic acid - Ureidopropionic acid 4 - GBA BCAA & aromatic amino acids / Nucleotide metabolism Metabolism of coenzymes BCAA & aromatic amino acids Central carbon metabolism / Lipid and amino acid BCAA & aromatic amino acids BCAA & aromatic amino acids BCAA & aromatic amino acids BCAA & aromatic amino acids BCAA & aromatic amino acids BCAA & aromatic amino acids BCAA & aromatic amino acids BCAA & aromatic amino acids Urea cycle relating Central carbon metabolism / Lipid and amino acid Nucleotide metabolism Pathway overview Urea cycle relating 4 - Hydroxyphenylacetaldehyde Pathway overview 2 - Oxoleucine BCAA & aromatic amino acids Page 67 of 159 Attorney Docket No. 2013404-01 4 - Methylthio - 2 - oxobutyric acid 4 - Pyridoxic acid 5,6 - Dimethylbenzimidazole - Amino - 4 - oxovaleric acid 4 - Pyridoxic acid 5 - ALA - Aminoimidazole - 4 - carboxamide ribotide AICAR 5 ' - Deoxy - 5 ' - methylthioadenosine 5 - Hydroxyindoleacetic acid 5 - Hydroxylysine 5 - Hydroxytryptophan 5 - Methoxyindoleacetic acid 5 - Methoxytryptamine 5 - Methyltetrahydrofolic acid 5 - Oxoproline - Phosphogluconic acid 7,8 - Dihydrofolic acid Acetoacetic acid - Hydroxy - IAA 5 - Hydroxylysine 5 - MIAA 5 - MTHF - PG Dihydrofolic acid Acetoacetic acid Acetoacetyl CoA_divalent Acetyl CoA_divalent Lipid and amino acid Metabolism of coenzymes Metabolism of coenzymes Lipid and amino acid metabolism Nucleotide metabolism Urea cycle relating metaboloism BCAA & aromatic amino acids Lipid and amino acid metabolism BCAA & aromatic amino acids BCAA & aromatic amino acids BCAA & aromatic amino acids Metabolism of coenzymes Urea cycle relating metaboloism Central carbon metabolism Metabolism of coenzymes BCAA & aromatic amino acids Central carbon metabolism / Lipid and amino acid metabolism Lipid and amino acid metabolism Central carbon metabolism / Lipid and amino acid metabolism / Metabolism of coenzymes Lipid and amino acid metabolism Nucleotide metabolism Nucleotide metabolism Page 68 of 159 Attorney Docket No. 2013404-01 Adenylosuccinic acid ADP - ribose Allantoic acid Succinyl AMP ADP - Rib Allantoic acid Nucleotide metabolism Central carbon metabolism / Nucleotide metabolism Central carbon metabolism / Metabolism of coenzymes BCAA & aromatic amino acids Urea cycle relating metaboloism Central carbon metabolism / Urea cycle relating metaboloism BCAA & aromatic amino acids Pathway overview † Metabolites which have been already known about pathway information were listed up . They included metaboites which were not detected in this study .

‡ Abbreviated names in Pathway Map .

Page 69 of 1 § Pathway information in the metabolites .

Attorney Docket No. 2013404-01 Appendix 1-1 . Metabolite Abbreviations Candidates + Pathway Label ‡ Anserine divalent Anthranilic acid Argininosuccinic acid Ascorbate 2 - glucoside Ascorbate 2 - phosphate Ascorbate 2 - sulfate Ascorbic acid Anthranilic acid Ascorbate 2 - glucoside Ascorbate 2 - phosphate Ascorbate 2 - sulfate Ascorbic acid Betaine aldehyde_ + O₂H Carbamoyl - P Pathway Index $ Nucleotide metabolism Urea cycle relating metaboloism BCAA & aromatic amino acids Central carbon metabolism / Urea cycle relating metaboloism Urea cycle relating metaboloism Metabolism of coenzymes Metabolism of coenzymes Metabolism of coenzymes Metabolism of coenzymes Urea cycle relating metaboloism Central carbon metabolism / Urea cycle relating metaboloism / Nucleotide metabolism Central carbon metabolism / Nucleotide metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism Metabolism of coenzymes Nucleotide metabolism Urea cycle relating metaboloism Lipid and amino acid metabolism Urea cycle relating metaboloism Page 70 of 159 Attorney Docket No. 2013404-01 CDP - choline Cholic acid cis -Aconitic acid cis - Hydroxyproline Citramalic acid Citric acid CDP - choline Cholic acid cis -Aconitic acid cis - Hydroxyproline Citramalic acid Citric acid CMP - N - acetylneuraminate CMP - NeuNAc Cys - Gly Cys - Gly Cysteic acid Cysteic acid Cysteinesulfinic acid Cysteinesulfinic acid Nucleotide metabolism Lipid and amino acid metabolism Nucleotide metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism Central carbon metabolism Urea cycle relating metaboloism Pathway overview Central carbon metabolism Urea cycle relating metaboloism Nucleotide metabolism Central carbon metabolism Central carbon metabolism / Metabolism of coenzymes Urea cycle relating metaboloism Urea cycle relating metaboloism Nucleotide metabolism Urea cycle relating metaboloism / Lipid and amino acid metabolism Urea cycle relating metaboloism Lipid and amino acid metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism Nucleotide metabolism Page 71 of 159 Attorney Docket No. 2013404-01 Nucleotide metabolism Nucleotide metabolism Nucleotide metabolism Nucleotide metabolism Nucleotide metabolism Nucleotide metabolism Deamido - NAD + Deamido - NAD Metabolism of coenzymes Metabolism of coenzymes Nucleotide metabolism Nucleotide metabolism Nucleotide metabolism Dihydroorotic acid Dihydroorotic acid Nucleotide metabolism Nucleotide metabolism Page 72 of 1 Dihydroxyacetone phosphate DHAP dTDP - glucose TDP - Glc Central carbon metabolism / Lipid and amino acid metabolism Nucleotide metabolism Nucleotide metabolism BCAA & aromatic amino acids BCAA & aromatic amino acids Nucleotide metabolism Pathway overview Nucleotide metabolism Nucleotide metabolism Attorney Docket No. 2013404-01 Erythrose 4 - phosphate Nucleotide metabolism Nucleotide metabolism Nucleotide metabolism Pathway overview Central carbon metabolism † Metabolites which have been already known about pathway information were listed up .

They included metaboites which were not detected in this study .

+ Abbreviated names in Pathway Map .

Page 73 of 1 § Pathway information in the metabolites .

Appendix 1-1 . Metabolite Abbreviations Attorney Docket No. 2013404-01 FAD divalent Folic acid Formylanthranilic acid Fructose 1 - phosphate Fructose 1,6 - diphosphate Pathway Labelf Folic acid Pathway Index $ Metabolism of coenzymes Metabolism of coenzymes Metabolism of coenzymes Pathway overview D - FIP Central carbon metabolism Central carbon metabolism Fructose 6 - phosphate Fumaric acid Fumaric acid Galactose 1 - phosphate GDP - fucose GDP - fucose GDP - mannose GDP - Man Glucosamine 6 - phosphate Glc - 6P Central carbon metabolism Central carbon metabolism / Urea cycle relating metaboloism Urea cycle relating metaboloism Central carbon metabolism Nucleotide metabolism Central carbon metabolism Central carbon metabolism Urea cycle relating metaboloism Central carbon metabolism / Urea cycle relating metaboloism Central carbon metabolism Central carbon metabolism Glucosaminic acid Glucosaminic acid Central carbon metabolism Glucose 1 - phosphate Central carbon metabolism Page 74 of 159 Attorney Docket No. 2013404-01 Glyceric acid Glycocholic acid Glycolic acid Glucose 6 - phosphate Glucuronic acid Glutaryl CoA_divalent Glutathione ( GSH ) Glutathione ( GSSG ) _divalent Glyceraldehyde 3 - phosphate Glyceric acid Glycerol 3 - phosphate Glycocholic acid Glycolic acid Glucuronic acid Glutaryl - CoA Central carbon metabolism Central carbon metabolism Lipid and amino acid metabolism Urea cycle relating metaboloism Urea cycle relating metaboloism Urea cycle relating metaboloism / Lipid and amino acid metabolism Central carbon metabolism / Lipid and amino acid metabolism Central carbon metabolism / Lipid and amino acid metabolism Central carbon metabolism / Glyoxylic acid Glyoxylic acid Lipid and amino acid metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism Nucleotide metabolism Guanidoacetic acid Guanidoacetic acid HMG COA divalent HMG - CoA Nucleotide metabolism Urea cycle relating metaboloism Nucleotide metabolism Nucleotide metabolism Urea cycle relating metaboloism Urea cycle relating metaboloism Lipid and amino acid metabolism Page 75 of 159 Attorney Docket No. 2013404-01 Homovanillic acid Imidazole - 4 - acetic acid Imidazole - 4 - acetic acid Indole - 3 - acetaldehyde Indole - 3 - acetic acid Indole - 3 - acetic acid Isobutyryl CoA_divalent Isobutyryl - CoA Isocitric acid Isocitric acid Kynurenic acid Kynurenic acid Lactic acid Lactic acid Malic acid Malic acid Lipid and amino acid metabolism BCAA & aromatic amino acids Urea cycle relating metaboloism Lipid and amino acid metabolism Nucleotide metabolism Nucleotide metabolism BCAA & aromatic amino acids Urea cycle relating metaboloism Nucleotide metabolism BCAA & aromatic amino acids BCAA & aromatic amino acids Nucleotide metabolism Lipid and amino acid metabolism / BCAA & aromatic amino acids Central carbon metabolism Nucleotide metabolism BCAA & aromatic amino acids BCAA & aromatic amino acids Central carbon metabolism / Urea cycle relating metaboloism BCAA & aromatic amino acids Lipid and amino acid metabolism Central carbon metabolism / Urea cycle relating metaboloism Page 76 of 159 Attorney Docket No. 2013404-01 Malonyl CoA_divalent Malonyl - CoA Mannose 1 - phosphate Mannose 6 - phosphate Methylmalonic acid Methylmalonic acid N , N - Dimethylglycine бN , N6 No - Trimethyllysine N - Acetylaspartic acid N - Acetylaspartic acid Central carbon metabolism / Lipid and amino acid metabolism Central carbon metabolism Central carbon metabolism BCAA & aromatic amino acids Lipid and amino acid metabolism Lipid and amino acid metabolism / BCAA & aromatic amino acid Lipid and amino acid metabolism Lipid and amino acid metabolism Urea cycle relating metaboloism † Metabolites which have been already known about pathway information were listed up . They included metaboites which were not detected in this study .

‡ Abbreviated names in Pathway Map .

Page 77 of 1 § Pathway information in the metabolites .

Appendix 1-1 . Metabolite Abbreviations Attorney Docket No. 2013404-01 N - Acetylglucosamine Pathway Label + N - Acetylglucosamine 1 - phosphate GlcNAc - P N - Acetylglucosamine 6 - phosphate NAcGlcNP N - Acetylglutamic acid N - Acetylmannosamine N - Acetylneuraminic acid N - Acetylornithine N - Acetylputrescine NADP + NADPH divalent N - Carbamoylaspartic acid N - Formylaspartic acid Nicotinic acid N - AcGlu N - Acorn N - Acetylputrescine NAD + NADP + Carbamoyl - Asp N - Formyl aspartic acid Nicotinic acid Pathway Index $ Central carbon metabolism Central carbon metabolism Central carbon metabolism Urea cycle relating metaboloism Central carbon metabolism Central carbon metabolism Urea cycle relating metaboloism Urea cycle relating metaboloism Central carbon metabolism / Metabolism of coenzymes Central carbon metabolism / Metabolism of coenzymes Central carbon metabolism / Metabolism of coenzymes Central carbon metabolism / Metabolism of coenzymes Urea cycle relating metaboloism / Nucleotide metabolism Urea cycle relating metaboloism Metabolism of coenzymes Metabolism of coenzymes Page 78 of 159 Attorney Docket No. 2013404-01 N - Methylserotonin N - Methyltryptamine N - Methyltyramine O - Acetylcarnitine o - Aminophenol o - Hydroxyphenylacetic acid O - Phosphoserine Orotic acid Orotidine 5 ' - monophosphate pl , p4 - Di ( adenosine - 5 ' ) Pantothenic acid N - Methylserotonin N - Methyltryptamine N - Methyltyramine - Aminophenoi 2 - HPAA Orotic acid Pantothenic acid Pathway overview BCAA & aromatic amino acids BCAA & aromatic amino acids Metabolism of coenzymes BCAA & aromatic amino acids Pathway overview Lipid and amino acid metabolism BCAA & aromatic amino acids BCAA & aromatic amino acids Lipid and amino acid metabolism Urea cycle relating metaboloism Nucleotide metabolism Nucleotide metabolism Phenaceturic acid Phenylpyruvic acid Phosphoenolpyruvic acid p - Hydroxyphenylacetic acid p - Hydroxyphenylpyruvic acid Phytic acid divalent Phenaceturic acid 4 - HPAA Phytic acid Nucleotide metabolism Metabolism of coenzymes BCAA & aromatic amino acids BCAA & aromatic amino acids BCAA & aromatic amino acids Urea cycle relating metaboloism Central carbon metabolism Lipid and amino acid metabolism BCAA & aromatic amino acids BCAA & aromatic amino acids Pathway overview Page 79 of 159 Pipecolic acid Propionic acid Propionyl CoA_divalent Page 80 of 1 Attorney Docket No. 2013404-01 Pipecolic acid Propionic acid Propanoyl - CoA Lipid and amino acid metabolism Lipid and amino acid metabolism Urea cycle relating metaboloism Lipid and amino acid metabolism / BCAA & aromatic amino acid Lipid and amino acid metabolism / BCAA & aromatic amino acids / Nucleotide metabolism Central carbon metabolism / Nucleotide metabolism Urea cycle relating metaboloism Metabolism of coenzymes Metabolism of coenzymes Metabolism of coenzymes Pyridoxal 5 - phosphate Pyridoxamine 5 ' - phosphate Pyruvic acid Quinolinic acid Ribose 1 - phosphate Pyridoxamine - P Pyruvic acid Quinolinic acid Metabolism of coenzymes Metabolism of coenzymes Central carbon metabolism / Urea cycle relating metaboloism / Lipid and amino acid metabolism BCAA & aromatic amino acids / Metabolism of coenzymes Metabolism of coenzymes Pathway overview Attorney Docket No. 2013404-01 Ribose 5 - phosphate Ribulose 5 - phosphate S - Adenosylhomocysteine S - Adenosylmethionine Sedoheptulose 7 - phosphate S - Lactoylglutathione S - Lactoylglutathione Succinic acid Succinic acid Succinic semialdehyde Succinic semialdehyde Central carbon metabolism / Metabolism of coenzymes Central carbon metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism Central carbon metabolism Lipid and amino acid metabolism BCAA & aromatic amino acids Urea cycle relating metaboloism Urea cycle relating metaboloism Urea cycle relating metaboloism Central carbon metabolism / Urea cycle relating metaboloism Urea cycle relating metaboloism † Metabolites which have been already known about pathway information were listed up . They included metaboites which were not detected in this study .

+ Abbreviated names in Pathway Map .

Page 81 of 1 § Pathway information in the metabolites .

Attorney Docket No. 2013404-01 Candidates + Appendix 1-1 . Metabolite Abbreviations Pathway Label + Succinyl CoA divalent SucCoA Taurine Taurine Taurocholic acid Taurocyamine Thiamine Taurocholic acid Taurocyamine Thiamine Thiamine diphosphate ThPP Thiamine phosphate Thr TMP Thr Thymidine Thymidine Thymine Trp Thymine Trp Pathway Index $ Central carbon metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism Metabolism of coenzymes Metabolism of coenzymes Metabolism of coenzymes Lipid and amino acid metabolism editoelcúN metabolism Nucleotide metabolism BCAA & aromatic amino acids Tryptamine Tyr Tyramine UDP Tryptamine Tyr BCAA & aromatic amino acids BCAA & aromatic amino acids Tyramine UDP UDP - glucose UDP - glucuronic acid UDP - N - acetyglucosamine UMP UDP - Glc UDP - GlcA UDP - GlcNAc UMP Uracil Urea Uric acid Uridine Urocanic acid UTP Val Uracil Urea Uric acid Uridine Urocanic acid UTP Val BCAA & aromatic amino acids Nucleotide metabolism Central carbon metabolism Central carbon metabolism Central carbon metabolism Nucleotide metabolism Nucleotide metabolism Urea cycle relating metaboloism Nucleotide metabolism Nucleotide metabolism Urea cycle relating metaboloism Nucleotide metabolism BCAA & aromatic amino acids Page 82 of 159 VanillyImandelic acid Xanthurenic acid Xanthurenic acid Xylulose 5 - phosphate u0000 - Ala u0000 - Ala Page 83 of 1 Y - Butyrobetaine Y - Glu - Cys g - Glu - Cys Attorney Docket No. 2013404-01 BCAA & aromatic amino acids Nucleotide metabolism Nucleotide metabolism BCAA & aromatic amino acids Nucleotide metabolism Nucleotide metabolism Central carbon metabolism Urea cycle relating metaboloism / Nucleotide metabolism / Metabolism of coenzymes Lipid and amino acid metabolism Urea cycle relating metaboloism Metabolites which have been already known about pathway information were listed up . They included metaboites which were not detected in this study .

+ Abbreviated names in Pathway Map . § Pathway information in the metabolites .

