US20220000950A1 - Compositions and Methods of Use of Novel Strains of Lactobacillus Fermentum - Google Patents
Compositions and Methods of Use of Novel Strains of Lactobacillus Fermentum Download PDFInfo
- Publication number
- US20220000950A1 US20220000950A1 US17/350,102 US202117350102A US2022000950A1 US 20220000950 A1 US20220000950 A1 US 20220000950A1 US 202117350102 A US202117350102 A US 202117350102A US 2022000950 A1 US2022000950 A1 US 2022000950A1
- Authority
- US
- United States
- Prior art keywords
- lactobacillus fermentum
- composition
- subject
- nrrl
- strains
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 241000186840 Lactobacillus fermentum Species 0.000 title claims abstract description 129
- 229940012969 lactobacillus fermentum Drugs 0.000 title claims abstract description 118
- 239000000203 mixture Substances 0.000 title claims abstract description 94
- 238000000034 method Methods 0.000 title claims abstract description 81
- 230000000975 bioactive effect Effects 0.000 claims abstract description 57
- 210000000987 immune system Anatomy 0.000 claims abstract description 34
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 51
- 239000000047 product Substances 0.000 claims description 46
- 235000013305 food Nutrition 0.000 claims description 34
- 235000013365 dairy product Nutrition 0.000 claims description 33
- 201000010099 disease Diseases 0.000 claims description 29
- 239000008194 pharmaceutical composition Substances 0.000 claims description 24
- 208000035475 disorder Diseases 0.000 claims description 22
- 108090000623 proteins and genes Proteins 0.000 claims description 21
- 235000015872 dietary supplement Nutrition 0.000 claims description 18
- 238000004519 manufacturing process Methods 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 15
- 102000004127 Cytokines Human genes 0.000 claims description 14
- 108090000695 Cytokines Proteins 0.000 claims description 14
- 230000036541 health Effects 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 11
- 230000028327 secretion Effects 0.000 claims description 11
- 239000007858 starting material Substances 0.000 claims description 11
- 102000004169 proteins and genes Human genes 0.000 claims description 10
- 208000023275 Autoimmune disease Diseases 0.000 claims description 9
- 239000003995 emulsifying agent Substances 0.000 claims description 7
- 229940124597 therapeutic agent Drugs 0.000 claims description 7
- 206010061218 Inflammation Diseases 0.000 claims description 6
- 208000027866 inflammatory disease Diseases 0.000 claims description 6
- 230000004054 inflammatory process Effects 0.000 claims description 6
- 239000002775 capsule Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 239000003755 preservative agent Substances 0.000 claims description 5
- 239000003826 tablet Substances 0.000 claims description 5
- 239000000654 additive Substances 0.000 claims description 4
- 230000000996 additive effect Effects 0.000 claims description 4
- 239000012867 bioactive agent Substances 0.000 claims description 4
- 239000006071 cream Substances 0.000 claims description 4
- 235000005911 diet Nutrition 0.000 claims description 4
- 239000000839 emulsion Substances 0.000 claims description 4
- 230000002708 enhancing effect Effects 0.000 claims description 4
- 239000007937 lozenge Substances 0.000 claims description 4
- 230000002335 preservative effect Effects 0.000 claims description 4
- 239000008299 semisolid dosage form Substances 0.000 claims description 4
- 239000007909 solid dosage form Substances 0.000 claims description 4
- 230000000378 dietary effect Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 239000002674 ointment Substances 0.000 claims description 3
- 239000008297 liquid dosage form Substances 0.000 claims description 2
- 239000008176 lyophilized powder Substances 0.000 claims description 2
- 239000008185 minitablet Substances 0.000 claims description 2
- 238000007911 parenteral administration Methods 0.000 claims description 2
- 239000008188 pellet Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 29
- 235000021001 fermented dairy product Nutrition 0.000 abstract description 25
- 235000013336 milk Nutrition 0.000 description 31
- 239000008267 milk Substances 0.000 description 31
- 210000004080 milk Anatomy 0.000 description 31
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 28
- 239000003795 chemical substances by application Substances 0.000 description 23
- 239000004310 lactic acid Substances 0.000 description 14
- 235000014655 lactic acid Nutrition 0.000 description 14
- 102000003814 Interleukin-10 Human genes 0.000 description 13
- 108090000174 Interleukin-10 Proteins 0.000 description 13
- 208000024891 symptom Diseases 0.000 description 13
- 102000004889 Interleukin-6 Human genes 0.000 description 11
- 108090001005 Interleukin-6 Proteins 0.000 description 11
- 108020004465 16S ribosomal RNA Proteins 0.000 description 10
- 241000894006 Bacteria Species 0.000 description 10
- 229940076144 interleukin-10 Drugs 0.000 description 10
- 238000011282 treatment Methods 0.000 description 10
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 9
- 208000029462 Immunodeficiency disease Diseases 0.000 description 9
- 229940100601 interleukin-6 Drugs 0.000 description 9
- 230000036961 partial effect Effects 0.000 description 9
- 239000006041 probiotic Substances 0.000 description 9
- 235000018291 probiotics Nutrition 0.000 description 9
- 235000018102 proteins Nutrition 0.000 description 9
- 239000003981 vehicle Substances 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 8
- 235000015140 cultured milk Nutrition 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 241000282414 Homo sapiens Species 0.000 description 7
- 102000000588 Interleukin-2 Human genes 0.000 description 7
- 108010002350 Interleukin-2 Proteins 0.000 description 7
- 230000003110 anti-inflammatory effect Effects 0.000 description 7
- 239000000969 carrier Substances 0.000 description 7
- 238000000855 fermentation Methods 0.000 description 7
- 230000004151 fermentation Effects 0.000 description 7
- 230000004968 inflammatory condition Effects 0.000 description 7
- 235000013618 yogurt Nutrition 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 241000282412 Homo Species 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 239000003242 anti bacterial agent Substances 0.000 description 5
- 229940088710 antibiotic agent Drugs 0.000 description 5
- 235000013361 beverage Nutrition 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 235000013376 functional food Nutrition 0.000 description 5
- 229940099472 immunoglobulin a Drugs 0.000 description 5
- 239000002773 nucleotide Substances 0.000 description 5
- 125000003729 nucleotide group Chemical group 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 201000004624 Dermatitis Diseases 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 230000001580 bacterial effect Effects 0.000 description 4
- 238000002869 basic local alignment search tool Methods 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 230000007812 deficiency Effects 0.000 description 4
- 230000002519 immonomodulatory effect Effects 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 230000002757 inflammatory effect Effects 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 230000000529 probiotic effect Effects 0.000 description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 108060003951 Immunoglobulin Proteins 0.000 description 3
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 201000004681 Psoriasis Diseases 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000003833 bile salt Substances 0.000 description 3
- 229940093761 bile salts Drugs 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 235000013351 cheese Nutrition 0.000 description 3
- -1 coatings Substances 0.000 description 3
- 235000009508 confectionery Nutrition 0.000 description 3
- 235000013861 fat-free Nutrition 0.000 description 3
- 235000013350 formula milk Nutrition 0.000 description 3
- 102000018358 immunoglobulin Human genes 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 208000028529 primary immunodeficiency disease Diseases 0.000 description 3
- 230000007112 pro inflammatory response Effects 0.000 description 3
- 230000000770 proinflammatory effect Effects 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 3
- 230000010641 Acidifying Activity Effects 0.000 description 2
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- 244000068988 Glycine max Species 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 2
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- 206010061598 Immunodeficiency Diseases 0.000 description 2
- 208000003456 Juvenile Arthritis Diseases 0.000 description 2
- 241000186660 Lactobacillus Species 0.000 description 2
- 240000002129 Malva sylvestris Species 0.000 description 2
- 235000006770 Malva sylvestris Nutrition 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- 230000028654 Type IV pili-dependent aggregation Effects 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- 206010047115 Vasculitis Diseases 0.000 description 2
- 208000036142 Viral infection Diseases 0.000 description 2
- 239000003070 absorption delaying agent Substances 0.000 description 2
- 230000023445 activated T cell autonomous cell death Effects 0.000 description 2
- 210000000577 adipose tissue Anatomy 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 230000001332 colony forming effect Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000002939 deleterious effect Effects 0.000 description 2
- 239000002612 dispersion medium Substances 0.000 description 2
- 239000002702 enteric coating Substances 0.000 description 2
- 238000009505 enteric coating Methods 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 230000002949 hemolytic effect Effects 0.000 description 2
- 235000015243 ice cream Nutrition 0.000 description 2
- 208000026278 immune system disease Diseases 0.000 description 2
- 230000007813 immunodeficiency Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 239000007951 isotonicity adjuster Substances 0.000 description 2
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 2
- 229940039696 lactobacillus Drugs 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 201000008383 nephritis Diseases 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 208000037920 primary disease Diseases 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 230000002797 proteolythic effect Effects 0.000 description 2
- 230000009291 secondary effect Effects 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 229960002622 triacetin Drugs 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 230000035899 viability Effects 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- MMRINLZOZVAPDZ-LSGRDSQZSA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(1-methylpyrrolidin-1-ium-1-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;chloride Chemical compound Cl.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 MMRINLZOZVAPDZ-LSGRDSQZSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 206010069002 Autoimmune pancreatitis Diseases 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- 241000186000 Bifidobacterium Species 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 206010006811 Bursitis Diseases 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 102100035882 Catalase Human genes 0.000 description 1