Attorney Docket No. 2013404-01 Appendix 1-2 . Pathway Abbreviations Pathway Label + 1 - Methylhistamine 1 - Methylnicotinamide 2 - Aminoadipic acid - Aminophenol 2 - HBA 2 - HPAA 2 - KIV 2 - OG 1 - Methylhistamine 1 - Methylnicotinamide 2 - Aminoadipic acid o - Aminophenol - Hydroxybutyric acid o - Hydroxyphenylacetic acid 3 - Methyl - 2 - oxovaleric acid 2 - Oxoisovaleric acid 2 - Oxoglutaric acid 2 - Oxoadipic acid 2 - Oxobutyric acid 2 - Oxoadipic acid 2 - Oxoleucine 2 - PG 3.5 - DI - Tyr - Aminoisobutyric acid 3 - HBA 3 - Methoxyanthranilic acid 3 - Methoxytyramine 3 - Methylcrotonyl - CoA 2 - Oxobutyric acid 4 - Methyl - 2 - oxovaleric acid 2 - Phosphoglyceric acid 3.5 - Diiodotyrosine - Aminoisobutyric acid 3 - Hydroxybutyric acid 3 - Methoxyanthranilic acid 3 - Methoxytyramine Pathway IndexS Urea cycle relating metaboloism Metabolism of coenzymes Lipid and amino acid metabolism BCAA & aromatic amino acids Lipid and amino acid metabolism BCAA & aromatic amino acids Lipid and amino acid metabolism BCAA & aromatic amino acids Central carbon metabolism / Urea cycle relating metaboloism Lipid and amino acid metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism Central carbon metabolism BCAA & aromatic amino acids BCAA & aromatic amino acids / Nucleotide metabolism Central carbon metabolism / Lipid and amino acid metabolism BCAA & aromatic amino acids BCAA & aromatic amino acids 3 - Methylcrotonyl - CoA_divalent BCAA & aromatic amino acids Page 84 of 159 Attorney Docket No. 2013404-01 3 - Methylhistidine 3 - OHAA 3 - OHKY 3 - PG 3 - Ureidopropionic acid 4 - Acetamidobutanoic acid 4 - GBA 4 - HPAA 4 - Hydroxyphenylacetaldehyde 4 - Pyridoxic acid 5 - ALA 5 - Hydroxy - IAA 5 - hydroxylysine 5 - MIAA 5 - MHTF - PG 3 - Methylhistidine 3 - Hydroxyanthranilic acid 3 - Hydroxykynurenine 3 - Phosphoglyceric acid Urea cycle relating metaboloism BCAA & aromatic amino acids BCAA & aromatic amino acids Central carbon metabolism / Lipid and amino acid metabolism Lipid and amino acid metabolism Nucleotide metabolism Pathway overview O - Phosphoserine - Ureidopropionic acid 4 - Acetamidobutanoic acid 4 - Guanidinobutyric acid p - Hydroxyphenylacetic acid 4 - Hydroxyphenylacetaldehyde Pathway overview 4 - Pyridoxic acid 5 - Amino - 4 - oxovaleric acid 5 - Hydroxyindoleacetic acid 5 - hydroxylysine 5 - Methoxyindoleacetic acid 5 - Methoxytryptamine 5 - Methyltetrahydrofolic acid 6 - Phosphogluconic acid Acetoacetyl CoA_divalent Acetyl CoA divalent Urea cycle relating metaboloism BCAA & aromatic amino acids Metabolism of coenzymes Lipid and amino acid metabolism BCAA & aromatic amino acids Lipid and amino acid metabolism BCAA & aromatic amino acids BCAA & aromatic amino acids Metabolism of coenzymes Central carbon metabolism Lipid and amino acid metabolism Central carbon metabolism / Lipid and amino acid metabolism / Metabolism of coenzymes BCAA & aromatic amino acids Page 85 of 159 Attorney Docket No. 2013404-01 Acetoacetic acid Acetoacetic acid y - Butyrobetaine ADP - Rib ADP - ribose Allantoic acid Anthranilic acid - Aminoimidazole - 4- carboxamdie ribotide O - Acetylcarnitine Allantoic acid Anserine divalent Anthranilic acid pl , p4 - Di ( adenosine - 5 ' ) Central carbon metabolism / Lipid and amino acid metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism Nucleotide metabolism Nucleotide metabolism Central carbon metabolism / Nucleotide Central carbon metabolism / Metabolism of coenzymes BCAA & aromatic amino acids Urea cycle relating metabolosim Nucleotide metabolism Central carbon metabolism / Urea cycle relating metabolosim / BCAA & aromatic amino acids Lipid and amino acid metabolism Pathway overview Nucleotide metabolism Urea cycle relating metabolosim BCAA & aromatic amino acids Nucleotide metabolism Central carbon metabolism / Urea cycle relating metabolosim Page 86 of 159 Attorney Docket No. 2013404-01 Ascorbate 2 - glucoside Ascorbate 2 - phosphate Ascorbate 2 - sulfate Ascorbic acid u0000 - Ala b - Lactate Argininosuccinic acid Ascorbate 2 - glucoside Ascorbate 2 - phosphate Ascorbate 2 - sulfate Ascorbic acid u0000 - Ala - Hydroxypropionic acid + Abbreviated names in Pathway Map .

Urea cycle relating metabolosim Metabolism of coenzymes Metabolism of coenzymes Metabolism of coenzymes Metabolism of coenzymes Urca cycle relating metabolosim Central carbon metabolism / Urea cycle relating metabolosim / Nucleotide Central carbon metabolism / Nucleotide Central carbon metabolism / Nucleotide metabolism / Metabolism of coenzymes Lipid and amino acid metabolism Metabolism of coenzymes BCAA & aromatic amino acids Metabolites which have been already known about pathway information were listed up . They included metaboites which were not detected in this study .

Page 87 of 1 § Pathway information in the metabolites .

Attorney Docket No. 2013404-01 Appendix 1-2 . Pathway Abbreviations Candidates + Carbamoyl - Asp Carbamoyl - P CDP - choline Cholic acid cis - Aconitic acid cis - Hydroxyproline Citramalic acid Citric acid CMP - NeuNAC Pathway Label + Betaine aldehyde_ + O₂H N - Carbamoylaspartic acid CDP - choline Cholic acid cis - Aconitic acid cis - Hydroxyproline Citramalic acid Citric acid CMP - N - acetylneuraminate CoA divalent Pathway Index $ Lipid and amino acid metabolism Nucleotide metabolism Urea cycle relating metaboloism / Nucleotide metabolism Urea cycle relating metaboloism Lipid and amino acid metabolism Urea cycle relating metaboloism Nucleotide metabolism Lipid and amino acid metabolism Nucleotide metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism Central carbon metabolism Urea cycle relating metaboloism Pathway overview Central carbon metabolism Urea cycle relating metaboloism Nucleotide metabolism Central carbon metabolism Central carbon metabolism / Metabolism of coenzymes Urea cycle relating metaboloism Page 88 of 159 Attorney Docket No. 2013404-01 Cys - Gly Cys - Gly Urea cycle relating metaboloism Nucleotide metabolism Urea cycle relating metaboloism / Lipid and amino acid metabolism / Metabolism of Urea cycle relating metaboloism Lipid and amino acid metabolism Lipid and amino acid metabolism Cysteic acid Cysteic acid Cysteinesulfinic acid Cysteinesulfinic acid Lipid and amino acid metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism Nucleotide metabolism 2 ' - Deoxyadenosine Nucleotide metabolism Nucleotide metabolism Nucleotide metabolism 1,3 - Diaminopropane Urea cycle relating metaboloism Nucleotide metabolism Nucleotide metabolism Nucleotide metabolism Nucleotide metabolism Deamido - NAD Dephospho - CoA D - F1P 2 ' - Deoxycytidine Deamido - NAD + 3 ' - Dephospho CoA Fructose 1 - phosphate Nucleotide metabolism Metabolism of coenzymes Metabolism of coenzymes Metabolism of coenzymes Central carbon metabolism Nucleotide metabolism Page 89 of 159 Attorney Docket No. 2013404-01 Nucleotide metabolism Dihydrofolic acid 2 ' - Deoxyguanosine Dihydroxyacetone phosphate Central carbon metabolism / Lipid and amino 3,4 - Dihydroxyphenylglycol Pathway overview 7,8 - Dihydrofolic acid Nucleotide metabolism Nucleotide metabolism acid metabolism Metabolism of coenzymes Dihydroorotic acid Dihydroorotic acid Nucleotide metabolism Nucleotide metabolism ,6 - Dimethylbenzimidazole Metabolism of coenzymes Nucleotide metabolism 2,3 - Diphosphoglyceric acid Central carbon metabolism Nucleotide metabolism N , N - Dimethylglycine Lipid and amino acid metabolism BCAA & aromatic amino acids BCAA & aromatic amino acids Nucleotide metabolism Nucleotide metabolism Nucleotide metabolism Nucleotide metabolism Nucleotide metabolism 2 ' - Deoxyuridine Nucleotide metabolism Page 90 of 159 Page 91 of 1 Erythrose 4 - phosphate Fructose 1,6 - diphosphate Fructose 6 - phosphate Nucleotide metabolism Central carbon metabolism Pathway overview Central carbon metabolism Central carbon metabolism Attorney Docket No. 2013404-01 Abbreviated names in Pathway Map .

† Metabolites which have been already known about pathway information were listed up . They included metaboites which were not detected in this study .

§ Pathway information in the metabolites .

Attorney Docket No. 2013404-01 Appendix 1-2 . Pathway Abbreviations Pathway Label + FAD FMN Folic acid Formylanthranilate Fumaric acid GIP G3P G6P GABA GallP GAP GDP GDP - fucose GDP - Man Gensigen g - Glu - Cys Glc - 6p GlcNAc GlcNAc - P Gln Glu Candidates + FAD divalent FMN Folic acid Formylanthranilic acid Fumaric acid Glucose 1 - phosphate Glycerol 3 - phosphate Glucose 6 - phosphate GABA Galactose 1 - phosphate Glyceraldehyde 1 - phosphate GDP GDP - fucose GDP - mannose 2,5 - Dihydroxybenzoic acid Y - Glu - Cys Glucosamine 6 - phosphate N - Acetylglucosamine N - Acetylglucosamine 1 - phosphate Gln Glu Pathway Index $ Metabolism of coenzymes Metabolism of coenzymes Metabolism of coenzymes Pathway overview Central carbon metabolism / Urea cycle relating metaboloism Central carbon metabolism Central carbon metabolism / Lipid and amino acid metabolism Central carbon metabolism Urea cycle relating metaboloism Central carbon metabolism Central carbon metabolism / Lipid and amino acid metabolism Nucleotide metabolism Central carbon metabolism Central carbon metabolism Pathway overview Urea cycle relating metaboloism Central carbon metabolism Central carbon metabolism Central carbon metabolism Urea cycle relating metaboloism Central carbon metabolism / Urea cycle relating metaboloism Page 92 of 159 Attorney Docket No. 2013404-01 Glucosamine Glucosaminic acid Glucuronic acid Glucosamine Glucosaminic acid Glucuronic acid Glutaryl - CoA Glyceric acid Glutaryl - CoA Gly Gly Glyceric acid Glycocholic acid Glycolic acid Glycocholic acid Glycolic acid Glyoxylic acid Glyoxylic acid GMP GMP GPCho GSH Guanidoacetic acid GSSG GTP Guanine Guanosine His Histamine HMG - CoA Homocysteine HPP HVA Hydroxyproline Hypotaurine Glycerophosphocholine Glutathione ( GSH ) Glutathione ( GSH ) _divalent GTP Guanidoacetic acid Guanine Guanosine His Histamine HMG CoA divalent Homocysteine p - Hydroxyphenylpyruvic acid Homovanillic acid Hydroxyproline Hypotaurine Central carbon metabolism Central carbon metabolism Central carbon metabolism Lipid and amino acid metabolism Urea cycle relating metaboloism / Lipid and amino acid metabolism Central carbon metabolism / Lipid and amino acid metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism Nucleotide metabolism Lipid and amino acid metabolism Urea cycle relating metaboloism Urea cycle relating metaboloism Nucleotide metabolism Urea cycle relating metaboloism Nucleotide metabolism Nucleotide metabolism Urea cycle relating metaboloism Urea cycle relating metaboloism Lipid and amino acid metabolism Lipid and amino acid metabolism BCAA & aromatic amino acids BCAA & aromatic amino acids Urea cycle relating metaboloism Lipid and amino acid metabolism Page 93 of 159 Attorney Docket No. 2013404-01 Hypoxanthine IDP Ile IMP Imidazole - 4 - acetic acid Imidazole - 4 - acetic acid Indole - 3 - acetic acid Indole - 3 - acetaldehyde Inosine Isobutyryl - CoA Isocitric acid ITP KMTB Kynurenic acid Kynurenine Lactic acid Hypoxanthine IDP Ile IMP Indole - 3 - acetic acid Indole - 3 - acetaldehyde Inosine Isobutyryl CoA_divalent Isocitric acid ITP - Methylthio - 2 - oxobutyric acid Kynurenic acid Kynurenine Lactic acid Malic acid Leu Leu Lys Lys Malic acid Malonyl - CoA Malonyl CoA_divalent - Nucleotide metabolism Nucleotide metabolism BCAA & aromatic amino acids Urea cycle relating metaboloism Nucleotide metabolism BCAA & aromatic amino acids BCAA & aromatic amino acids Nucleotide metabolism Lipid and amino acid metabolism / BCAA & aromatic amino acids Central carbon metabolism Nucleotide metabolism Lipid and amino acid metabolism BCAA & aromatic amino acids BCAA & aromatic amino acids Central carbon metabolism / Urea cycle relating metaboloism BCAA & aromatic amino acids Lipid and amino acid metabolism Central carbon metabolism / Urea cycle relating metaboloism Central carbon metabolism / Lipid and amino acid metabolism Page 94 of 159 Attorney Docket No. 2013404-01 Man1P Man6P ManNAc Melatonin Met Mannose 1 - phosphate Central carbon metabolism Central carbon metabolism Mannose 6 - phosphate N - Acetylmannosamine Melatonin Met Abbreviated names in Pathway Map .

Central carbon metabolism BCAA & aromatic amino acids Lipid and amino acid metabolism Metabolites which have been already known about pathway information were listed up . They included metaboites which were not detected in this study . Page 95 of 1§ Pathway information in the metabolites .

Appendix 1-2 . Pathway Abbreviations Attorney Docket No. 2013404-01 Pathway Label + Methylmalonic acid Methylmalonic acid 3 - Methoxy - N - Acetylaspartic acid N - Acetylputrescine N - AcGlu N - Acorn 1 - Methyl - 4 - imidazoleacetic acid 3 - Iodotyrosine 5 ' - Deoxy - 5 ' - methylthioadenosine N - Acetylaspartic acid N - Acetylputrescine N - Acetylglucosamine 6 - phosphate N - Acetylglutamic acid N - Acetylornithine NAD + NAD + NADP + NADP + N - Formyl aspartic acid Nicotinic acid NADPH divalent N - Acetylneuraminic acid N - Formylaspartic acid Nicotinic acid Pathway Index $ Lipid and amino acid metabolism / BCAA & aromatic amino acids BCAA & aromatic amino acids Urea cycle relating metaboloism BCAA & aromatic amino acids Urea cycle relating metaboloism Urea cycle relating metaboloism Urea cycle relating metaboloism Central carbon metabolism Urea cycle relating metaboloism Urea cycle relating metaboloism Central carbon metabolism / Metabolism of coenzymes Central carbon metabolism / Metabolism of coenzymes Central carbon metabolism / Metabolism of coenzymes Central carbon metabolism / Metabolism of coenzymes Central carbon metabolism Urea cycle relating metaboloism Metabolism of coenzymes Metabolism of coenzymes Page 96 of 159 Attorney Docket No. 2013404-01 N - Methylserotonin N - Methyltryptamine N - Methyltyramine Orotic acid Pantothenic acid Phenaceturic acid Phytic acid Pipecolic acid N - Methylserotonin N - Methyltryptamine N - Methyltyramine Orotic acid Orotidine 5 ' - monophosphate - Oxoproline 1 - Pyrroline 5 - carboxylic acid Pantothenic acid Phosphoenolpyruvic acid Phenaceturic acid 2 - Phenylethylamine Phenylpyruvic acid Phytic acid divalent Pipecolic acid Pyridoxal 5 - phosphate - Hydroxytryptophan Metabolism of coenzymes Pathway overview BCAA & aromatic amino acids BCAA & aromatic amino acids BCAA & aromatic amino acids Pathway overview Urea cycle relating metaboloism Nucleotide metabolism Nucleotide metabolism Urea cycle relating metaboloism Urea cycle relating metaboloism Metabolism of coenzymes Central carbon metabolism BCAA & aromatic amino acids BCAA & aromatic amino acids BCAA & aromatic amino acids BCAA & aromatic amino acids Urea cycle relating metaboloism Lipid and amino acid metabolism Pathway overview Lipid and amino acid metabolism Metabolism of coenzymes Lipid and amino acid metabolism BCAA & aromatic amino acids Urea cycle relating metaboloism Page 97 of 159 Attorney Docket No. 2013404-01 Phytic acid_divalent Pipecolic acid Pyridoxal 5 - phosphate - Hydroxytryptophan Propionyl CoA_divalent Phytic acid Propanoyl - CoA Propionic acid Propionic acid Pyridoxamine - P Pyruvic acid Pyridoxamine 5 ' - phosphate Pyruvic acid Quinolinic acid Ribose 1 - phosphate Ribose 5 - phosphate Pathway overview Lipid and amino acid metabolism Metabolism of coenzymes Lipid and amino acid metabolism BCAA & aromatic amino acids Urea cycle relating metaboloism Lipid and amino acid metabolism / BCAA & aromatic amino acids / Nucleotide metabolism Lipid and amino acid metabolism / BCAA & aromatic amino acids Central carbon metabolism / Nucleotide Urea cycle relating metaboloism Metabolism of coenzymes Metabolism of coenzymes Metabolism of coenzymes Metabolism of coenzymes Central carbon metabolism / Urea cycle relating metaboloism / Lipid and amino acid BCAA & aromatic amino acids / Metabolism of coenzymes Pathway overview Central carbon metabolism / Metabolism of Page 98 of 159 Attorney Docket No. 2013404-01 S - Lactoylglutathione Succinic acid Ribulose 5 - phosphate Sedoheptulose 7 - phosphate S - Adenosylhomocysteine S - Adenosylmethionine S - Lactoylglutathione Succinic acid Succinic semialdehyde Succinic semialdehyde Metabolism of coenzymes Central carbon metabolism Central carbon metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism BCAA & aromatic amino acids Urea cycle relating metaboloism Urea cycle relating metaboloism Urea cycle relating metaboloism Central carbon metabolism / Urea cycle relating metaboloism Urea cycle relating metaboloism Page 99 of 1 Adenylosuccinic acid Nucleotide metabolism Abbreviated names in Pathway Map . Metabolites which have been already known about pathway information were listed up . They included metaboites which were not detected in this study .

$ Pathway information in the metabolites .

Succinyl AMP Attorney Docket No. 2013404-01 Appendix 1-2 . Pathway Abbreviations Pathway Label + Taurocholic acid Candidates * Succinyl CoA_divalent 3.3 ' , 5 - Triiodothyronine Taurocholic acid dTDP - glucose Thamine diphosphate Thamine phosphate б№ , б№¸б№ - Trimethyllysine TDP - Glc UDP - Glc UDP - GlcA UDP - glucuronic acid UDP - GlcNAc Uric acid Uric acid UDP - glucose UDP - N - acetyglucosamine Pathway Index $ Central carbon metabolism BCAA & aromatic amino acids Lipid and amino acid metabolism Lipid and amino acid metabolism Lipid and amino acid metabolism Pathway overview Metabolism of coenzymes Metabolism of coenzymes Lipid and amino acid metabolism Nucleotide metabolism Nucleotide metabolism Metabolism of coenzymes Lipid and amino acid metabolism BCAA & aromatic amino acids BCAA & aromatic amino acids BCAA & aromatic amino acids BCAA & aromatic amino acids Nucleotide metabolism Central carbon metabolism Central carbon metabolism Central carbon metabolism Nucleotide metabolism Nucleotide metabolism Urea cycle relating metaboloism Nucleotide metabolism Nucleotide metabolism Page 100 of 159 Attorney Docket No. 2013404-01 Urocanic acid Urocanic acid Vanillylmandelic acid Xylulose 5 - phosphate Xanthurenic acid Xanthurenic acid Urea cycle relating metaboloism Nucleotide metabolism BCAA & aromatic amino acids BCAA & aromatic amino acids Central carbon metabolism Nucleotide metabolism Nucleotide metabolism BCAA & aromatic amino acids Nucleotide metabolism Nucleotide metabolism Page 101 of 1 Abbreviated names in Pathway Map .

* Metabolites which have been already known about pathway information were listed up . They included metabolites which were not detected in this study .