- 108010053835 Catalase Proteins 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 1
- 208000015943 Coeliac disease Diseases 0.000 description 1
- 240000007154 Coffea arabica Species 0.000 description 1
- 102100024133 Coiled-coil domain-containing protein 50 Human genes 0.000 description 1
- 201000003874 Common Variable Immunodeficiency Diseases 0.000 description 1
- 206010010317 Congenital absence of bile ducts Diseases 0.000 description 1
- 206010010741 Conjunctivitis Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 208000014311 Cushing syndrome Diseases 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 206010012442 Dermatitis contact Diseases 0.000 description 1
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 1
- 206010013774 Dry eye Diseases 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 229920005682 EO-PO block copolymer Polymers 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 206010017533 Fungal infection Diseases 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 206010017943 Gastrointestinal conditions Diseases 0.000 description 1
- 229930182566 Gentamicin Natural products 0.000 description 1
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000024869 Goodpasture syndrome Diseases 0.000 description 1
- 206010018634 Gouty Arthritis Diseases 0.000 description 1
- 208000003807 Graves Disease Diseases 0.000 description 1
- 208000015023 Graves' disease Diseases 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 208000001204 Hashimoto Disease Diseases 0.000 description 1
- 101000910772 Homo sapiens Coiled-coil domain-containing protein 50 Proteins 0.000 description 1
- 101000878605 Homo sapiens Low affinity immunoglobulin epsilon Fc receptor Proteins 0.000 description 1
- 208000028622 Immune thrombocytopenia Diseases 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- 208000009319 Keratoconjunctivitis Sicca Diseases 0.000 description 1
- 241000194036 Lactococcus Species 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 102100038007 Low affinity immunoglobulin epsilon Fc receptor Human genes 0.000 description 1
- 208000005777 Lupus Nephritis Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 102000016943 Muramidase Human genes 0.000 description 1
- 108010014251 Muramidase Proteins 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 1
- RZCHTMXTKQHYDT-UHFFFAOYSA-N N-Lactoyl ethanolamine Chemical compound CC(O)C(=O)NCCO RZCHTMXTKQHYDT-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000192001 Pediococcus Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 102000057297 Pepsin A Human genes 0.000 description 1
- 108090000284 Pepsin A Proteins 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 206010036774 Proctitis Diseases 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 206010039705 Scleritis Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 206010039793 Seborrhoeic dermatitis Diseases 0.000 description 1
- 229920002385 Sodium hyaluronate Polymers 0.000 description 1
- 201000002661 Spondylitis Diseases 0.000 description 1
- 206010041955 Stasis dermatitis Diseases 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- GCSPRLPXTPMSTL-IBDNADADSA-N [(2s,3r,4s,5s,6r)-2-[(2s,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)O[C@@]1([C@]2(CO)[C@H]([C@H](O)[C@@H](CO)O2)O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O GCSPRLPXTPMSTL-IBDNADADSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 201000011040 acute kidney failure Diseases 0.000 description 1
- 208000012998 acute renal failure Diseases 0.000 description 1
- 238000011374 additional therapy Methods 0.000 description 1
- 210000004404 adrenal cortex Anatomy 0.000 description 1
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 208000002029 allergic contact dermatitis Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 238000009635 antibiotic susceptibility testing Methods 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000006472 autoimmune response Effects 0.000 description 1
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 1
- 235000008452 baby food Nutrition 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 239000007640 basal medium Substances 0.000 description 1
- 201000005271 biliary atresia Diseases 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 239000006161 blood agar Substances 0.000 description 1
- 238000009534 blood test Methods 0.000 description 1
- 235000008429 bread Nutrition 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 235000015155 buttermilk Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- XIURVHNZVLADCM-IUODEOHRSA-N cefalotin Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC(=O)C)C(O)=O)C(=O)CC1=CC=CS1 XIURVHNZVLADCM-IUODEOHRSA-N 0.000 description 1
- 229960000603 cefalotin Drugs 0.000 description 1
- 229960002100 cefepime Drugs 0.000 description 1
- 229960001668 cefuroxime Drugs 0.000 description 1
- JFPVXVDWJQMJEE-IZRZKJBUSA-N cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 JFPVXVDWJQMJEE-IZRZKJBUSA-N 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 235000010675 chips/crisps Nutrition 0.000 description 1
- 229940045110 chitosan Drugs 0.000 description 1
- 235000019219 chocolate Nutrition 0.000 description 1