§ Pathway information in the metabolites .

Attorney Docket No. 2013404-01 Appendix 1-3 Metabolites of Interest C10H1003S C32H300C6H101 - Methyl - 4 - imidazoleacetic acid - Methyladenosine - Methylhistamine - Methylhistidine - Methylhistidine - Methylhistidine 3 - Methylhistidine - Methylnicotinamide - Palmitoyl - glycero - 3 - phosphocholine - 1,2 - Dipalmitoyl - glycero - 3 - phosphoethanolamine - 1,2 - Dipalmitoyl - glycero - 3 - phosphoethanolamine - 11 - amino - undecanoic acid ( S ) -HETE α71 - Hydroxyprogesterone α71 - Hydroxyprogesterone - Deoxycorticosterone - 1H - Imidazole - 4 - propionic acid 1H - Imidazole - 4 - propionic acid ; 1 - Methyl - 4 - imidazoleacetic acid 2- ( beta - D - Glucosyl ) -sn - glycerol - Aminoadipic acid - Aminoisobutyric acid 2 - Aminobutyric acid - Arachidonoylglycerol - Diethylaminoethanol - Hydroxy - 4 - methylvaleric acid - Hydroxybutyric acid - Hydroxyglutaric acid - Hydroxyisobutyric acid - Hydroxyvaleric acid 2 - Methylserine - Keto - glutaramic acid 2 - Oxoarginine - Oxoglutaric acid - Oxoisovaleric acid - Oxoisovaleric acid ; 2 - Oxovaleric acid - Phosphoglyceric acid - Phosphoglyceric acid 3 - Phosphoglyceric acid - Thiopheneacetic acid 2,3 - Diphosphoglyceric 2,6 - Diaminopimelic acid acid 2 ' - Deoxycytidine Page 102 of 159 Attorney Docket No. 2013404-01 2 ' - Deoxyuridine α02 - Hydroxyprogesterone - Deoxycortisol - 21 - Hydroxypregnenolone 3- ( 4 - Hydroxyphenyl ) propionic acid 2- ( 4 - Hydroxyphenyl ) propionic acid 3- ( 3 - Hydroxyphenyl ) propionic acid 3- ( 4 - Hydroxyphenyl ) propionic acid : 2- ( 4 - Hydroxyphenyl ) propionic acid : 3- ( 3 - Hydroxyphenyl ) propionic acid ; Tropic acid ; 3- ( 2 - Hydroxyphenyl ) propionic acid ; m - Ethoxybenzoic acid : 3 - Phenyllactic acid : p- Methoxyphenylacetic acid - cis - Hydroxy - be - Caroten - 3 ' - one - Guanidinopropanoate - Hydroxy - 2 - methyl - 4 - pyrone - Hydroxy - 3 - methylglutaric acid - Hydroxy - 3 ' , 4 ' - didehydro - y.ß - carotene - Hydroxybutyric acid - Hydroxybutyric acid ; 2 - Hydroxybutyric acid ; 2 - Hydroxyisobutyric acid - Hydroxybutyric acid 2 - Hydroxyisobutyric acid - Hydroxyglutaric acid - Hydroxytetradecanoic acid - 3 - Indoxylsulfuric acid - Mercaptolactic acid - Methylhistamine : 1 - Methylhistamine - Methylhistidine ; 1 - Methylhistidine - oxocholic acid - Phosphoglyceric acid - Urcidopropionic acid 3,4 - Dihydroxyhydrocinnamic acid ; Homovanillic acid ; Hydroxyphenyllactic acid - Acetamidobutanoic acid - Guanidinobutyric acid - Hydroxyquinoline - Methyl - 2 - oxovaleric acid - Methyl - 2 - oxovaleric acid - Oxohexanoic acid - Methyl - 2 - oxovaleric acid ; 3 - Methyl - 2 - oxovaleric acid ; 2 - Oxohexanoic acid - Oxopyrrolidine - 2 - carboxylic acid - Amino - 4 - hydroxynaphthalene - 1,3 - disulfonic acid - Amino - 4 - oxovaleric acid - Hydroxyindoleacetic acid - Hydroxylysine - Hydroxypentanoic acid : Àf - Hydroxyisovaleric acid ; 2 - Hydroxyvaleric acid - Hydroxytryptophan - Isopropyl - 2 - deoxyuridine triphosphate Page 103 of 159 Attorney Docket No. 2013404-01 - Methoxyindoleacetic acid ; Indole - 3 - lactic acid - Methyl - 2 ' - deoxycytidine - Oxoproline α5 - Cholestan - 3 - one - 5a - Cholestan - 3 - one - α5 - Pregnane - 3,20 - dione acid 6 - Hydroxyhexanoic - Hydroxyhexanoic acid ; 2 - Hydroxy - 4 - methylvaleric acid - Hydroxynicotinic acid - Dehydrocholesterol - Dehydrocholesterol - Dehydrocholesterol - Desmosterol - 7 - Dehydrocholesterol - Desmosterol - 7 - Methoxy - 2 - methylisoflavone - Methylguanine - Methylguanine 3 - Methylguanine 7,8 - Dihydrobiopterin 7.8 - Dihydroneopterin Abietic acid Abietic acid - Abietic acid - AC ( 10 : 0 ) AC ( 12 : 0 ) -AC ( 12 : 0 ) -AC ( 12 : 1 ) AC ( 12 : 1 ) -AC ( 12 : 1 ) -AC ( 13 : 1 ) AC ( 13 : 1 ) -AC ( 14 : 0 ) -AC ( 14 : 0 ) -AC ( 14 : 1 ) -AC ( 14 : 1 ) -AC ( 14 : 1 ) -AC ( 14 : 1 ) -AC ( 14 : 2 ) -AC ( 14 : 2 ) -AC ( 14 : 2 ) -AC ( 14 : 3 ) -AC ( 14 : 3 ) - Page 104 of 159 Attorney Docket No. 2013404-01 AC ( 14 : 3 ) -AC ( 14 : 3 ) -AC ( 15 : 0 ) -AC ( 15 : 0 ) -AC ( 16 : 1 ) AC ( 16 : 2 ) -AC ( 16 : 2 ) -AC ( 17 : 0 ) -AC ( 17 : 0 ) -AC ( 17 : 1 ) AC ( 18 : 0 ) AC ( 18 : 1 ) AC ( 18 : 2 ) -AC ( 18 : 2 ) -AC ( 20 : 0 ) AC ( 20 : 1 ) AC ( 22 : 0 ) Acetohydroxamic acid Gly ADMA : SDMA ADP ADP - ribose AEA ( 22 : 6 ) Ala ala ser / gly thr Aminoacetone AMP AMP : dGMP Anandamide ANDS ( C - SCOPE IS ) Anserine Arachidic acid Arachidonic acid Arg Argininosuccinic acid Ascorbic acid Asiatic acid Asiatic acid - Asn Asp Asp Asp Pro Ser Asp Gly His Asp Asp Leu Asn Arg Asp - Pro Page 105 of 159 Attorney Docket No. 2013404-01 ATP Baicalcin Behenic acid Betaine Betaine aldehyde + HBetulinic acid Betulinic acid - Biopterin Biotin Butyrylcarnitine C : C C3H8N4O C4H7NC5H12N2C5H6C6H10C6H11NC6H12N2C7H9N3C8H17NO C8H18N2C9H18NCAMP Campesterol Carbachol Carboxymethyllysine Carnitine Carnosine Carnosine His - Ala : Ala - His Chenodeoxycholic acid Cholesterol Cholesterol sulfate Cholic acid Choline cis - 11 - Eicosenoic acid cis - 11,14 - Eicosadienoic acid - ﻭ cis - 11.14 - Eicosadienoic acid - ﻭ cis - 4,7,10,13,16,19 - Docosahexaenoic acid cis - 5,8,11,14,17 - Eicosapentaenoic acid epa cis - 8,11,14 - Eicosatrienoic acid cis - Aconitic acid Citric acid Citrulline Page 106 of 159 Attorney Docket No. 2013404-01 Corosolic acid Cortexolone Corticosterone - Deoxycortisol - Cortisol - Hydroxycorticosterone Humulone Creatine Creatinine Crotonic acid CSA : CSA Cyclodopa glucoside Cyclohexylamine Cys Cys ysČ Asn Asn Cystathionine Cysteine glutathione disulfide Cystine Cytidine Cytosine Daidzein Dansyl acid ( C - SCOPE IS ) Deoxycholic acid Dethiobiotin dGDP : ADP dGTP : ATP Diethanolamine Dimethylaminoethanol DOPA DPA : DPA Dyphylline Ectoine Erucic acid Ethanolamine Ethanolamine phosphate Ethyl arachidonate Ethyl glucuronide FA 16 : FA C18 : FA ( 12 : 0 ) FA ( 13 : 0 ) FA ( 14 : 1 ) FA ( 14 : 1 ) -Page 107 of 159 Attorney Docket No. 2013404-01 FA ( 14 : 2 ) -FA ( 14 : 2 ) -FA ( 14 : 3 ) FA ( 15 : 0 ) FA ( 15 : 0 ) -FA ( 15 : 1 ) FA ( 15 : 1 ) -FA ( 16 : 2 ) -FA ( 16 : 2 ) -FA ( 16 : FA ( 16 : 3 ) -FA ( 17 : 0 ) FA ( 17 : 1 ) FA ( 17 : 2 ) FA ( 17 : 3 ) FA ( 19 : 0 ) FA ( 19 : 0 ) -FA ( 19 : 1 ) FA ( 19 : 2 ) FA ( 20 : 3 ) FA ( 22 : 2 ) FA ( 22 : 3 ) -FA ( 22 : 3 ) -FA ( 22 : 4 ) -FA ( 22 : 4 ) -FA ( 22 : 5 ) -FA ( 22 : 5 ) -FA ( 24 : 0 ) FA ( 24 : 2 ) FA ( 24 : 4 ) FA ( 24 : 5 ) -FA ( 24 : 5 ) -Flavanone Formiminoglutamic acid Formononetin Fucosyl tryptophan Fucosyl - Lysine Fumaric acid Ąƒ - Ala fA - Butyrobetaine fA - Glu - Gly fA - Glu - Met Aƒ - Glu - Phe Page 108 of 159 Attorney Docket No. 2013404-01 fA - Glu - Ser Aƒ - Glu - Tyr fA - Glu - Val - Gly GABA GABA 3 - Aminoisobutyric acid Galactosylhydroxylysine Galacturonic acid - Glucuronic acid - Galacturonic acid : Glucuronic acid Gamma - Glu - Gln GDP Genistein Gln Glu Glu ; lsoglutamic acid ; threo - fA - Methylaspartic acid ; N - Methylaspartic acid N - Acetylserine Glucaric acid Gluconic acid Gluconolactone Glucosamine Glucosamine 6 - sulfuric acid Glucose 6 - phosphate Glucosyl - glycerol Glutaric acid Methylsuccinic acid Glutaric acid Methylsuccinic acid Glutathione ( GSSG ) _divalent Gly Glv Lvs Gly - Ala Gly - Asp Gly - Asp Asp - Gly Gly - Leu N - Acetyllysine ; Val - Ala ; Ala - Val ; Leu - Gly Glyceric acid Glycerol Glycerol 3 - phosphate Glycerophosphocholine Glycitein Glycochenodeoxycholic acid Glycocholic acid Glycodeoxycholic acid Glyoxylic acid GMP Page 109 of 159 Attorney Docket No. 2013404-01 Guanidinosuccinic acid Guanidoacetic acid Gulonolactone : Gluconolactone Hecogenin Heneicosanoic acid - Methylarachidic acid Heptadecanoic acid - FA ( 17 : 0 ) -Heptadecanoic acid - FA ( 17 : 0 ) -Heptanoic acid Hexanoic acid Hippuric acid Hippuric acid ( benzyl glycine ) His His Pro Ser Val Arg Tyr Thr His - Asp Histamine Homo Arginine Homo Proline Betaine Homocarnosine Homocitrulline Homocysteinesulfinic acid Homoserine Homovanillic acid Hydroxyphenyllactic acid Hydroxyindole Hydroxyoctanoic acid Hydroxyprogesterone caproate Hydroxyproline Hydroxytetradecanoic acid Hyodeoxycholic acid Hypotaurine IDP Ile lle : Leu : Alloisoleucine lle Leu : A - Leucine : Alloisoleucine ; 6 - Aminohexanoic acid Imidazole - 4 - acetic acid Imidazolelactic acid IMP Indole - 3 - acetic acid Indole - 3 - carboxaldehyde Page 110 of 159 Attorney Docket No. 2013404-01 Indole - 3 - lactic acid - 5 - Methoxyindoleacetic acid - Indole - 3 - lactic acid ; 5 - Methoxyindoleacetic acid Indole - 3 - propionic acid Indole - 3 - propionic acid ( IPA ) Inosine 2 ' , 3 ' - cyclic phosphate cIMP Isethionic acid Isobutyrylcarnitine Butyrylcarnitine Isocitric acid Isoglutamic acid Isoliquiritigenin - Isoliquiritigenin - Isoliquiritigenin - Isonicotinamide : Nicotinamide Isovalerylalanine - N - Acetylleucine - Isovalerylalanine ; N - Acetylleucine Isovalerylcarnitine Kynurenic acid Kynurenine Lactamide Lactic acid Lanosterol Lauric acid Leu Leukotriene BLinoleic acid Linolenic acid Linolevl ethanolamide Liquiritigenin Lithocholic acid Luteolin Lys Lys - Asp Lys - Val Malic acid Mannosamine MCA Met Methionine sulfone Methionine sulfoxide Methylmalonic acid ; Succinic acid Page 111 of 159 Attorney Docket No. 2013404-01 Morpholine Mucic acid Myristic acid Myristic acid 14 : Myristoleic acid N- ( 1 - Deoxy - 1 - fructosyl ) valine N - Acetyl - beta - alanine N - Acetyl - p - alanine N - Acetylalanine N - Acetylalanine ; N - Acetyl - Àƒ - alanine N - Acetylasparagine N - Acetylaspartic acid N - Acetylgalactosamine : N - Acetylglucosamine ; N - Acetylmannosamine N - Acetylglucosamine N - Acetylglutamic acid N - Acetylglutamine N - Acetylglycine N - Acetylhistidine N - Acetylleucine N - Acetyllysinc N - Acetylmethionine N - Acetylneuraminic acid N - Acetylornithine N - Acetylphenylalanine N - Acetyltryptophan N - Acetyltyrosine N - Carbamylglutamate N - Carboxymethylserine N - Ethylmaleimide + H2O N - Formylaspartic acid N - Formylglycine N - Formylmethionine N - Glycolylneuraminic acid N - Hydroxy - L - tryptophan N - Methylethanolamine phosphate N - Methylproline N , N - Dimethylglycine N ' - Formylkynurenine N1 - Acetylspermidine N1 - Acetylspermidine ; N8 - Acetylspermidine N1 - Methyl - 4 - pyridone - 5 - carboxamide N1 - Methylguanosine N5 - Ethylglutamine Page 112 of 159 Attorney Docket No. 2013404-01 N5 - Ethylglutamine : N - Acetylornithine N6 - Acetyllysine N6 - Methyl - 2 ' - deoxyadenosine N6 - Methyllysine N6 , N6 , N6 - Trimethyllysine Naringenin Nervonic acid Nervonyl carnitine Propyl Betaine ( Triethylamine ) N f - Formylkynurenine Nicotinamide no matches Norophthalmic acid Norvaline ; 2 - Amino - 2 - methylbutyric acid ; 5 - Aminovaleric acid ; Val Noo - Methylarginine O - Acetylcarnitine O - Acetylhomoserine o - Coumaric acid p - Coumaric acid o - Hydroxybenzoic acid Oleanolic acid Oleic acid Oleovl ethanolamide AEA ( 18 : 1 ) Ophthalmic acid Ornithine Orotidine : Uridine : Pseudouridine p - Hydroxyphenylpyruvic acid p - Hydroxyphenylpyruvic acid ; Caffeic acid Palmitic acid Palmitoleic acid Palmitoylcarnitine Palmitoylethanolamide Pantothenic acid Penicillamine Penicillamine : Met Pentadecanoic acid Phe Phe Met His Glu Phe Phe Trp Trp Phe - Thr Phenaceturic acid Phenol Page 113 of 159 Attorney Docket No. 2013404-01 Phenyl Sulfate Phenylpyruvic acid Phosphocreatine Phosphoenolpyruvic acid Phosphorylcholine Picolinic acid Pipecolic acid Pipecolic acid N - Methylproline ; 1 - Aminocyclopentanecarboxylic acid Piperidine Pro Pro - Gly ; Gly - Pro Progesterone Proline Betaine Propionylcarnitine XC00Propionylcarnitine ; XC00Prostaglandin E1-Prostaglandin D1-Prostaglandin E1-Prostaglandin D1-Putrescine Pyridoxal Pyrrolidine Pyruvic acid Retinol Vit A Retinol - Riboflavin Ribose 5 - phosphate Ribulose 5 - phosphate Ribulose 5 - phosphate ; Ribose 1 - phosphate ; Xylulose 5 - phosphate Ricinoleic acid Ricinoleic acid 18 : 1 Hydroxy Ricinoleic acid - Ricinoleic acid - S - Acetyldihydrolipoamide ( XC0086 ) S - Adenosylhomocysteine S - Adenosylmethionine S - Carboxymethylcysteine S - Methylcysteine S - Methylglutathione S - Methylmethionine S - Sulfocysteine Page 114 of 159 Attorney Docket No. 2013404-01 Sarcosine SDMA Sedoheptulose 7 - phosphate Ser Ser Ala / Thr gly Ser Glu Pro Thr Asp Pro Serotonin Sitosterol Spermidine Spermine Sphinganine Sphingomyelin ( d18 : 1/16 : 0 ) -Sphingomyelin ( d18 : 1/16 : 0 ) -Sphingomyelin ( d18 : 1/18 : 0 ) -Sphingomyelin ( d18 : 1/18 : 0 ) -Sphingosine Stearic acid Stearidonic acid Stearoyl ethanolamide Stigmasterol - Stigmasterol - Succinic acid Sulfaguanidine ( C - SCOPE IS ) Sulfolithocholylglycine Taurine Taurochenodeoxycholic acid Taurocholic acid Taurodeoxycholic acid Taurolithocholic acid Tauroursodeoxycholic acid Terephthalic acid Theobromine ; Aminophylline : Paraxanthine Thiamine Thiamine phosphate Thr Thr Ala Ala Thr Asp or Ser Glu threo - 3 - Hydroxyaspartic acid threo - 3 - Hydroxyaspartic acid - threo - 3 - Hydroxyaspartic acid - Threonic acid Thymidine Thyroxine Page 115 of 159 Attorney Docket No. 2013404-01 trans - Glutaconic acid trans - Glutaconic acid ; ltaconic acid Tricosanoic acid Trigonelline Trilaurin Trimesic acid : Trimesic acid Trimethylamine Trimethylamine N - oxide Trimethylaminoacetone Trp Tyr UDP - galactose UDP - glucose Uracil Urea Uric acid Uridine Urocanic acid Uridine Pseudouridine Ursodeoxycholic acid Val XA00XA00XA00XA00XA00XA00XA00XA00XA00XA00XA00XA00XA00Xanthosine XC00XC00XC00XC00XC00XC0054 ; XC0055 ; Áf - Glu - Gly XC00XC00Page 116 of 159 Attorney Docket No. 2013404-01 XC00XC00XC00XC00XC00XC00XC00XC00XCO1XC01XC0107 ; fA - Glu - Gln XC0114 fA - Glu - His XC01XC01XC01XC01XC01XC01XC01XC01XC01XC01Zeaxanthin α - Tocopherol α - Tocopherol acetate u0000 - Ala u0000 - Estradiol α71 - Estradiol B - Hydroxyisovaleric acid y - Butyrobetaine -Glu - Ala y - Glu - Arg y - Glu - Asp y - Glu - Asn -Glu - Citrulline -Glu - Gln y - Glu - Glu -Glu - Gly y - Glu - His y - Glu - Leu y - Glu - Lys y - Glu - Met y - Glu - Ornitine Page 117 of 159 Attorney Docket No. 2013404-01 y - Glu - Phe y - Glu - Ser y - Glu - Taurine y - Glu - Thr y - Glu - Trp y - Glu - Tyr y - Glu - Val y - Glu - Val - Gly y - Tocopherol Page 118 of 159 Attorney Docket No. 2013404-01 Appendix 2. Known - Unknown Peaks The " known - unknown " peaks with out annotation based on the chemical standards are shown in the label of " XA / XC " in result tables . Among them , several peaks which have been detected from a variety of biological samples are listed in Appendix 2 .

Candidate compounds HMT ID Peak ID Mode * mass PubChem database HMDB database M90001 XA0001 Anion 107.9M90002 XA00Anion 111.993 757M90003 XA0003 Anion M90004 XA0004 Anion 125.999 78145.038 440726 : 48 HMDB01511389478 ; 125409 ; 135191 ; 439195 : 439203 : 439204 : 439205 : 439240 : 439245 : M900439508 : 439678 : 439731 : XA0005 Anion 150.0 HMDB00098 ; HMDB00283 ; HMDB00366 ; HMDB00621 ; HMDB00646 ; HMDB00751 ; , 439764 : 440921 : 441474 : HMDB01644 ; HMDB03371 ; 441481 : 441482 : 447347 : HMDB12194 ; HMDB1235460157 ; 5460291 ; 5779 ; 6027 ; 619 : 69M90006 XA0006 Anion M90007 XA0007 Anion M90008 XA0008 Anion M90009 XA0009 Anion M90010 XA0010 Anion M90011 XA0011 Anion M90012 XA0012 Anion M90013 XA0013 Anion M90014 XA0014 Anion M90015 XA0015 Anion M90016 XA0016 Anion M90017 XA0017 Anion 150.0152.0154.003 1034 ; 150865 ; 4401 154.026 19 ; 3469 ; 4696 ; 155.035 439436 ; 440231 ; 4402165.0 HMDB00152 ; HMDB00397 ; HMDB018 167.025 HMDB064173.999 4765 : 744174.016 440667 ; 444212 ; 4784 HMDB00958 ; HMDB012174.1186.0187.121 173 : 52820 Page 119 of 159 Attorney Docket No. 2013404-01 M90018 XA0018 Anion M90019 XA0019 Anion 188.115 440139 ; 92832 ; 92843 ; 929 102287 ; 36681 ; 439290 ; 192.027 440165 ; 440390 ; 447805 ; 53185 HMDB00206 ; HMDB00446 ; HMDB007 HMDB01874 ; HMDB05971 ; HMDB065 M90020 XA00 M90021 XA0021 Anion Anion 197.036 30823146355 : 439910 ; 5206 : 200.054598M90022 XA0022 Anion 200.0M90023 XA0023 Anion 208,021 6812 : 84M900M90025 XA0025 Anion XA0024 Anion 217.1224.0M90026 XA0026 Anion 225.0M90027 XA0027 Anion 228.208 11005 HMDB00806 ; HMDB022M90028 XA0028 Anion 231.5M90029 XA0029 Anion 237.0M900M90031 XA0031 Anion M90032 XA0032 Anion M90033 XA0033 Anion M90034 XA0034 Anion M90035 XA0035 Anion M90036 XA0036 Anion XA0030 Anion 238.068 119228 ; 4397240.0240.1243.087 53297342 ; 6175 ; 62HMDB000243.1255.988 546757255.988 546757M90037 XA0037 Anion 274.0 Molecular ions with positive and negative charge are measured in Cation and Anion Mode , respectively Predicted mass value was calculated as mono - valent ion .

Page 120 of 159 Attorney Docket No. 2013404-01 Appendix 2. Known - Unknown Peaks Candidate compounds HMT ID Peak ID Mode mass PubChem database HMDB database M90038 XA0038 Anion 274.045 159428M90039 XA0039 Anion 287.0M90040 XA0040 Anion 290.1M90041 XA0041 Anion 303.5M90042 XA0042 Anion 309.1M90043 XA0043 Anion 310.511954062 ; 18172 ; 5280720 ; HMDB03871 ; HMDB04706 ; , M90044 XA0044 Anion 312.229 5281026 ; 5283016 ; 5460412 ; HMDB06940 ; HMDB10201 ; ﻭ 6438758 ; 95488HMDB10208 ; HMDB102M90045 XA0045 Anion 321.0M90046 XA0046 Anion 326.5M90047 XA0047 Anion 333.0440418 ; 44224013 ; 442419 ; M90048 XA0048 Anion 334.066 HMDB11645480545 : 906588M90049 XA0049 Anion 337.0M90050 XA0050 Anion 339.010267 : 105021 : 125004 : HMDB00968 ; HMDB01047 ; M90051 XA0051 Anion 339.995 128419 ; 3036654 ; 439444 ; HMDB03514 ; HMDB06234 ; 440117 ; 440211 ; 824HMDB06235 ; HMDB068M90052 XA00M90053 XA0053 Anion M90054 XA0054 Anion M90055 XA00 Anion 343.093 109259353.0368.163 12594 : 2400HMDB01032 ; HMDB028Anion 370.006 164735 ; 469060 Page 121 of 159 Attorney Docket No. 2013404-01 M90056 XA0056 Anion 383.0M90057 XA0057 Anion 397.1M90058 XA0058 Anion 400.0M90059 XA0059 Anion 421.0M90060 XA0060 Anion 422.0M90061 XA0061 Anion 423.0M90062 XA0062 Anion 424.0M90063 XA0063 Anion 425.5M90064 XA0064 Anion 437.9M90065 XA0065 Anion 446.060 123727 HMDB015M90066 XA0066 Anion 448.141 736M90067 XA0067 Anion 495.1M90068 XA00 M90069 XA0069 Anion Anion 536.023724459 ; 23724466 ; 439536 ; HMDB01018 ; HMDB12301 ; 46174047 HMDB123536.0M90070 XA0070 Anion 537.076 1651M90071 XA0071 Anion 542.274 HMDB103M90072 XA0072 Anion 548.1M90073 XA0073 Anion M90074 XA0074 Anion M90075 XA0075 Anion M90076 XA0076 Anion M90077 XA0077 Anion M90078 XA0078 Anion M90079 XC0001 Cation 633.213 HMDB00825 ; HMDB065745.093 5884 HMDB002747.0767.117 876HMDB014785.160 643975 HMDB012841.071.073 4437M90080 XC0002 Cation 73.053 215 ; 6228 ; 67180 ; HMDB01106 ; HMDB01888 ; HMDB021M90081 XC0003 Cation 89.0M90082 XC0004 Cation 89.0 * Molecular ions with positive and negative charge are measured in Cation and Anion Mode , respectively * Predicted mass value was calculated as mono - valent ion .

Page 122 of 159 Attorney Docket No. 2013404-01 Appendix 2. Known - Unknown Peaks Candidate compounds HMT ID Peak ID Mode mass * PubChem database HMDB database M90083 XC0005 Cation 99.0M90084 XC0006 Cation 103.0M90085 XC0007 Cation 108.5M90086 XC0008 Cation 112.0M90087 XC00009 Cation 113.0M90088 XC00Cation 114.0M90089 XC0011 Cation 115.0M90090 XC0012 Cation 116.094 4393 HMDB003 HMDB121M90091 XC0013 Cation 120.0M90092 XC0014 Cation 122.5M90093 XC0015 Cation 125.0194461 : 24892813 ; 3017497 ; 4362 : 54604M90094 XC0016 Cation 128.058 440769 ; 440770 ; 935HMDB000M90095 XC0017 Cation 129.089 5M90096 XC0018 Cation 129.5M90097 XC0019 Cation 130.5M90098 XC0020 Cation 133.036 5960 ; 838HMDB117M90099 XC0021 Cation 133.0M90100 XC0022 Cation 133.0M90101 XC0023 Cation 133.0M90102 XC0024 Cation 133.1M90103 XC0025 Cation 133.5M90104 XC00M90105 XC0027 Cation M90106 XC0028 Cation M90107 XC00M90108 XC00 Cation 133.5142.1143.094 115244 : 54621Cation 143.094 115244 ; 54621Cation 144.5 Page 123 of 159 Attorney Docket No. 2013404-01 HMDB00730 ; HMDB00808 ; 160603 ; 18189 ; 439954 ; M90109 XC0031 Cation 145.073 HMDB01263 ; HMDB03681 ; 440077 ; 4408HMDB12131 ; HMDB121ﻭ M90110 XC0032 Cation M90111 XC0033 Cation 151.0M90112 XC0034 Cation 147.034 4401 151.5M901M901XC00XC0036 Cation Cation 157.109 442645 ; 44792160.084 439925 ; 4410HMDB03424906320 : 439377 ; 439389 ; M90115 XC0037 Cation 161.068 439943 ; 440550 ; 440959 ; 46173947 : 921M90116 XC00M90117 XC0039 Cation Cation 170.0172.047 656724 : 7M90118 XC0040 Cation 173.0HMDB012HMDB042M90119 XC00Cation 175.0M90120 XC00Cation 175.1M90121 XC0043 Cation 178.1M90122 XC0044 Cation 185.104 443003 ; 443845 ; 52817HMDB06348 ; HMDB065M90123 XC0045 Cation 190.0M901M90125 XC0047 Cation XC0046 Cation 190.0190.0121396 ; 4414439283 ; 992HMDB111HMDB013M90126 XC0048 Cation 190.127661 ; 443054 ; 46173773 ; M90127 XC0049 Cation 191.087 * Molecular ions with positive and negative charge are measured in Cation and Anion Mode , respectively Predicted mass value was calculated as mono - valent ion .

Page 124 of 159 Attorney Docket No. 2013404-01 Appendix 2. Known - Unknown Peaks Candidate compounds HMT ID Peak ID Mode * mass * PubChem database HMDB database M90128 XC0050 Cation 192.0M90129 XC0051 Cation 193.0M90130 XC0052 Cation 197.057 4402M90131 XC0053 Cation 203.1M90132 XC0054 Cation 204.073 26879 HMDB11162 ; HMDB116M901M90134 XC0056 Cation M90135 XC0057 Cation M90136 XC0058 Cation M90137 XC0059 Cation M90138 XC0060 Cation M90139 XC00M90140 XC0062 Cation M90141 XC0063 Cation M90142 XC0064 Cation M90143 XC0065 Cation M90144 XC0066 Cation M90145 XC00 XC0055 Cation 204.074 HMDB11162 : HMDB116204.110 128597 ; 128888 ; 57204.1208.051 5281921 ; 6763 ; 67212.115 2479 HMDB111216.073 461738Cation 217.130 107738 HMDB008218.089 151284 HMDB03764 ; HMDB062218.125 1931220.069 HMDB111220.083 144 ; 439280 ; 4425HMDB004221.0Cation 223.1M90146 XC0068 Cation 225.1M901M90148 XC0070 Cation XC0069 Cation 228.121 4411228.1M90149 XC0071 Cation 233.1M90150 XC0072 Cation 234.0190151 XC0073 Cation 234.0 HMDB11174 ; HMDB111HMDB111HMDB111HMDB111 Page 125 of 159 Attorney Docket No. 2013404-01 M90152 XC0074 Cation 236.0 M90153 XC0075 Cation 237.0128973 ; 2380 ; 439921 ; 440036 ; HMDB00633 ; HMDB00817 , 5460401 : 652 HMDB00238 ; HMDB00468 ; HMDB01195 : HMDB022M90154 XC0076 Cation 240.146 4845 ; 497870M90155 XC0077 Cation 241.6M90156 XC0078 Cation 242.1M90157 XC0079 Cation 245.1M90158 XC0080 Cation 246.1M90159 XC0081 Cation 246.1HMDB11166 ; HMDB111IIMDB11166 ; IIMDB111ﻭ M90160 XC0082 Cation 247.0M90161 XC0083 Cation 247.140 HMDB131M90162 XC0084 Cation 248.063 2955 HMDB111M90163 XC0085 Cation 248.1M901XC0086 Cation 249.084 1076 HMDB01526 ; HMDB068M90165 XC0087 Cation 253.1M90166 XC0088 Cation 254.038 681M90167 XC0089 Cation 254.089 10400039 ; 99213M90168 XC0090 Cation 255.0M90169 XC0091 Cation 255.0M90170 XC0092 Cation 256.1M90171 XC0093 Cation 257.1M90172 XC0094 Cation M901M901XC0095 Cation 258.1XC0096 Cation 260.136 103 HMDB00884 ; HMDB02331 ; HMDB048 HMDB11170 ; HMDB111 Molecular ions with positive and negative charge are measured in Cation and Anion Mode , respectively 258.084 440569 ; 650 ﻭ * Predicted mass value was calculated as mono - valent ion .

Page 126 of 159 Attorney Docket No. 2013404-01 Appendix 2. Known - Unknown Peaks Candidate compounds HMT ID Peak ID Mode * mass * PubChem database HMDB database M90175 XC00M90176 XC0098 Cation Cation 261.0261.120 181804 ; 441467 ; 4428HMDB131HMDB02248 ; HMDB04985 ; M90177 XC0099 Cation 261.131 40HMDB049 M90178 XC0100 Cation 261.131 40HMDB02248 ; HMDB04985 ; HMDB049M90179 XC0101 Cation 261.1M90180 XC0102 Cation 262.079 HMDB111M90181 XC0103 Cation M90182 XC0104 Cation M90183 XC0105 Cation M90184 XC0106 Cation M90185 XC0107 Cation M90186 XC0108 Cation M90187 XC0109 Cation 265.115 1689267.094 107795 ; 35370 ; 4410HMDB00085 ; HMDB008268.116 4396270.095 1262275.110 150914 : 25137932 HMDB05766 ; HMDB 117275.135 HMDB131276.096 69925 ; 9117 ; 928HMDB117M90188 XC0110 Cation 277.5M90189 XC0111 Cation 278.0M90190 XC0112 Cation 279.1 M90191 XC0113 Cation 281.110 733HMDB04044 ; HMDB04326 ; HMDB060M90192 XC0114 Cation 284.110 254M90193 XC0115 Cation 287.0128861 ; 441648 ; 444150 ; 68429M90194 XC0116 Cation 289.151 HMDB005 Page 127 of 159 Attorney Docket No. 2013404-01 M90195 XC0117 Cation 293.1M90196 XC0118 Cation 294.105 4400M90197 XC0119 Cation 294.1M90198 XC0120 Cation 297.044 HMDB007M90199 XC0121 Cation 297.1M90200 XC0122 Cation 302.1M90201 XC0123 Cation 305.7M90202 XC0124 Cation 308.1M90203 XC0125 Cation 308.1M90204 XC0126 Cation 309.104 439197 ; 4400HMDB00230 ; HMDB007M90205 XC0127 Cation 310.114 HMDB117M90206 XC0128 Cation 311.122 HMDB01961 ; HMDB048M90207 XC0129 Cation 319.0M902M90209 XC0131 Cation M90210 XC0132 Cation M90211 XC0133 Cation XC0130 Cation 321.098 115260 ; 4403322.1324.152 46174023 HMDB006327.1M90212 XC0134 Cation M90213 XC0135 Cation M90214 XC0136 Cation M90215 XC0137 Cation M90216 XC0138 Cation M90217 XC0139 Cation M90218 XC0140 Cation M902M90220 XC0142 Cation 335.132 123826 HMDB004336.1337.092 447123 ; 53600HMDB046349.093 11954074 ; 4405366.1383.106 23724526 HMDB009387.1XC0141 Cation 388.123 509098428.1M90221 XC0143 Cation 469.1 * Molecular ions with positive and negative charge are measured in Cation and Anion Mode , respectively * Predicted mass value was calculated as mono - valent ion .

Page 128 of 159 Attorney Docket No. 2013404-01 Appendix 3. Metabolites Detected Information • • Table 7 ' Putative Metabolites " Peak ID consists of analysis mode and number . The alphabets shows measurement mode ; Cation ( C ) and Anion ( A ) mode . • Putative metabolites listed in " Compound name " were assigned on the basis of m / z and MT .

• • • Those listed in " PubChem ID / HMDB ID / peptide " were assigned on the basis of m / z only . " N.D. " and " N.A " represent " Not Detected " and " Not Available " , respectively . " Ratio " was calculated between two indicated groups ( left : numerator right : dominator ) . " p - value " was calculated on the basis of t - test . The information about each result was indicated under the table .

Page 129 of 159 Attorney Docket No. 2013404-01 HMT DB + Relative Area Comparative Analysis Control vs Treatment C_0056 1 - Methyl - 4 - imidazoleacetic acid C_0124 1 - Methyladenosine Compound name S.D. Mean S.D. p - value 9.7E - 05 N.A. 1.2E - 04 3.5E - 05 0.8 5.8E - 05 3.4E - 06 | 5.2E - 05 4.4E - 06 | 1 - Methylhistidine 2.2E - 03 5.4E - 04 2.1E - 03 4.4E - 04 1. 3 - Methylhistidine C_0051 1 - Methylnicotinamide 2.9E - 1.4E - 04 2.4E - 04 1.2E - 04 | _0057 1H - Imidazole - 4 - propionic acid 1.2E - 2.3E - 05 | 1.0E - 04 1.9E - 05 | C_0108 2 ' - Deoxycytidine 2.1E - 1.9E - 05 [ 2.0E - 04 1.4E - 05 ] 0109 2 ' - Deoxyuridine 4.2E - 04 8.2E - 05 4.1E - 04 8.8E - 051 1. 2 - Aminoisobutyric acid C 00 2.2E - 03 5.8E - 04 2.0E - 03 5.1E - 0.027 * 2 - Aminobutyric acid A_0025 2 - Hydroxy - 4 - methylvaleric acid 4.0E - 04 3.4E - 05 2.7E - 04 1.1E - 04 1.

A_0008 2 - Hydroxybutyric acid 2.6E - 9.6E - 04 2.4E - 03 4.7E - 04 1.

A_00182 - Hydroxyvaleric acid 1.1E - 6.5E - 049.9E - 04 6.4E - A_00322 - Oxoglutaric acid 4.5E - 2.7E - 03 6.8E - 03 3.3E - A 00132 - Oxoisovaleric acid 1.1E - 1.9E - 049.2E - 04 1.9E - 04 9.2E - 04 1.1E - A_0034 3- ( 4 - Hydroxyphenyl ) propionic acid 3.1E - 4.8E - 05 2.5E - 04 8.0E - A_00093 - Hydroxybutyric acid 2.8E - 1.6E - 02 1.6E - 02 8.5E - 03 1.