- 208000019069 chronic childhood arthritis Diseases 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 235000016213 coffee Nutrition 0.000 description 1
- 235000013353 coffee beverage Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 235000014510 cooky Nutrition 0.000 description 1
- 235000014048 cultured milk product Nutrition 0.000 description 1
- 235000015142 cultured sour cream Nutrition 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- YFAGHNZHGGCZAX-JKIFEVAISA-N dicloxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(Cl)C=CC=C1Cl YFAGHNZHGGCZAX-JKIFEVAISA-N 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 235000021113 dry cheese Nutrition 0.000 description 1
- 210000000750 endocrine system Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229960002518 gentamicin Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 244000005709 gut microbiome Species 0.000 description 1
- 230000007407 health benefit Effects 0.000 description 1
- 230000008821 health effect Effects 0.000 description 1
- 235000013402 health food Nutrition 0.000 description 1
- 210000005003 heart tissue Anatomy 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000031261 interleukin-10 production Effects 0.000 description 1
- 230000017306 interleukin-6 production Effects 0.000 description 1
- 201000006334 interstitial nephritis Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 201000004614 iritis Diseases 0.000 description 1
- 208000001875 irritant dermatitis Diseases 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 235000015141 kefir Nutrition 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 235000020191 long-life milk Nutrition 0.000 description 1
- 235000004213 low-fat Nutrition 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 239000004325 lysozyme Substances 0.000 description 1
- 235000010335 lysozyme Nutrition 0.000 description 1
- 229960000274 lysozyme Drugs 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000007257 malfunction Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229940117841 methacrylic acid copolymer Drugs 0.000 description 1
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 230000000050 nutritive effect Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 238000009928 pasteurization Methods 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229940111202 pepsin Drugs 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 208000002440 photoallergic dermatitis Diseases 0.000 description 1
- 208000007578 phototoxic dermatitis Diseases 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 201000009395 primary hyperaldosteronism Diseases 0.000 description 1
- 201000000742 primary sclerosing cholangitis Diseases 0.000 description 1
- 235000020991 processed meat Nutrition 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 208000006934 radiodermatitis Diseases 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 235000020185 raw untreated milk Nutrition 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 235000021067 refined food Nutrition 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000250 revascularization Effects 0.000 description 1
- 208000010157 sclerosing cholangitis Diseases 0.000 description 1
- 208000008742 seborrheic dermatitis Diseases 0.000 description 1
- 208000037921 secondary disease Diseases 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229940010747 sodium hyaluronate Drugs 0.000 description 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 235000021262 sour milk Nutrition 0.000 description 1
- 235000011496 sports drink Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 235000000891 standard diet Nutrition 0.000 description 1
- 238000011476 stem cell transplantation Methods 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 201000003067 thrombocytopenia due to platelet alloimmunization Diseases 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008256 whipped cream Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
- A61K35/741—Probiotics
- A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
- A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
- A23C9/00—Milk preparations; Milk powder or milk powder preparations
- A23C9/12—Fermented milk preparations; Treatment using microorganisms or enzymes
- A23C9/123—Fermented milk preparations; Treatment using microorganisms or enzymes using only microorganisms of the genus lactobacteriaceae; Yoghurt
- A23C9/1234—Fermented milk preparations; Treatment using microorganisms or enzymes using only microorganisms of the genus lactobacteriaceae; Yoghurt characterised by using a Lactobacillus sp. other than Lactobacillus Bulgaricus, including Bificlobacterium sp.
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0031—Rectum, anus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2400/00—Lactic or propionic acid bacteria
- A23V2400/11—Lactobacillus
- A23V2400/143—Fermentum
-
- A23Y2220/35—
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K2035/11—Medicinal preparations comprising living procariotic cells
- A61K2035/115—Probiotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
Definitions
- Lactic acid bacteria including those of the genera Lactococcus, Lactobacillus, Streptococcus, Bifidobacterium , and Pediococcus , have long been utilized as fermenting agents for the preservations of food and for preparing from milk a variety of different foodstuff such as cheese, yogurt and other fermented dairy products. More recently, some lactic acid bacteria strains have been found to exhibit beneficial properties for humans and animals including, e.g., the enhancement of immune system function.