Table 7 Putative Metabolites ( 1 ) Page 130 of 159 Attorney Docket No. 2013404-01 A_0067 3 - Indoxylsulfuric acid A_0024 3 - Ureidopropionic acid A 0031 4 - Acetamidobutanoic acid 4 - Methyl - 2 - oxovaleric acid 3 - Methyl - 2 - oxovaleric acid 0025 5 - Aminovaleric acid C_0074 5 - Hydroxylysine _0104 5 - Hydroxytryptophan A_0062 5 - Methoxyindoleacetic acid A_0020 5 - Oxoproline C 0043 6 - Aminohexanoic acid C_0112 7,8 - Dihydrobiopterin 0006 Acetoacetic acid 1.9E - 03 8.2E - 04 2.5E - 03 1.2E - 03 2.2E - 04 6.8E - 05 2.8E - 04 1.2E - 041 4.2E - 04 2.1E - 04 2.9E - 04 8.7E - 05 2.8E - 03 6.9E - 04 2.6E - 03 3.2E - 04 8.7E - 04 N.A. 6.7E - 04 N.A. 1.7E - 04 7.1E - 05 2.1E - 04 4.9E - 05 8.2E - 05 1.9E - 05 7.9E - 05 1.4E - 05 ] 1.8E - 04 2.9E - 05 1.9E - 04 4.4E - 05 ] 6.6E - 04 8.4E - 05 6.0E - 04 1.9E - 04 2.9E - 04 7.5E - 05 1.9E - 04 N.A.

A 01 ADP - ribose C 0007 C 00A 00C 00 Anserine divalent C 00 12.2E - 4.8E - 05 5.2E - 0615.6E - 05 1.2E - 05 3.6E - 04 1.9E - 04 2.5E - 04 4.3E - 05 4.1E - 05 N.A. 8.3E - 05 6.6E - 05 1.2E - 04 2.8E - 05 5.6E - 04 1.1E - 03 0.2 9.4E - 7.3E - 02 8.7E - 03 19.1E - 02 1.9E - 02 1.5E - 03 2.4E - 04 1.7E - 03 2.5E - 04 3.5E - 04 1.2E - 04 5.3E - 04 6.9E - 04 3.0E - 04 1.3E - 04 3.1E - 04 1.3E - 2.3E - 03 12.8E - 02 5.1E - 2.2E - 05 | 1.9E - 04 7.8E - Page 131 of 159 Attorney Docket No. 2013404-01 C_0127 Argininosuccinic acid C 0044 Asn C_0047 Asp A 0104 ATP C 0026 Betaine 9.2E - 05 2.2E - 05 8.7E - 05 6.7E - 03 3.4E - 03 1.0E - 02 1.4E - 03 3.6E - 04 1.9E - 03 4.8E - 04 3.0E - 04 4.6E - 05 1.6E - 03 2.3E - 03 2.6E - 02 7.5E - 03 2.8E - 02 1.3E - 1.3E - 05 5.8E - { ) .

C_0111 Butyrylcarnitine 1.3E - 4.8E - 04 1.6E - 03 4.3E - C_0101 Carboxymethyllysine 1.8E - 2.2E - 05 1.8E - 04 3.1E - C 0073 Carnitine 1.6E - 2.8E - 03 1.8E - 02 3.0E - C 0107 Carnosine A 0095 Cholic acid C 0014 Choline A 0044 cis - Aconitic acid A 0055 Citric acid C 0084 Citrulline C 0040 Creatine 1.2E - 04 1.1E - 05 1.1E - 04 1.1E - 05 5.0E - 03 8.0E - 03 13.8E - 03 5.0E - 03 1.1E - 02 1.4E - 03 1.0E - 02 2.5E - 03 4.8E - 03 3.8E - 04 4.9E - 03 5.1E - 04 5.7E - 02 5.4E - 03 15.6E - 02 6.8E - 03 1.6E - 02 1.5E - 03 1.8E - 02 3.0E - 03 4.4E - 02 7.4E - 03 5.6E - 02 8.4E - C 0021 Creatinine C 0106 Cystathionine C_0133 Cysteine glutathione disulfide C 0113 Cystine C_0116 Cytidine C 0016 Diethanolamine C_0119 Dyphylline C 0058 Ectoine C 0002 Ethanolamine 0030 Ethanolamine phosphate 2.4E - 03 2.2E - 04 3.0E - 03 2.6E - 04 2.2E - 04 3.0E - 05 2.3E - 04 4.8E - 05 6.2E - 03 2.6E - 03 4.9E - 03 8.0E - 04 6.1E - 03 4.2E - 04 14.9E - 03 8.8E - 04 7.5E - 04 7.9E - 05 6.6E - 04 1.6E - 04 1.4E - 04 4.1E - 05 1.3E - 04 6.9E - 05 2.8E - 03 1.0E - 03 2.7E - 03 5.0E - 04 3.4E - 04 6.6E - 05 5.0E - 04 9.9E - 05 1.3E - 03 7.6E - 04 1.1E - 03 3.2E - 04 2.4E - 04 2.4E - 05 2.4E - 04 1.2E - 0.004 ** / 0.024 * 1. 0.026 * Page 132 of 159 Attorney Docket No. 2013404-01 ID consists of analysis mode and number . ' C ' and ' A ' showed cation and anion modes , respectively .

N.D. ( Not Detected ) : The target peak or metabolite was below detection limits . N.A. ( Not Available ) : The calculation was impossible because of insufficience of the data . Putative metabolites which were assigned on the basis of m / z and MT in HMT standard compound library .

The ratio is of computed by using averaged detection values . The latter was used as denominator .

|| The p - value is computed by Welch's t - test . ( * < 0.05 , ** < 0.01 , *** < 0.001 ) The data are sorted by Compound name in ascending order .

Page 133 of 159 Attorney Docket No. 2013404-01 Table 7 Putative Metabolites ( 2 ) HMT DBt Compound name Relative Area S.D. Mean Control vs Treatment p - valuel A 00C 00 Fumaric acid .1E - 2.1E - 046.5E - 1.1E - 1.1E - 1.3E - 052.9E - 1.7E - 8.3E - 1.2E - 06 ] 1.1E - 4.5E - A 00C 00 N.A. 3.5E - < I 1.7E - 2.3E - 02 1.8E - 3.7E - C 00 6.1E - 2.8E - 031 7.9E - 3.7E - A 00 Glucaric acid 1.2E - 4.1E - 05 1.6E - 4.7E - A 00 Gluconic acid 1.7E - 1.2E - 03 1.4E - 3.5E - C 00 8.5E - .6E - 04 6.3E - 1.6E - A 00 Glucose 6 - phosphate 1.5E - 4.2E - 05 1.8E - 1.0E - 04 0.

A_0057 Glucuronic acid Galacturonic acid 3.6E - 4.2E - 05 3.2E - 2.4E - A 00 Glutaric acid 2.7E - 3.3E - 05 2.7E - .8E - C 01 ( GSSG ) _divalent 6.2E - 3.9E - 03 5.3E - 1.3E - C 00 4.6E - 6.9E - 03 4.5E - 1.1E - A 00 Glyceric acid .7E - 6.1E - 05 5.4E - 3.5E - Page 134 of 159 Attorney Docket No. 2013404-01 C 00 7.3E - A 00 Glycerol 3 - phosphate A 00 Glycolic acid 3.5E - 03 6.7E - 03 1.4E - 03 1.1 0.7 6.3E - 04 1.3E - 04 6.3E - 04 9.2E - 05 1.0 9.8E - 03 3.7E - 03 1.2E - 02 1.6E - 03 3.2E - 03 2.3E - 04 3.2E - 03 2.2E - A 00 Glyoxylic acid 4.1E - 04 9.5E - 05 4.5E - 04 1.7E - C 00A 01 Guanidinosuccinic acid C 00 Guanidoacetic acid A 0014 Hexanoic acid A 00 Hippuric acid C 00 9.2E - 05 7.3E - 06 1.2E - 04 2.1E - N.A. N.A. 3.4E - 04 N.A. 9.8E - 05 3.0E - 05 19.9E - 05 3.0E - 05 8.3E - 04 4.1E - 04 7.4E - 04 2.8E - 04 1.3E - 04 1.3E - 05 1.2E - 04 2.5E - 05 3.6E - 04 2.2E - 04 7.9E - 04 1.7E - 04 1.6E - 02 3.9E - 03 2.0E - 02 6.4E - 03 1.7E - 04 8.9E - 05 9.5E - 05 5.0E - 0.039 * < I 1.1 0.502 1.7 0.2 C 00 7.8E - 05 9.8E - 06 7.8E - 05 1.8E - 05 2.9E - 04 5.2E - 05 13.2E - 04 3.2E - 05 0.

C 00 2.2E - N.A. 2.2E - 04 5.3E - A 00 Homovanillic acid 3.6E - 2.0E - 05 [ 3.6E - 04 4.4E - C 00 4.5E - 2.0E - 03 14.7E - 03 1.1E - ( ) .

Page 135 of 159 Attorney Docket No. 2013404-01 C 0017 C 00 Isethionic acid 1.2E - 03 8.5E - 04 5.0E - 04 1.2E - 03 9.3E - 04 0.7 0.524 5.7E - 02 6.8E - 03 6.5E - 02 7.8E - 03 0. 1.2E - 04 1.1E - 03 2.6E - 04 1.

A 00 Isobutyric acid Butyric acid 2.7E - 1.7E - 04 3.4E - 04 2.5E - 041 0.

A 00 Isocitric acid 2.8E - 04 1.2E - 04 3.3E - 04 1.2E - 04 ] 0.8 4.3E - 03 7.4E - 04 4.3E - 03 1.0E - 03 1.

A 00 Isovalerylalanine - N - Acetylleucine - 4.4E - 04 1.2E - 3.7E - 04 1.1E - 04 ] 1.

A 00 Isovalerylalanine - 1.7E - 04 4.6E - 2.3E - 04 3.9E - 05 ] 0.

C 01A 00 N - Acetylleucine - Lactic acid A 00 Lauric acid C 0041 C 00 Malic acid 1.5E - 04 N.A. 2.5E - 04 9.2E - 05 ] 0.6 2.4E - 04 1.9E - 05 2.9E - 04 6.0E - 05 ] 0.9 3.1E - 01 6.6E - 02 4.2E - 01 7.2E - 02 0.7 4.0E - 04 2.6E - 05 3.3E - 04 3.3E - 05 1.2 9.3E - 02 1.3E - 02 1.1E - 01 1.6E - 02 0.8 4.9E - 02 4.9E - 03 6.1E - 02 1.1E - 02 0.8 7.9E - 03 3.2E - 03 1.0E - 02 1.8E - 03 ] 0.8 1.2E - 02 2.5E - 03 1.9E - 02 4.3E - 03 ] 0. 0.042 * 0.008 ** 0.049 * 0.011 * Page 136 of 159 Attorney Docket No. 2013404-01 N - Acetylaspartic acid N - Acetylgalactosamine N - Acetylmannosamine C 00A 00 Methionine sulfoxide Mucic acid N , N - Dimethylglycine N - Acetylalanine 9.6E - 04 4.4E - 04 | 1.7E - 4.4E - 04 1.7E - 2.9E - 04 N.A. 2.4E - 04 2.5E - .7E - 0.5 0.041 * 3.4E - 04 5.1E - 053.2E - 8.1E - 1.1 0.6 1.7E - 03 5.0E - 04 1.7E - 03 1.6E - 04 2.9E - 05 1.4E - 04 2.7E - 05 1.3E - 04 1.8E - 05 1.3E - 1.6E - 1.0 0.81.2 0.2 1.0E - 1.0 0.81.2 N.A.

N - Acetylglucosamine N - Acetylglutamine N - Acetylglycine C 00 N - Acetylhistidine C 00 N - Acetyllysine A 00 N - Acetylphenylalanine 1.9E - 04 9.2E - 05 1.1E - 04 8.3E - 06 1.7 0.444 6.9E - 04 1.4E - 044.4E - 04 2.1E - 04 1.2E - 04 2.8E - 05 1.4E - 04 2.8E - N.A. N.A. 1.5E - 04 2.7E - 1.5E - 04 3.7E - 05 2.1E - 04 2.5E - 05 0.7 0.030 * 1.6 0.057 0.9 0.4 Page 137 of 1 ID consists of analysis mode and number . ' C ' and ' A ' showed cation and anion modes , respectively . N.D. ( Not Detected ) : The target peak or metabolite was below detection limits . N.A. ( Not Available ) : The calculation was impossible because of insufficience of the data .

Putative metabolites which were assigned on the basis of m / z and MT in HMT standard compound library .

The ratio is of computed by using averaged detection values . The latter was used as denominator . The p - value is computed by Welch's t - test . ( * < 0.05 , ** < 0.01 , *** < 0.001 ) The data are sorted by Compound name in ascending order .

Attorney Docket No. 2013404-01 Table 7 Putative Metabolites ( 3 ) HMT DBT Relative Area Comparative Analysis Control vs Treatment Compound name C_0065 N - Acetylserine A_0072 N - Acetyltryptophan C_0059 N - Ethylmaleimide_ + O₂H A_0007 N - Formylglycine Mean S.D. Mean S.D. 1.5E - 04 3.2E - 05 1.9E - 04 3.7E - 05 ) 2.3E - 04 6.6E - 05 1.8E - 04 3.4E - 05 ) 3.0E - 04 N.A. 1.4E - 04 N.A. 8.3E - 05 3.8E - 05 1.0E - 04 2.8E - p - value ( 0.4 [ 0038 N - Methylproline 2.5E - 04 9.0E - 05 2.3E - 04 4.5E - 05 ) 0069 N - Methyl - 4 - pyridone - 5 - carboxamide 6.3E - 04 8.0E - 05 4.8E - 04 1.5E - 04 0080 5№ - Ethylglutamine 1.7E - 03 5.5E - 04 2.0E - 03 1.9E - [ 0094 бN¸бNб№ - Trimethyllysine C 0092 N - Acetyllysine [ 0071 No - Methyllysine C 0032 Nicotinamide 3.7E - 04 6.9E - 05 4.0E - 04 1.3E - 04 2.5E - 04 7.5E - 06 3.0E - 04 2.2E - 05 1.5E - 03 1.8E - 04 1.9E - 03 3.2E - 0.002 ** N8 - Acetylspermidine C 00 No - Methylarginine O - Acetylcarnitine .6E - 05 1.0E - 05 4.8E - 05 8.2E - 06 ] 8.6E - 04 4.3E - 04 8.7E - 04 4.4E - 04 1.N.A. N.A. 7.9E - 05 1.8E - 05 | 2.4E - 02 3.1E - 03 [ 2.2E - 02 3.9E - 03 ] < I C_0072 O - Acetylhomoserine 1.9E - 03 8.4E - 04 1.8E - 03 4.4E - 04 1. 2 - Aminoadipic acid ( 0.7 Page 138 of 159 Attorney Docket No. 2013404-01 o - Hydroxybenzoic acid Ophthalmic acid C 00A 0048 A 00 p - Hydroxyphenylpyruvic acid Pantothenic acid 2.0E - 04 N.A. 3.9E - 04 1.4E - 04 1.7E - 04 1.0E - 04 1.9E - 04 9.0E - 05 | 9.1E - 03 9.5E - 04 | 1.5E - 02 5.2E - 03 3.5E - 04 1.4E - 04 6.7E - 04 2.3E - 04 | 5.4E - 04 2.3E - 04 5.4E - 04 2.0E - 04 | 0.040 * 0.040 * C 00A 00 Phenaceturic acid C 0089 C 00 Picolinic acid 4.0E - 02 5.6E - 03 5.3E - 02 1.5E - 02 2.3E - 04 1.0E - 04 3.9E - 04 1.4E - 04 9.7E - 05 6.0E - 06 1.0E - 04 2.3E - 05 4.4E - 04 7.7E - 05 15.5E - 04 9.6E - 05 8.0E - 05 1.2E - 05 | 1.2E - 04 3.0E - C 00 Pipecolic acid C 0022 C 0006 C 00A 00 2.7E - 03 8.5E - 04 [ 2.6E - 03 4.7E - 04 ] 3.0E - 02 8.3E - 03 4.0E - 02 1.5E - N.A. N.A. 2.5E - 04 N.A. 1.2E - 04 3.6E - 05 1.1E - 04 2.3E - 05 9.1E - 04 9.2E - 05 8.7E - 04 7.4E - 05 ] < I A 0003 A 00C 0048 C 00A 00 Ribulose 5 - phosphate S - Methylcysteine S - Methylmethionine S - Sulfocysteine .8E - 03 5.2E - 04 7.5E - 03 9.9E - 04 1.9E - 04 3.0E - 05 2.1E - 04 5.8E - 05 3.2E - 04 1.7E - 04 2.4E - 04 8.1E - 05 5.7E - 05 6.5E - 06 6.1E - 05 1.7E - 0.009 ** 4.4E - 04 3.5E - 04 4.3E - 04 1.6E - C 0008 C 0097 C 00 2.2E - 03 5.0E - 04 2.6E - 03 6.9E - 04 7.6E - 05 9.4E - 06 6.5E - 05 1.3E - 05 1.8E - 02 5.0E - 03 2.3E - 02 7.4E - 03 3.0E - 04 7.9E - 05 [ 3.0E - 04 1.7E - 0 Page 139 of 159 Attorney Docket No. 2013404-01 A 00 Succinic acid C 00A 01 Taurocholic acid C 00 Terephthalic acid 4.4E - 03 9.1E - 04 6.1E - 03 1.8E - 03 1.3E - 02 2.4E - 03 1.5E - 02 5.0E - 03 9.9E - 03 8.4E - 04 9.4E - 03 1.5E - 03 1.0E - 02 1.9E - 02 13.2E - 02 3.2E - 02 | 1.6E - 04 2.3E - 05 1.7E - 04 2.5E - 05 4.8E - 04 N.A. 3.8E - 04 4.6E - C 01 1.4E - 04 1.2E - 05 1.8E - 04 2.8E - 05 ) 0.016 * C 01 Thiamine phosphate C 00A 00C 00 .4E - 05 1.1E - 05 5.5E - 05 7.7E - 06 1.3E - 04 3.5E - 05 1.3E - 04 2.3E - 05 3.0E - 02 5.1E - 03 13.6E - 02 5.3E - 03 | Threonic acid 2.1E - 03 4.3E - 04 2.2E - 03 3.6E - 04 6.3E - 04 8.4E - 05 6.5E - 04 1.6E - 04 1.1E - 03 4.0E - 04 1.8E - 03 4.8E - 0.032 * Trimethylamine N - oxide 1.3E - 03 6.4E - 04 1.3E - 03 7.9E - C 01 2.8E - 02 8.2E - 03 13.6E - 02 3.8E - 03 2.7E - 02 8.0E - 03 13.4E - 02 7.7E - 03 ) C 0020 C 00A 00 3.0E - 04 5.9E - 05 [ 3.0E - 04 9.1E - 05 ) 7.8E - 01 1.7E - 01 8.1E - 01 5.6E - Ureidoglycolic acid Uric acid 1.4E - 04 4.5E - 05 2.1E - 04 7.4E - 05 6.0E - 03 3.3E - 04 15.6E - 03 6.2E - 04 1.8E - 03 4.6E - 04 1.7E - 03 4.9E - Page 140 of 159 Attorney Docket No. 2013404-01 ID consists of analysis mode and number . ' C ' and ' A ' showed cation and anion modes , respectively . N.D. ( Not Detected ) : The target peak or metabolite was below detection limits . N.A. ( Not Available ) : The calculation was impossible because of insufficience of the data .

Putative metabolites which were assigned on the basis of m / z and MT in HMT standard compound library .

The ratio is of computed by using averaged detection values . The latter was used as denominator . The p - value is computed by Welch's t - test . ( * < 0.05 , ** < 0.01 , *** < 0.001 ) The data are sorted by Compound name in ascending order .

Page 141 of 159 Table 7 Putative Metabolites ( 4 ) Attorney Docket No. 2013404-01 HMT DBT Relative Area Compound name Comparative Analysis Control vs Treatment p - valuell C 00 Urocanic acid 7.8E - 7.0E - 06 9.6E - 1.9E - 0 A 01 N.A. 2.5E - 04 N.A. < I C 00 9.6E - 1.4E - 02 1.1E - 01 1.5E - A 00 4.2E - 1.4E - 04 4.0E - 04 1.1E - 0 A 0035 A 0043 XA0013 A 00 3.2E - 04 3.2E - 04 5.7E - 04 2.0E - 04 6.4E - 04 3.2E - 8.9E - 05 5.5E - 04 9.6E - 05 5.7E - 05 3.1E - 04 9.8E - 05 ] A 00 .0E - 8.0E - 05 3.7E - 04 8.9E - 05 ] A 0074 XA0035 A 0073 XA00C 0036 XC00 1.1E - 3.2E - 04 8.6E - 04 4.4E - C 0103 C 00 8 - Ala 2.7E - B - Hydroxyisovaleric acid C 00 Y - Butyrobetaine 2.0E - 04 1.6E - 03 1.5E - 04 3.0E - 05 1.3E - 04 1.9E - 04 4.0E - 04 7.1E - 05 3.9E - 04 4.1E - 05 ) 8.6E - 04 3.4E - 04 1.3E - 03 5.8E - 04 ) 7.9E - 05 9.4E - 06 6.5E - 05 1.6E - 05 ) 1.1E - 04 3.0E - 04 1.8E - 04 3.9E - 05 2.3E - 04 6.0E - 04 ] 1.1E - 04 1.7E - 03 4.8E - 0 Page 142 of 1 ID consists of analysis mode and number . ' C ' and ' A ' showed cation and anion modes , respectively . N.D. ( Not Detected ) : The target peak or metabolite was below detection limits . N.A. ( Not Available ) : The calculation was impossible because of insufficience of the data .

Putative metabolites which were assigned on the basis of m / z and MT in HMT standard compound library .

The ratio is of computed by using averaged detection values . The latter was used as denominator .

|| The p - value is computed by Welch's t - test . ( * < 0.05 , ** < 0.01 , *** < 0.001 ) The data are sorted by Compound name in ascending order .

Attorney Docket No. 2013404-01 Table 8 Quantitative Estimation of Target Metabolites ( 1 ) Concentration ( uM ) Mean S.D.

Comparative Analysis Control vs Treatment Ratio p - value A 00 2 - Hydroxybutyric acid A 00 2 - Oxoglutanic acid A 00 2 - Oxoisovaleric acid A 00 2 - Phosphogluceric acid A. 00 3 - Hydrocybutric acid A 00 3 - Phosphoglyceric acid A 00 6 - Phosphogluconic acid A. 00 Acetyl CoA_divalent C 00 N.A. N.A.

C 0122 C 00A 00C 00 Anthranilic acid C 00 Page 143 of 159 Attorney Docket No. 2013404-01 C 0044 C 00A 01C 0026 C 00 Betaine aldehyde_ + O₂H A 00C 01A 00 cis -Aconitic acid A 01 Citric acid C 00 { { } A 0081 A 0089 Attorney Docket No. 2013404-01 C 0040 Creatine C 0121 Creatining 0.004 ** A 0101 CTP 0031 Cys C_0116 Cytidine C 0018 Cytosine 0103 dATP A 0099 dCTP N.A. N.A.

A_0038 Dihydroxyacetone phosphate A 0091 dTDP Page 145 of 1 A 0080 dTMP A 0100 dTTP N.A. N.A.

A_0059 Erythrose 4 - phosphate N.A. N.A.

N.A. N.A.

A_0084 Fructose 1,6 - diphosphate N.A. N.A.

A_0077 Fructose 6 - phosphate Attorney Docket No. 2013404-01 A 0012 Fumaric acid C 00A 0098 GDP A 0063 Gln A 0066 Glu A 0058 Gluconic acid C_0076 Glucose 1 - phosphate A_0075 Glucose 6 - phosphate A 0130 Glutathione ( GSH ) A_0129 Glutathione ( GSSG ) _divalent C 0004 Gly C_0039 Glyceraldehyde 3 - phosphate A_0040 Glycerol 3 - phosphate A_0002 Glycolic acid A_0001 Glyoxylic acid Page 146 of 1 ID consists of analysis mode and number . ' C ' and ' A ' showed cation and anion modes , respectively . N.D. ( Not Detected ) : The target peak or metabolite was below detection limits . N.A. ( Not Available ) : The calculation was impossible because of insufficience of the data . The ratio is of computed by using averaged detection values . The latter was used as denominator . The p - value is computed by Welch's t - test . ( * < 0.05 , ** < 0.01 , *** < 0.001 ) The data are sorted by Compound name in ascending order .

Attorney Docket No. 2013404-01 Table 8 Quantitative Estimation of Target Metabolites ( 2 ) Concentration ( uM ) Comparative Analysis Control vs Treatment p - value || S.D. [ Mean S.D. Ratio A 00 N.A. N.A.

N.A. N.A.

A 01 N.A. 4.

C 00 N.A. N.A.

N.A. N.A.

C 0125 C 0028 C 0039 C 00A 00 N.A. N.A. 14 70 7.7 18 N.A. | N.A.

N.A. | N.A. 12 0.

N.A. | N.A .

C 01 N.A. N.A.

A 00 Isocitric acid 4.4 A 00 Lactic acid 1,000 6,3 0.042 * C 0041 C 00 17 147 23 2 0.049 * A 00 Malic acid 241 A 00 Malonyl CoA_divalent N.A. N.A.

N.A. NA .

C 00 6.9 12 0. 0.011 * C 00 N , N - Dimethylglycine 1.7 5. 0.6 1.

A 01 NAD + Page 147 of 159 Attorney Docket No. 2013404-01 A 01C 00 4.21 0.040 * C 00 11 1 A 00 Phosphoenolpyruvic acid N.A. | N.A.

C 00 A 00 N.A. | N.A.

C 00 N.A. 1.

A 00 Pyruvic acid 12 1 0.009 ** A. 00 Ribose 5 - phosphate N.A. | N.A.

A 00 Ribulose 5 - phosphate 0.41 3.

C 0132 C 00 S - Adenosylmethionine N.A. | N.A. 1.9 9.

A 00 Sedoheptulose 7 - phosphate N.A. | N.A.

C 00 28 1 C 00 0.31 1.

C 00 N.A. | N.A.

A 00 Succinic acid C 0027 C 0115 C 0100 C 00 4. { } N.A. | N.A. { 0 } N.A. | N.A.

A 00 N.A. | N.A.

A 00 N.A. N.A. N.A. N.A. << Page 148 of 159 Attorney Docket No. 2013404-01 0.9 4.6 3.6 13 N.A. 2.2 29 222 0.5 1.

ID consists of analysis mode and number . ' C ' and ' A ' showed cation and anion modes , respectively . N.D. ( Not Detected ) : The target peak or metabolite was below detection limits . C 00A 01C 0024 C 00 u0000 - Ala Page 149 of 1 N.A. ( Not Available ) : The calculation was impossible because of insufficience of the data .

Putative metabolites which were assigned on the basis of m / z and MT in HMT standard compound library .

The ratio is of computed by using averaged detection values . The latter was used as denominator .

|| The p - value is computed by Welch's t - test . ( * < 0.05 , ** < 0.01 , *** < 0.001 ) The data are sorted by Compound name in ascending order .

Attorney Docket No. 2013404-01 Appendix 4. Metabolites of Interest Metabolite Name 2 - Oxoglutaric acid Trimesic acid ; Trimesic acid Sphingomyelin ( d18 : 1/16 : 0 ) -Thyroxine Threonic acid 3 - Phosphoglyceric acid Urea Biopterin | Trp Indole - 3 - propionic acid ( IPA ) - Hydroxybutyric acid ; 2 - Hydroxyisobutyric acid y - Glu - Taurine N6 - Acetyllysine Creatinine GMP N6 - Methyllysine - Hydroxy - 2 - methyl - 4 - pyrone O - Acetylcarnitine ' - Deoxycytidine XC00Indole - 3 - lactic acid ; 5 - Methoxyindoleacetic acid Palmitoylcarnitine Page 150 of 159 Attorney Docket No. 2013404-01 DPA : DPA - Guanidinobutyric acid Daidzein N6 , N6 , N6 - Trimethyllysine XC002,3 - Diphosphoglyceric acid Stearoyl ethanolamide Phenol | AC ( 12 : 0 ) -XA00Pyruvic acid Ascorbic acid 1 - Methyl - 4 - imidazoleacetic acid Carnosine FA ( 16 : 3 ) -XA00XC00Progesterone NS - Ethylglutamine FA ( 22 : 3 ) -Lactic acid Ribulose 5 - phosphate ; Ribose 1 - phosphate ; Xylulose 5 - phosphate lle ; Leu ; fA - Leucine ; Alloisoleucine ; 6 - Aminohexanoic acid XC01 Page 151 of 159 Attorney Docket No. 2013404-01 1H - Imidazole - 4 - propionic acid ; 1 - Methyl - 4 - imidazoleacetic acid | AC ( 18 : 0 ) Sulfaguanidine ( C - SCOPE IS ) AC ( 18 : 1 ) Carbachol Ser Glu Pro Thr Asp Pro 7,8 - Dihydrobiopterin Stearic acid Lanosterol AC ( 14 : 2 ) -Taurine Val Phosphoenolpyruvic acid Myristic acid XA00Homocitrulline Isoliquiritigenin - Leu Ribulose 5 - phosphate Norvaline ; 2 - Amino - 2 - methylbutyric acid ; 5 - Aminovaleric acid ; Val y - Butyrobetaine Acetohydroxamic acid ; Gly C8H18N2 Page 152 of 159 Attorney Docket No. 2013404-01 XC00AC ( 18 : 2 ) -3 - Ureidopropionic acid Ile N - Carbamylglutamate - Diethylaminoethanol FA ( 15 : 1 ) -AC ( 10 : 0 ) fA - Butyrobetaine FA ( 24 : 5 ) -N , N - Dimethylglycine Methionine sulfoxide Kynurenine Isoliquiritigenin - 21 - Deoxycortisol - Glycerophosphocholine Creatine Ricinoleic acid - AC ( 15 : 0 ) - y - Glu - Val - Gly p - Hydroxyphenylpyruvic acid Behenic acid Histamine S - Carboxymethylcysteine Page 153 of 159 Attorney Docket No. 2013404-01 | Asp Leu Asn Arg Phosphorylcholine - Methylguanine XA00 Thymidine Thiamine phosphate Isoliquiritigenin - 3 - Guanidinopropanoate y - Glu - Phe | AC ( 16 : 2 ) -C7H9N3N - Hydroxy - L - tryptophan Cytosine Trimethylamine | Áƒ - Glu - Phe Asiatic acid - | AC ( 20 : 0 ) Heptanoic acid XC01Glycerol 3 - phosphate Hexanoic acid Glutathione ( GSSG ) _divalent Glycitein Page 154 of 159 Attorney Docket No. 2013404-01 FA ( 17 : 3 ) XC00 y - Glu - Val ( S ) -HETE | AC ( 14 : 1 ) -5a - Cholestan - 3 - one - | N- ( 1 - Deoxy - 1 - fructosyl ) valine 20a - Hydroxyprogesterone AC ( 14 : 2 ) -Argininosuccinic acid | AC ( 14 : 3 ) -Ophthalmic acid Ornithine Glucosamine 6 - sulfuric acid Aminoacetone | AC ( 17 : 1 ) o - Hydroxybenzoic acid Glucosyl - glycerol FA ( 14 : 2 ) -AC ( 13 : 1 ) -y - Glu - Leu Citrulline O - Acetylhomoserine Thr Page 155 of 159 Attorney Docket No. 2013404-01 Lys FA ( 24 : 0 ) AC ( 17 : 0 ) -Pyrrolidine | y - Glu - Trp Gly - Asp ; Asp - Gly FA ( 14 : 3 ) XC00IDP Arg His - Asp - Hydroxyglutaric acid Phe Met His Glu Tyr Lys - Asp | y - Glu - Tyr y - Glu - Glu Glucose 6 - phosphate - amino - undecanoic acid Biotin Sarcosine y - Glu - Ornitine B - Estradiol Page 156 of 159 Attorney Docket No. 2013404-01 α71 - Estradiol - Aminoadipic acid - Aminoisobutyric acid 2 - Aminobutyric acid N ' - Formylkynurenine XC012 ' - Deoxyuridine y - Glu - Thr AC ( 20 : 1 ) Cys Cys Csy Asn Asn Ethanolamine phosphate y - Glu - Lys - Methylguanine ; 3 - Methylguanine C6H12N2 | y - Glu - Asp AC ( 14 : 3 ) -N - Methylethanolamine phosphate XC01 | p - Hydroxyphenylpyruvic acid ; Caffeic acid | 3 - Hydroxy - 3 ' , 4 ' - didehydro - ß , y - carotene - Hydroxylysine y - Glu - Arg C6H10C6H10N - Methylproline Page 157 of 159 Attorney Docket No. 2013404-01 S - Methylglutathione Methionine sulfone Imidazole - 4 - acetic acid N - Formylaspartic acid CA : C XC01XC01Betulinic acid y - Glu - Met Norophthalmic acid Heneicosanoic acid 19- Methylarachidic acid N - Acetyltyrosine - Hydroxypentanoic acid ; fA - Hydroxyisovaleric acid ; 2 - Hydroxyvaleric acid Oleanolic acid Cyclodopa glucoside Thr Ala Ala Pipecolic acid ; N - Methylproline ; 1 - Aminocyclopentanecarboxylic acid N - Acetylneuraminic acid Corosolic acid N - Acetyl - ß - alanine XC01 | 3 - cis - Hydroxy - b , e - Caroten - 3 ' - one Page 158 of 159 Attorney Docket No. 2013404-01 N - Acetylgalactosamine ; N - Acetylglucosamine ; N - Acetylmannosamine C9H18NGly - Asp N - Acetylasparagine Lactamide Cys Cys His Asp Inosine 2 ' , 3 ' - cyclic phosphate clMP XC00 2 - Hydroxyisobutyric acid fA - Glu - Tyr | Àƒ - Glu - Met Sedoheptulose 7 - phosphate CA : CA α - Tocopherol acetate Gamma - Glu - Gln Page 159 of 159

Claims (148)

WO 2025/0540 CLAIMS PCT / US2024 / 0440 We claim :

1. A method comprising : administering to a subject a composition comprising one or more microbial strains or microbial components , wherein the subject has been diagnosed with or is at high risk of a lipid disease , disorder , or condition , wherein the lipid disease , disorder , or condition includes one or more of body weight gain , lipid accumulation in liver , accumulation of visceral fat , elevated blood triglyceride levels , hypercholesterolemia , inflammation , and / or high blood- cholesterol levels ( e.g. Low Density Lipoprotein ( LDL ) levels ) .

2. A method comprising : administering to a subject a composition comprising one or more microbial metabolites , wherein the subject has been diagnosed with or is at high risk of a lipid disease , disorder , or condition , wherein the lipid disease , disorder , or condition includes one or more of body weight gain , lipid accumulation in liver , accumulation of visceral fat , elevated blood triglyceride levels , hypercholesterolemia , inflammation , and / or high blood - cholesterol levels ( e.g. LDL levels ) .

3. A method comprising : administering to a subject a composition comprising : ( i ) one or more microbial strains or microbial components , or ( ii ) one or more microbial metabolites , wherein the subject has been diagnosed with or is at high risk of a metabolic disease , disorder , or condition . 110 WO 2025/054048 PCT / US2024 / 0440

4. The method of any one of the preceding claims , wherein the subject has been diagnosed with or is at high risk of lipid - induced metabolic syndrome , cerebral infarction / stroke , myocardial infarction / heart attack , Type II diabetes / diabetes mellitus , glucose intolerance , alcoholism , metabolic syndrome , kidney disease , cardiorenal syndrome , vascular diseases ( e.g. , hypertension , peripheral arterial disease ) , Alzheimer's disease , asthma ( e.g. , due to abdominal obesity or central / truncal obesity ) , atherosclerosis , hypothyroidism , liver disease , LDL - hypercholesterolemia , hypertriglyceridemia , mixed hyperlipoproteinemia , coronary heart disease , stroke , peripheral arterial disease , high blood pressure , hyperlipidemia , steatosis , non - alcoholic steatohepatitis ( NASH ) , fatty - liver disease , metabolic associated fatty liver disease ( MAFLD ) , non - alcoholic fatty liver disease ( NAFLD ) , liver fibrosis , cirrhosis , or hepatocellular carcinoma .

5. The method of any one of the preceding claims , wherein the subject is a mammal .

6. The method of any one of the preceding claims , wherein the subject is a human .

7. The method of any one of claims 1 or 3-6 , wherein the one or more microbial strains are from a mammalian microbiome .

8. The method of any one of claims 1 or 3-7 , wherein the one or more microbial strains are from a human microbiome .

9. subject . The method of claim 8 , wherein the human microbiome is the microbiome of the 111 WO 2025/054048 PCT / US2024 / 0440

10. The method of claim 9 , wherein the human microbiome is administered to maintain or modulate the microbiome of the subject .

11. The method of any one of the preceding claims , wherein one or more microbial components or microbial metabolites are selected from Appendix 1 , Appendix 3 , or Appendix 4 .

12. The method of any one of the preceding claims , wherein the one or more microbial metabolites is or comprises a bile acid , Cholesterol , chenodeoxycholic acid , -αchenodeoxycholic acid ( CDCA ) , oxysterols , taurochenodeoxycholic acid , cholic acid , lithocholic acid , ursodeoxycholic acid , triglycerides , very - low density lipoprotein ( VLDL ) , VLDL - TG , cholesterol , eicosanoids , arachidonic acid , docosahexaenoic acid , eicosapentaenoic acid , trimethylamines ( TMA ) , trimethylamine - N - oxide ( TMAO ) , endogenous ethanol , acetone , acetaldehyde , butyrate , choline , or any combination thereof .

13. The method of any one of the preceding claims , wherein the one or more microbial metabolites is or comprises Tauroursodeoxycholic acid , taurocholic acid , long - chain acyl- CoA dehydrogenase ( LCAD ) , deoxycholic acid ( DCA ) , lithocholic acid ( LCA ) , taurochenodeoxycholic acid , ursodeoxycholic acid , α7 - hydroxycholesterol , chenodeoxycholic acid , 27 - hydroxycholesterol , α7 - hydroxy - 4 - cholestene - 3 - one , or any combination thereof .