- This disclosure relates to new Lactobacillus fermentum strains, NRRL B-67059 or NRRL B-67060, and a bacterial preparation containing the same, that can produce a bioactive fermented dairy product, particularly one that modulates the immune system for better health.
- the present disclosure provides a composition or edible product including one or more Lactobacillus fermentum strains that shares at least 80% to 100% genome sequence identity with Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060.
- the present disclosure provides a composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% sequence identity with the partial 16S rRNA gene sequence of SEQ ID NO: 1 or SEQ ID NO: 2.
- the composition includes Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060.
- the modulation of the immune system is the modulation of systemic IgA and the anti-inflammatory cytokine interleukin-10 (IL-10).
- the modulation of the immune system is the modulation of the pro inflammatory cytokines interleukin-6 (IL-6) and interleukin-2 (IL-2).
- IL-6 interleukin-6
- IL-2 interleukin-2
- This biologically active fermented dairy product can be manufactured for the production of a functional food.
- Another aspect relates to the isolation of biologically active fractions from this fermented dairy product and their addition to a food as part of the formulation or as part of a food supplement or a pharmaceutical preparation.
- Lactobacillus fermentum strains can be used to produce a bioactive fermented dairy product that has remarkable capacity to modulate the immune system in humans or mammals.
- Such bioactive fermented dairy product or its isolated biologically active fractions provides a method for inducing, increasing or stimulating the secretion of cytokines, such as interleukin-10 (IL-10) and antibodies immunoglobulin A (IgA).
- cytokines such as interleukin-10 (IL-10) and antibodies immunoglobulin A (IgA).
- IL-10 interleukin-10
- IgA immunoglobulin A
- bioactive fermented dairy product or its active fractions did not induce a pro-inflammatory response, such as that shown by interleukin-2 (IL-2) or interleukin-6 (IL-6).
- bioactive fermented dairy product or its isolated fractions described herein is a viable option to modulate the immune system without secondary effects which are produced by some drugs. Additionally, such bioactive fermented dairy product or its isolated fractions induces anti-inflammatory effect at the systemic level. Therefore, the mentioned Lactobacillus fermentum strains, NRRL B-67059 or NRRL B-67060, and the bioactive compounds produced by them, may be used in pharmaceutical preparations as well as in food products.
- novel Lactobacillus fermentum NRRL B-67059 or NRRL B-67060 and bioactive products incorporating or derived from the novel Lactobacillus fermentum NRRL B-67059 or NRRL B-67060 can be administered to persons suffering from immune system deficiencies and, in particular, deficiencies in the secretion of cytokines to modulate and improve the functioning of their immune system and the secretion of cytokines.
- Bioactive compounds can be generated by the action of novel Lactobacillus fermentum NRRL B-67059 or NRRL B-67060 during the fermentation of dairy substrates.
- One objective is the manufacture of food products with bioactive compounds, for the production of functional foods as a consequence of the action of specific Lactobacillus fermentum NRRL B-67059 or NRRL B-67060 on a substrate within the food.
- these bioactive compounds could be used in an edible product such as a food supplement or as a pharmaceutical composition.
- the novel Lactobacillus fermentum NRRL B-67059 or NRRL B-67060 can be concentrated in manufactured food products to provide enhanced efficacy.
- FIG. 1 is a graph showing cell growth of Lactobacillus fermentum NRRL B-67059 and NRRL B-67060.
- NRRL B-67059 and NRRL B-67060 have been deposited at the National Center for Agricultural Utilization Research, United States Department of Agriculture, United States of America, on Apr. 17, 2015.
- NRRL B-67059 and NRRL B-67060 are understood to refer to the deposited strains of Lactobacillus fermentum as well as progeny obtained from the subculture of the isolated strains or their mutants that maintain the biological properties of the deposited NRRL B-67059 and NRRL B-67060 strains.
- Lactobacillus fermentum of the present disclosure shares at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% genome sequence identity with the deposited NRRL B-67059 and NRRL B-67060.
- a Lactobacillus fermentum of the present disclosure shares at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the partial 16S rRNA gene sequence of SEQ ID NO: 1 or SEQ ID NO: 2, respectively.
- the present disclosure provides a composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% genome sequence identity with Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060.
- the present disclosure provides a composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% sequence identity with the partial 16S rRNA gene sequence of SEQ ID NO: 1 or SEQ ID NO: 2.