14. The method of any one of the preceding claims , wherein one or more microbial components or microbial metabolites is Butyrylcamitine , Theobromine , p- Hydroxyphenylpyruvic acid , Propionic acid , Picolinic acid , 2 - Hydroxy - 4methylvaleric acid , N6 - Acetylysine , Urocanic acid , N5 - Ethylglutamine , Trigonelline , Stachydrine , Ectoine , 5- Hydroxylysine , Arginine ( arg ) , Cholic acid , 2- ( 4 - Hydroxyphenyl ) propionic acid , N- Acetyltryptophan , Hydroxyproline , Argininosuccinic acid , Glutamic acid ( Glu ) , Sarcosine , 112 WO 2025/054048 PCT / US2024 / 0440 5 - Methoxyindoleacetic acid , Indole - 3 - lactic acid , Isovalerylalanine , N - Acetylleucine , 1- Methylhistidine , N - Acetylephenylalanine , Proline ( Pro ) , or any combination thereof .

15. The method of any one of the preceeding claims , wherein one or more microbial components or microbial metabolites is 4 - Hydroxyphenylpyruvic , Ectoine , Gramine , N- Acetyl - L - phenylalanine , Nepsilon - Acetyl - L - lysine , Stachydrine , Trigonelline , 3- Ureidopropionic acid , Theobromine , Hippuric acid , Imidazolepropionic acid , NG - Methyl - L- arginine , trans - Urocanic Acid , N - Acetyl - L - leucine , Sarcosine , Isobutyrylcarnitine , b- Hydroxyisovaleric acid , L - Theanine / N5 - Ethylglutamine , 5 - Hydroxylysine , Phenaceturic acid , betaine , hydroxyproline , Picolinic acid , 2 - Aminoadipic acid , Glycerophosphocholine , carnitine , Glycerol 3 - phosphate , Argininosuccinic acid , creatine , Terephthalic acid , Homocitrulline , Mucic acid , Homocysteinesulfinic acid , Trimethyllysine , Spermidine , Glyoxylic acid , XA0013 C6H6O4S , 3 - Indoxylsulfuric acid , Nicotinamide , N- Formylglycine , Ureidoglycolate , N - Methylproline , Glucaric acid , Butyrylcarnitine , Methionine sulfoxide , Carboxymethyllysine , Glycolic acid , Phenaceturic acid , Diethanolamine , Phosphorylcholine , Guanidinosuccinic acid , N - Acetylhistidine , Glyceric acid , S - Methylmethionine , Cysteine glutathione disulfide , Kynurenine , N- Acetylphenylalanine , Threonic acid , Malic acid , 7,8 - Dihydrobiopterin , Homovanillic acid , Taurocholic acid , 5 - Methoxyindoleacetic acid , butyrate , b - Hydroxyisovaleric acid , 2- Oxoglutaric acid , N - Acetyltryptophan , Thiaproline , Hypotaurine , Cholic acid , Acetoacetic acid , Ethanolamine , Guanidoacetic acid , S - Sulfocysteine , Myristic acid C14 : 0 XA0027 , or any combination thereof .

16. The method of any one of claims 1 or 3-15 , wherein the one or more microbial strains are or comprise Gluconacetobacter hansenii , Terrisporobacter glycolicus , Coprococcus sp . , Lactobacillus plantarum , Clostridium butyricum , Paenibacillus sp . , Veillonella sp . , Bifidobacterium sp . , Bacillus subtilis , Acidaminococcus sp . , or a combination thereof . 113 WO 2025/054048 PCT / US2024 / 0440

17. The method of any one of claims 1 or 3-16 , wherein the one or more microbial strains are or comprise Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus sp . , Lactobacillus plantarum , Veillonella sp . , Bifidobacterium sp . , or a combination thereof .

18. The method of any one of claims 1 or 3-17 , wherein the one or more microbial strains are or comprise Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus catus , Lactobacillus plantarum , Veillonella atypica , Bifidobacterium breve , or a combination thereof .

19. The method of any one of claims 1 or 3-18 , wherein the one or more microbial strains is or comprises Bacillus subtilis .

20. The method of any one of claims 1 or 3-19 , wherein the composition comprises two or more microbial strains .

21. The method of any one of claims 1 or 3-20 , wherein the composition comprises five or more microbial strains .

22. The method of any one of claims 1 or 3-21 , wherein the composition comprises ten or more microbial strains .

23. The method of any one of the preceding claims , wherein the composition is administered topically , orally , subcutaneously , intravenously , intramuscularly , intracerebrally , intrathecally , rectally , opthalmically , intravitreally , or suprachoroidally . 114 WO 2025/0540

24. PCT / US2024 / 0440 The method of claim 20 , wherein the composition is administered orally .

25. The method of claim 20 , wherein the composition is administered intravenously .

26. The method of any one of the preceding claims , wherein the composition is formulated as a syrup , a liquid , a tablet , a troche , a gummy , a capsule , a powder , a gel , a film , an injection , or an eye drop .

27. The method of any one of claims 1 or 3-26 , wherein each microbial strain of the one or more microbial strains is present in the composition at a concentration from 10¹ to 10CFU .

28. The method of any one of claims 1 or 3-27 , wherein each microbial strain of the one or more microbial strains is present in the composition at a concentration of at least 1CFU .

29. A composition for use in treating a metabolic disease , disorder , or condition comprising one or more microbial strains or microbial components .

30. A composition for use in treating a metabolic disease , disorder , or condition comprising one or more microbial metabolites .

31. The composition of claim 29 , wherein the one or more microbial strains are from a mammalian microbiome . 115 WO 2025/054048 PCT / US2024 / 0440

32. The composition of claim 29 or 31 , wherein the one or more microbial strains are from a human microbiome .

33. The composition of claim 32 , wherein the human microbiome is the microbiome of the subject .

34. The composition of claim 33 , wherein the human microbiome is administered to maintain or modulate the microbiome of the subject .

35. The composition of any one of claims 29-34 , wherein one or more microbial components or microbial metabolites are selected from Appendix 1 , Appendix 3 , or Appendix 4 .

36. The composition of any one of claims 29-35 , wherein the one or more microbial metabolites is or comprises a bile acid , Cholesterol , chenodeoxycholic acid , -αchenodeoxycholic acid ( CDCA ) , oxysterols , taurochenodeoxycholic acid , cholic acid , lithocholic acid , ursodeoxycholic acid , triglycerides , very - low density lipoprotein ( VLDL ) , VLDL - TG , cholesterol , eicosanoids , arachidonic acid , docosahexaenoic acid , eicosapentaenoic acid , trimethylamines ( TMA ) , trimethylamine - N - oxide ( TMAO ) , endogenous ethanol , acetone , acetaldehyde , butyrate , choline , or any combination thereof .

37. The composition of any one of claims 29-36 , wherein the one or more microbial metabolites is or comprises Tauroursodeoxycholic acid , taurocholic acid , long - chain acyl- CoA dehydrogenase ( LCAD ) , deoxycholic acid ( DCA ) , lithocholic acid ( LCA ) , taurochenodeoxycholic acid , ursodeoxycholic acid , α7 - hydroxycholesterol , chenodeoxycholic acid , 27 - hydroxycholesterol , α7 - hydroxy - 4 - cholestene - 3 - one , or any combination thereof . 116 WO 2025/054048 PCT / US2024 / 0440

38. The composition of any one of claims 29-35 , wherein one or more microbial components or microbial metabolites is Butyrylcamitine , Theobromine , p- Hydroxyphenylpyruvic acid , Propionic acid , Picolinic acid , 2 - Hydroxy - 4methylvaleric acid , N6 - Acetylysine , Urocanic acid , N5 - Ethylglutamine , Trigonelline , Stachydrine , Ectoine , 5- Hydroxylysine , Arginine ( arg ) , Cholic acid , 2- ( 4 - Hydroxyphenyl ) propionic acid , N- Acetyltryptophan , Hydroxyproline , Argininosuccinic acid , Glutamic acid ( Glu ) , Sarcosine , - Methoxyindoleacetic acid , Indole - 3 - lactic acid , Isovalerylalanine , N - Acetylleucine , 1- Methylhistidine , N - Acetylephenylalanine , Proline ( Pro ) , or any combination thereof .

39. The composition of any one of claims 29-35 , wherein one or more microbial components or microbial metabolites is 4 - Hydroxyphenylpyruvic , Ectoine , Gramine , N- Acetyl - L - phenylalanine , Nepsilon - Acetyl - L - lysine , Stachydrine , Trigonelline , 3- Ureidopropionic acid , Theobromine , Hippuric acid , Imidazolepropionic acid , NG - Methyl - L- arginine , trans - Urocanic Acid , N - Acetyl - L - leucine , Sarcosine , Isobutyrylcarnitine , b- Hydroxyisovaleric acid , L - Theanine / N5 - Ethylglutamine , 5 - Hydroxylysine , Phenaceturic acid , betaine , hydroxyproline , Picolinic acid , 2 - Aminoadipic acid , Glycerophosphocholine , carnitine , Glycerol 3 - phosphate , Argininosuccinic acid , creatine , Terephthalic acid , Homocitrulline , Mucic acid , Homocysteinesulfinic acid , Trimethyllysine , Spermidine , Glyoxylic acid , XA0013 C6H604S , 3 - Indoxylsulfuric acid , Nicotinamide , N- Formylglycine , Ureidoglycolate , N - Methylproline , Glucaric acid , Butyrylcarnitine , Methionine sulfoxide , Carboxymethyllysine , Glycolic acid , Phenaceturic acid , Diethanolamine , Phosphorylcholine , Guanidinosuccinic acid , N - Acetylhistidine , Glyceric acid , S - Methylmethionine , Cysteine glutathione disulfide , Kynurenine , N- Acetylphenylalanine , Threonic acid , Malic acid , 7,8 - Dihydrobiopterin , Homovanillic acid , Taurocholic acid , 5 - Methoxyindoleacetic acid , butyrate , b - Hydroxyisovaleric acid , 2- Oxoglutaric acid , N - Acetyltryptophan , Thiaproline , Hypotaurine , Cholic acid , Acetoacetic acid , Ethanolarnine , Guanidoacetic acid , S - Sulfocysteine , Myristic acid C14 : 0 XA0027 , or any combination thereof . 117 WO 2025/054048 PCT / US2024 / 0440

40. The composition of any one of claims 29 or 31-39 , wherein the one or more microbial strains are or comprise Gluconacetobacter hansenii , Terrisporobacter glycolicus , Coprococcus sp . , Lactobacillus plantarum , Clostridium butyricum , Paenibacillus sp . , Veillonella sp . , Bifidobacterium sp . , Bacillus subtilis , Acidaminococcus sp . , or a combination thereof .

41. The composition of any one of claims 29 or 31-40 , wherein the one or more microbial strains are or comprise Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus sp . , Lactobacillus plantarum , Veillonella sp . , Bifidobacterium sp . , or a combination thereof .

42. The composition of any one of claims 29 or 31-41 , wherein the one or more microbial strains are or comprise Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus catus , Lactobacillus plantarum , Veillonella atypica , Bifidobacterium breve , or a combination thereof .

43. The composition of any one of claims 29 or 31-42 , wherein the one or more microbial strains is or comprises Bacillus subtilis .

44. The composition of any one of claims 29 or 31-43 , wherein the composition comprises two or more microbial strains .

45. The composition of any one of claims 29 or 31-44 , wherein the composition comprises five or more microbial strains . 118 WO 2025/054048 PCT / US2024 / 0440

46. The composition of any one of claims 29 or 31-45 , wherein the composition comprises ten or more microbial strains .

47. The composition of any one of claims 29-46 , wherein the composition is for topical , oral , subcutaneous , intravenous , intramuscular , intracerebral , intrathecal , rectal , opthalmical , intravitreal , or suprachoroidal administration .

48. The composition of claim 47 , wherein the composition is for oral administration .

49. The composition of claim 47 , wherein the composition is for intravenous administration .

50. The composition of any one of claims 29-49 , wherein the composition is formulated as a syrup , a liquid , a tablet , a troche , a gummy , a capsule , a powder , a gel , a film , an injection , or an eye drop . The composition of any one of claims 29 or 31-50 , wherein each microbial strain of the one or more microbial strains is present in the composition at a concentration from 10¹ to 1015 CFU .

51.

52. The composition of any one of claims 29 or 31-50 , wherein each microbial strain of the one or more microbial strains is present in the composition at a concentration of at least 106 CFU . 119 WO 2025/054048 PCT / US2024 / 0440

53. Use of a composition of any one of claims 29-52 for modulating one or more microbial metabolites in a subject .

54. Use of a composition of any one of claims 29-52 for modulating one or more features in a subject .

55. Use of a composition of claim 54 , wherein the one or more features is or comprises : ( i ) level of cell viability ; ( ii ) level or activity of a nucleic acid or protein , or form thereof ; ( iii ) body weight gain ; ( iv ) lipid accumulation in liver ; ( v ) accumulation of visceral fat ; ( vi ) elevated blood triglyceride levels ; ( vii ) blood - cholesterol levels ; ( viii ) oxidative stress ; ( ix ) hypercholesterolemia ; or ( x ) inflammation .

56. Use of a composition of any one of claims 29-52 for characterizing the ability of one more microbial strains to modulate one or more microbial metabolites in a subject . 120 WO 2025/054048 PCT / US2024 / 0440

57. Use of a composition of any one of claims 29-52 for treating or ameliorating a disease , disorder , or condition in a subject , wherein the disease , disorder , or condition is a metabolic disease , disorder , or condition associated with one or more microbial metabolites .

58. The use of a composition of claim 57 , wherein the disease , disorder , or condition is lipid - induced metabolic syndrome , cerebral infarction / stroke , myocardial infarction / heart attack , Type II diabetes / diabetes mellitus , glucose intolerance , alcoholism , metabolic syndrome , kidney disease , cardiorenal syndrome , vascular diseases ( e.g. , hypertension , peripheral arterial disease ) , Alzheimer's disease , asthma ( e.g. , due to abdominal obesity or central / truncal obesity ) , atherosclerosis , hypothyroidism , liver disease , LDL- hypercholesterolemia , hypertriglyceridemia , mixed hyperlipoproteinemia , coronary heart disease , stroke , peripheral arterial disease , high blood pressure , hyperlipidemia , steatosis , non - alcoholic steatohepatitis ( NASH ) , fatty - liver disease , metabolic associated fatty liver disease ( MAFLD ) , non - alcoholic fatty liver disease ( NAFLD ) , liver fibrosis , cirrhosis , or hepatocellular carcinoma .

59. The use of a composition of claim 58 , wherein the disease , disorder , or condition is fatty liver disease , metabolic associated fatty liver disease ( MAFLD ) , non - alcoholic fatty liver disease ( NAFLD ) , steatosis , non - alcoholic steatohepatitis ( NASH ) , liver fibrosis , cirrhosis , or hepatocellular carcinoma .

60. A method of screening a microbial strain , comprising : contacting the microbial strain to a culture comprising liver cells or liver cell lines that model a metabolic disease , disorder , or condition , and determining whether the microbial strain altered a feature of the culture , wherein the feature is associated with the metabolic disease , disorder , or condition . 121 WO 2025/054048 PCT / US2024 / 0440

61. The method of claim 60 , wherein the step of determining comprises comparing the feature before and after performance of the step of contacting .

62. The method of claim 60 , wherein the step of determining comprises comparing the feature after the step of contacting with a comparable reference .

63. The method of claim 62 , wherein the comparable reference is a historical reference .

64. The method of claim 63 , wherein the comparable reference is a negative control . reference .

65. The method of claim 63 , wherein the comparable reference is a positive control . reference .

66. The method of any one of claims 60-65 , wherein the feature is a level of cell viability .

67. The method of any one of claims 60-65 , wherein the feature is level or activity of a nucleic acid or protein , or form thereof .

68. gain . The method of any one of claims 60-65 , wherein the feature is or comprises weight 122 WO 2025/054048 PCT / US2024 / 0440

69. The method of any one of claims 60-65 , wherein the feature is or comprises lipid accumulation in liver cells .

70. The method of any one of claims 60-65 , wherein the feature is or comprises accumulation of visceral fat .

71. The method of any one of claims 60-65 , wherein the feature is or comprises triglyceride levels . .

72. The method of any one of claims 60-65 , wherein the feature is or comprises cholesterol levels .

73. The method of any one of claims 60-65 , wherein the feature is or comprises inflammation .

74. The method of any one of claims 60-65 , wherein the microbial strain altered one or more features of the culture , wherein the one or more features is associated with the metabolic disease , disorder , or condition , and wherein the one or more features is or comprises ( i ) level of cell viability ; ( ii ) level or activity of a nucleic acid or protein , or form thereof ; ( iii ) body weight gain ; ( iv ) lipid accumulation in liver ; ( v ) accumulation of visceral fat ; 123 WO 2025/0540 ( vi ) elevated blood triglyceride levels ; ( vii ) blood - cholesterol levels ; ( viii ) oxidative stress ; ( ix ) hypercholesterolemia ; or ( x ) inflammation . PCT / US2024 / 0440

75. A method comprising : administering to a subject a composition comprising one or more microbial strains or microbial components .

76. A method comprising : administering to a subject a composition comprising one or more microbial metabolites .

77. The method of claim 75 or 76 , wherein the subject is a mammal .

78. The method of any one claims 75-77 , wherein the subject is a human .

79. The method of any one claims 75 or 77-78 , wherein the one or more microbial strains are from a mammalian microbiome .

80. The method of any one claims 75 or 77-79 , wherein the one or more microbial strains are from a human microbiome . 124 WO 2025/054048 PCT / US2024 / 0440

81. The method of claim 80 , wherein the human microbiome is the microbiome of the subject .

82. The method of claim 81 , wherein the human microbiome is administered to maintain or modulate the microbiome of the subject .

83. The method of any one claims 75-82 , wherein one or more microbial components or microbial metabolites are selected from Appendix 1 , Appendix 3 , or Appendix 4 .

84. The method of any one claims 75-83 , wherein the one or more microbial metabolites is or comprises a bile acid , Cholesterol , chenodeoxycholic acid , 16a - chenodeoxycholic acid ( CDCA ) , oxysterols , taurochenodeoxycholic acid , cholic acid , lithocholic acid , ursodeoxycholic acid , triglycerides , very - low density lipoprotein ( VLDL ) , VLDL - TG , cholesterol , eicosanoids , arachidonic acid , docosahexaenoic acid , eicosapentaenoic acid , trimethylamines ( TMA ) , trimethylamine - N - oxide ( TMAO ) , endogenous ethanol , acetone , acetaldehyde , butyrate , choline , or any combination thereof .

85. The method of any one claims 75-84 , wherein the one or more microbial metabolites is or comprises Tauroursodeoxycholic acid ,, taurocholic acid , long - chain acyl - CoA dehydrogenase ( LCAD ) , deoxycholic acid ( DCA ) , lithocholic acid ( LCA ) , taurochenodeoxycholic acid , ursodeoxycholic acid , α7 - hydroxycholesterol , chenodeoxycholic acid , 27 - hydroxycholesterol , α7 - hydroxy - 4 - cholestene - 3 - one , or any combination thereof .

86. The method of any one of claims 75-83 , wherein one or more microbial components or microbial metabolites is Butyrylcamitine , Theobromine , p - Hydroxyphenylpyruvic acid , 125 WO 2025/054048 PCT / US2024 / 0440 Propionic acid , Picolinic acid , 2 - Hydroxy - 4methylvaleric acid , N6 - Acetylysine , Urocanic acid , N5 - Ethylglutamine , Trigonelline , Stachydrine , Ectoine , 5 - Hydroxylysine , Arginine ( arg ) , Cholic acid , 2- ( 4 - Hydroxyphenyl ) propionic acid , N - Acetyltryptophan , Hydroxyproline , Argininosuccinic acid , Glutamic acid ( Glu ) , Sarcosine , 5- Methoxyindoleacetic acid , Indole - 3 - lactic acid , Isovalerylalanine , N - Acetylleucine , I- Methylhistidine , N - Acetylephenylalanine , Proline ( Pro ) , or any combination thereof .

87. The method of any one of claims 75-83 , wherein one or more microbial components or microbial metabolites is 4 - Hydroxyphenylpyruvic , Ectoine , Gramine , N - Acetyl - L- phenylalanine , Nepsilon - Acetyl - L - lysine , Stachydrine , Trigonelline , 3 - Ureidopropionic acid , Theobromine , Hippuric acid , Imidazolepropionic acid , NG - Methyl - L - arginine , trans- Urocanic Acid , N - Acetyl - L - leucine , Sarcosine , Isobutyrylcarnitine , b - Hydroxyisovaleric acid , L - Theanine / N5 - Ethylglutamine , 5 - Hydroxylysine , Phenaceturic acid , betaine , hydroxyproline , Picolinic acid , 2 - Aminoadipic acid , Glycerophosphocholine , carnitine , Glycerol 3 - phosphate , Argininosuccinic acid , creatine , Terephthalic acid , Homocitrulline , Mucic acid , Homocysteinesulfinic acid , Trimethyllysine , Spermidine , Glyoxylic acid , XA0013 C6H604S , 3 - Indoxylsulfuric acid , Nicotinamide , N - Formylglycine , Ureidoglycolate , N - Methylproline , Glucaric acid , Butyrylcarnitine , Methionine sulfoxide , Carboxymethyllysine , Glycolic acid , Phenaceturic acid , Diethanolamine , Phosphorylcholine , Guanidinosuccinic acid , N - Acetylhistidine , Glyceric acid , S - Methylmethionine , Cysteine glutathione disulfide , Kynurenine , N - Acetylphenylalanine , Threonic acid , Malic acid , 7,8- Dihydrobiopterin , Homovanillic acid , Taurocholic acid , 5 - Methoxyindoleacetic acid , butyrate , b - Hydroxyisovaleric acid , 2 - Oxoglutaric acid , N - Acetyltryptophan , Thiaproline , Hypotaurine , Cholic acid , Acetoacetic acid , Ethanolamine , Guanidoacetic acid , S- Sulfocysteine , Myristic acid C14 : 0 XA0027 , or any combination thereof .

88. The method of any one claims 75 or 77-87 , wherein the one or more microbial strains are or comprise Gluconacetobacter hansenii , Terrisporobacter glycolicus , Coprococcus sp . , Lactobacillus plantarum , Clostridium butyricum , Paenibacillus sp . , Veillonella sp . , Bifidobacterium sp . , Bacillus subtilis , Acidaminococcus sp . , or a combination thereof . 126 WO 2025/054048 PCT / US2024 / 0440

89. The method of any one claims 75 or 77-88 , wherein the one or more microbial strains are or comprise Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus sp . , Lactobacillus plantarum , Veillonella sp . , Bifidobacterium sp . , or a combination thereof .

90. The method of any one claims 75 or 77-89 , wherein the one or more microbial strains are or comprise Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus catus , Lactobacillus plantarum , Veillonella atypica , Bifidobacterium breve , or a combination thereof .

91. The method of any one claims 75 or 77-90 , wherein the one or more microbial strains is or comprises Bacillus subtilis .

92. The method of any one claims 75 or 77-91 , wherein the composition comprises two or more microbial strains .

93. The method of any one claims 75 or 77-92 , wherein the composition comprises five or more microbial strains .

94. The method of any one claims 75 or 77-93 , wherein the composition comprises ten or more microbial strains . .

95. The method of any one claims 75-94 , wherein the composition is administered topically , orally , subcutaneously , intravenously , intramuscularly , intracerebrally , intrathecally , rectally , opthalmically , intravitreally , or suprachoroidally . 127 WO 2025/0540

96. PCT / US2024 / 0440 The method of claim 95 , wherein the composition is administered orally .

97. The method of claim 95 , wherein the composition is administered intravenously .

98. The method of any one claims 75-97 , wherein the composition is formulated as a syrup , a liquid , a tablet , a troche , a gummy , a capsule , a powder , a gel , a film , an injection , or an eye drop .

99. The method of any one claims 75 or 77-98 , wherein each microbial strain of the one or more microbial strains is present in the composition at a concentration from 10¹ to 10CFU .

100. The method of any one claims 75 or 77-99 , wherein each microbial strain of the one or more microbial strains is present in the composition at a concentration of at least 1CFU .

101. The method of any one of claims 75-100 , the microbial strain or the microbial metabolite altered a feature of the subject .

102. The method of claim 101 , wherein the feature is a level of cell viability .

103. The method of claim 101 , wherein the feature is level or activity of a nucleic acid or protein , or form thereof . 128 WO 2025/054048 PCT / US2024 / 0440

104. The method of claim 101 , wherein the feature is or comprises body weight gain .

105. liver . The method of claim 101 , wherein the feature is or comprises lipid accumulation in

106. The method of claim 101 , wherein the feature is or comprises accumulation of visceral fat .

107. The method of claim 101 , wherein the feature is or comprises triglyceride levels .

108. The method of claim 101 , wherein the feature is or comprises cholesterol levels .

109. The method of claim 101 , wherein the feature is or comprises inflammation .

110. The method of claim 101 , wherein the microbial strain altered one or more features of the subject , and wherein the one or more features is or comprises ( i ) level of cell viability ; ( ii ) level or activity of a nucleic acid or protein , or form thereof ; ( iii ) body weight gain ; ( iv ) lipid accumulation in liver ; ( v ) accumulation of visceral fat : 129 WO 2025/0540 ( vi ) elevated blood triglyceride levels ; ( vii ) blood - cholesterol levels ; ( viii ) oxidative stress ; ( ix ) hypercholesterolemia ; or ( x ) inflammation . PCT / US2024 / 0440

111. The method of any one of claims 101-110 , wherein the feature is associated with the metabolic disease , disorder , or condition .

112. A method of characterizing a microbial strain , comprising : adding the microbial strain to a culture comprising liver cells or liver cell lines that model a metabolic disease , disorder , or condition , and determining whether the microbial strain affects levels of one or more features of the liver cells or liver cell lines , wherein the one or more features are associated with the metabolic disease , disorder , or condition .

113. A method of manufacturing a pharmaceutical treatment comprising characterizing one or more microbial strains , microbial components , or microbial metabolites comprising the steps of : adding the one or more microbial strains to a culture comprising liver cells or liver cell lines that model a metabolic disease , disorder , or condition , and determining whether the one or more microbial strains affect levels of one or more features of the liver cells or liver cell lines , wherein the one or more features are associated with the metabolic disease , disorder , or condition . 130 WO 2025/054048 PCT / US2024 / 0440

114. A method of manufacturing a pharmaceutical treatment comprising : adding one or more microbial strains or microbial components , to a syrup , a liquid , a tablet , a troche , a gummy , a capsule , a powder , a gel , a film , an injection , or an eye drop .

115. A method of manufacturing a pharmaceutical treatment comprising : adding one or more microbial metabolites , to a syrup , a liquid , a tablet , a troche , a gummy , a capsule , a powder , a gel , a film , an injection , or an eye drop .

116. A method of assessing a microbial strain for the ability to affect one or more features of a culture , comprising : adding the microbial strain to the culture comprising liver cells or liver cell lines that model a metabolic disease , disorder , or condition , and determining whether the microbial strain affects levels of one or more features of the liver cells or liver cell lines , wherein the one or more features are associated with the metabolic disease , disorder , or condition .

117. The method of any one of claims 112-114 or 116 , further comprising : before adding the microbial strain to the culture , determining levels of one or more features of the liver cells or liver cell lines in the culture . after adding the microbial strain to the culture , determining the levels of the same one or more features of the liver cells or liver cell lines in the culture , and comparing the levels of one or more features determined before adding the microbial strain with the levels of one or more features determined after adding the microbial strain . 131 WO 2025/054048 PCT / US2024 / 0440

118. The method of any one of claims 112-117 , wherein the one or more features includes : ( i ) level of cell viability ; ( ii ) level or activity of a nucleic acid or protein , or form thereof ; ( iii ) body weight gain ; ( iv ) lipid accumulation in liver ; ( v ) accumulation of visceral fat ; ( vi ) elevated blood triglyceride levels ; ( vii ) blood - cholesterol levels : ( viii ) oxidative stress ; ( ix ) hypercholesterolemia ; ( x ) inflammation ; or ( xi ) a combination thereof .

119. The method of any one of claims 60-118 , wherein the disease , disorder , or condition is lipid - induced metabolic syndrome , cerebral infarction / stroke , myocardial infarction / heart attack , Type II diabetes / diabetes mellitus , glucose intolerance , alcoholism , metabolic syndrome , kidney disease , cardiorenal syndrome , vascular diseases ( e.g. , hypertension , peripheral arterial disease ) , Alzheimer's disease , asthma ( e.g. , due to abdominal obesity or central / truncal obesity ) , atherosclerosis , hypothyroidism , liver disease , LDL- hypercholesterolemia , hypertriglyceridemia , mixed hyperlipoproteinemia , coronary heart disease , stroke , peripheral arterial disease , high blood pressure , hyperlipidemia , steatosis , non - alcoholic steatohepatitis ( NASH ) , fatty - liver disease , metabolic associated fatty liver disease ( MAFLD ) , non - alcoholic fatty liver disease ( NAFLD ) , liver fibrosis , cirrhosis , or hepatocellular carcinoma . 132 WO 2025/054048 PCT / US2024 / 0440

120. A composition for use in treating or preventing a metabolic disease , disorder , or condition , comprising one or more microbial strains or microbial components .

121. A composition for use in treating or preventing a metabolic disease , disorder , or condition , comprising one or more microbial metabolites .

122. The use of claim 120 , wherein the one or more microbial strains are from a mammalian microbiome .

123. 123 The use of claim 120 or 122 , wherein the one or more microbial strains are from a human microbiome .

124. subject . The use of claim 123 , wherein the human microbiome is the microbiome of the

125. The use of claim 124. wherein the human microbiome is administered to maintain or modulate the microbiome of the subject .

126. The use of any one of claims 120-125 , wherein one or more microbial components or microbial metabolites are selected from Appendix 1 , Appendix 3 , or Appendix 4 .

127. The use of any one of claims 120-126 , wherein the one or more microbial metabolites is or comprises a bile acid , Cholesterol , chenodeoxycholic acid , -αchenodeoxycholic acid ( CDCA ) , oxysterols , taurochenodeoxycholic acid , cholic acid , 133 WO 2025/054048 PCT / US2024 / 0440 lithocholic acid , ursodeoxycholic acid , triglycerides , very - low density lipoprotein ( VLDL ) , VLDL - TG , cholesterol , eicosanoids , arachidonic acid , docosahexaenoic acid , eicosapentaenoic acid , trimethylamines ( TMA ) , trimethylamine - N - oxide ( TMAO ) , endogenous ethanol , acetone , acetaldehyde , butyrate , choline , or any combination thereof .

128. The use of any one of claims 120-127 , wherein the one or more microbial metabolites is or comprises Tauroursodeoxycholic acid ,, taurocholic acid , long - chain acyl- CoA dehydrogenase ( LCAD ) , deoxycholic acid ( DCA ) , lithocholic acid ( LCA ) , taurochenodeoxycholic acid , ursodeoxycholic acid , α7 - hydroxycholesterol , chenodeoxycholic acid , 27 - hydroxycholesterol , α7 - hydroxy - 4 - cholestene - 3 - one , or any combination thereof .

129. The use of any one of claims 120-126 , wherein one or more microbial components or microbial metabolites is Butyrylcamitine , Theobromine , p - Hydroxyphenylpyruvic acid , Propionic acid , Picolinic acid , 2 - Hydroxy - 4methylvaleric acid , N6 - Acetylysine , Urocanic acid , N5 - Ethylglutamine , Trigonelline , Stachy drine , Ectoine , 5 - Hydroxylysine , Arginine ( arg ) , Cholic acid , 2- ( 4 - Hydroxyphenyl ) propionic acid , N - Acetyltryptophan , Hydroxyproline , Argininosuccinic acid , Glutamic acid ( Glu ) , Sarcosine , 5- Methoxyindoleacetic acid , Indole - 3 - lactic acid , Isovalerylalanine , N - Acetylleucine , 1- Methylhistidine , N - Acetylephenylalanine , Proline ( Pro ) , or any combination thereof .

130. The use of any one of claims 120-126 , wherein one or more microbial components or microbial metabolites is 4 - Hydroxyphenylpyruvic , Ectoine , Gramine , N - Acetyl - L- phenylalanine , Nepsilon - Acetyl - L - lysine , Stachydrine , Trigonelline , 3 - Ureidopropionic acid , Theobromine , Hippuric acid , Imidazolepropionic acid , NG - Methyl - L - arginine , trans- Urocanic Acid , N - Acetyl - L - leucine , Sarcosine , Isobutyrylcarnitine , b - Hydroxyisovaleric acid , L - Theanine / N5 - Ethylglutamine , 5 - Hydroxylysine , Phenaceturic acid , betaine , hydroxyproline , Picolinic acid , 2 - Aminoadipic acid , Glycerophosphocholine , carnitine , Glycerol 3 - phosphate , Argininosuccinic acid , creatine , Terephthalic acid , Homocitrulline , Mucic acid , Homocysteinesulfinic acid , Trimethyllysine , Spermidine , Glyoxylic acid , 134 WO 2025/054048 PCT / US2024 / 0440 XA0013 C6H604S , 3 - Indoxylsulfuric acid , Nicotinamide , N - Formylglycine , Ureidoglycolate , N - Methylproline , Glucaric acid , Butyrylcarnitine , Methionine sulfoxide , Carboxymethyllysine , Glycolic acid , Phenaceturic acid , Diethanolamine , Phosphorylcholine , Guanidinosuccinic acid , N - Acetylhistidine , Glyceric acid , S - Methylmethionine , Cysteine glutathione disulfide , Kynurenine , N - Acetylphenylalanine , Threonic acid , Malic acid , 7,8- Dihydrobiopterin , Homovanillic acid , Taurocholic acid , 5 - Methoxyindoleacetic acid , butyrate , b - Hydroxyisovaleric acid , 2 - Oxoglutaric acid , N - Acetyltryptophan , Thiaproline , Hypotaurine , Cholic acid , Acetoacetic acid , Ethanolamine , Guanidoacetic acid , S- Sulfocysteine , Myristic acid C14 : 0 XA0027 , or any combination thereof .

131. The use of any one of claims 120 or 122-130 , wherein the one or more microbial strains are or comprise Gluconacetobacter hansenii , Terrisporobacter glycolicus , Coprococcus sp . , Lactobacillus plantarum , Clostridium butyricum , Paenibacillus sp . , Veillonella sp . , Bifidobacterium sp . , Bacillus subtilis , Acidaminococcus sp . , or a combination thereof .

132. The use of any one of claims 120 or 122-131 , wherein the one or more microbial strains are or comprise Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus sp . , Lactobacillus plantarum , Veillonella sp . , Bifidobacterium sp . , or a combination thereof .

133. The use of any one of claims 120 or 122-132 , wherein the one or more microbial strains are or comprise Gluconacetobacter hanseni , Terrisporobacter glycolicus , Coprococcus catus , Lactobacillus plantarum , Veillonella atypica , Bifidobacterium breve , or a combination thereof .

134. The use of any one of claims 120 or 122-133 , wherein the one or more microbial strains is or comprises Bacillus subtilis . 135 WO 2025/054048 PCT / US2024 / 0440

135. The use of any one of claims 120 or 122-134 , wherein the composition comprises two or more microbial strains .

136. The use of any one of claims 120 or 122-135 , wherein the composition comprises five or more microbial strains .

137. The use of any one of claims 120 or 122-136 , wherein the composition comprises ten or more microbial strains .

138. The use of any one of claims 120-137 , wherein the composition is for topical , oral , subcutaneous , intravenous , intramuscular , intracerebral , intrathecal , rectal , opthalmical , intravitreal , or suprachoroidal administration .

139. The use of claim 138 , wherein the composition is for oral administration .

140. The use of claim 138 , wherein the composition is for intravenous administration .

141. The use of any one of claims 120-140 , wherein the composition is formulated as a syrup , a liquid , a tablet , a troche , a gummy , a capsule , a powder , a gel , a film , an injection , or an eye drop .

142. The use of any one of claims 120 or 122-141 , wherein each microbial strain of the one or more microbial strains is present in the composition at a concentration from 10 ' to 1015 CFU . 136 WO 2025/054048 PCT / US2024 / 0440

143. The use of any one of claims 120 or 122-141 , wherein each microbial strain of the one or more microbial strains is present in the composition at a concentration of at least 1CFU .

144. The use of any one of claims 120-143 , wherein the metabolic disease , disorder , or condition is lipid - induced metabolic syndrome , cerebral infarction / stroke , myocardial infarction / heart attack , Type II diabetes / diabetes mellitus , glucose intolerance , alcoholism , metabolic syndrome , kidney disease , cardiorenal syndrome , vascular diseases ( e.g. , hypertension , peripheral arterial disease ) , Alzheimer's disease , asthma ( e.g. , due to abdominal obesity or central / truncal obesity ) , atherosclerosis , hypothyroidism , liver disease , LDL - hypercholesterolemia , hypertriglyceridemia , mixed hyperlipoproteinemia , coronary heart disease , stroke , peripheral arterial disease , high blood pressure , hyperlipidemia , steatosis , non - alcoholic steatohepatitis ( NASH ) , fatty - liver disease , metabolic associated fatty liver disease ( MAFLD ) , non - alcoholic fatty liver disease ( NAFLD ) , liver fibrosis , cirrhosis , or hepatocellular carcinoma .

145. The use of claim 144 , wherein the metabolic disease , disorder , or condition is fatty- liver disease , metabolic associated fatty liver disease ( MAFLD ) , non - alcoholic fatty liver disease ( NAFLD ) , steatosis , non - alcoholic steatohepatitis ( NASH ) , liver fibrosis , cirrhosis , or hepatocellular carcinoma .

146. An injection comprising the composition of any one of claims 29-52 .

147. A food supplement comprising the composition of any one of claims 29-52 . 137 WO 2025/054048 PCT / US2024 / 0440

148. A kit comprising the composition of claim any one of claims 29-52 or 120 for use in treating or preventing a metabolic disease , disorder , or condition . 138