- the composition includes Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060.
- Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060 are purified.
- the composition does or may include a bioactive agent, an additive, an excipient, an emulsifier, a therapeutic agent, and/or a preservative.
- the composition of the present disclosure is formulated as a pharmaceutical composition or an edible product.
- the pharmaceutical composition is or may be a solid dosage form, a semisolid dosage form, or a liquid dosage form.
- the solid dosage form is or may be a tablet, a lozenge, or a capsule.
- the tablet or the capsule includes microtablets, minitablets, pellets, or granulates comprising lyophilized powder of the strain.
- the semisolid dosage form is a gel, a cream, an ointment, or a chewable lozenge.
- the liquid is or may be an emulsion or a solution.
- composition or the pharmaceutical composition of the present disclosure may be or is formulated for oral, rectal, or parenteral administration to a subject in need thereof.
- the edible product of the present disclosure is a food product or a food supplement.
- the food product or a food supplement includes or may include a food delivery vehicle.
- the food product or food supplement includes or may include a dairy product.
- the edible product of the present disclosure is a dairy product.
- the edible product of the present disclosure is a beverage.
- the present disclosure provides an edible product or a pharmaceutical composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% genome sequence identity with Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060.
- the edible product and/or the pharmaceutical composition includes Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060.
- the present disclosure provides an edible product and/or a pharmaceutical composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% sequence identity with the partial 16S rRNA gene sequence of SEQ ID NO: 1 or SEQ ID NO: 2.
- Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060 are purified.
- the edible product or the pharmaceutical composition of the present disclosure does or may include a bioactive agent, an additive, an excipient, an emulsifier, a therapeutic agent, and/or a preservative.
- the edible product is a food product or a food supplement.
- the food product or a food supplement includes a food delivery vehicle.
- the food product or food supplement includes a dairy product.
- the edible product is prepared as a dairy product.
- the edible product is prepared as a beverage.
- compositions that include Lactobacillus fermentum strains, e.g., the deposited NRRL B-67059 and NRRL B-67060 strains, and a physiologically acceptable delivery vehicle.
- physiologically acceptable carrier or “pharmaceutically acceptable carrier” means buffers, carriers, and excipients suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
- the carrier(s) should be “acceptable” in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient.
- a physiologically acceptable carrier can be administered to an individual along with the relevant active compound without causing clinically unacceptable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
- Physiologically acceptable carriers include buffers, solvents, dispersion media, coatings, isotonic and absorption-delaying agents, and the like, that are compatible with pharmaceutical administration.
- Physiologically acceptable carriers include any of the standard carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents.
- the compositions also can include stabilizers and preservatives.
- Physiologically acceptable carriers include buffers, solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is known in the art.
- the composition is administered orally and includes an enteric coating suitable for regulating the site of absorption of the encapsulated substances within the digestive system or gut.
- an enteric coating can include an ethylacrylate-methacrylic acid copolymer.
- vehicle refers to a medium used to carry an active agent. Vehicles of the present invention typically comprise components such as polymers and solvents.
- fermented dairy products produced using Lactobacillus fermentum strains, e.g., the deposited NRRL B-67059 or NRRL B-67060 strains.
- the term “fermented dairy product” refers to products which are obtained by the multiplication of lactic acid bacteria, e.g., Lactobacillus fermentum , in a milk base leading to a milk coagulum.
- the milk preparation used as raw material for the fermentation may be skimmed or non-skimmed milk, optionally concentrated or in the form of powder. Furthermore, this milk preparation may have been subjected to a thermal processing operation which is at least as efficient as pasteurization.
- fermented dairy products manufactured herein include, for instance, various types of regular yogurt, low fat yogurt, non-fat yogurt, kefir, ymer, buttermilk, butterfat, sour cream and sour whipped cream as well as fresh cheeses.
- Processes for making fermented dairy products are well known in the art.
- bioactive dairy product refers to a fermented dairy product that can affect a biological function.
- the biological activity of a bioactive dairy product may, e.g., result from particular compounds generated by Lactobacillus fermentum strains during the fermentation of dairy products. Accordingly, also provided herein are isolated fractions of a bioactive dairy product, i.e., bioactive dairy product fractions, or isolated compounds of a bioactive dairy product, i.e., bioactive compounds, that possess the same biological properties as the bioactive diary product. Methods for fractionating fermented dairy products or isolating compounds from fermented dairy products are well known in the art.
- Lactobacillus fermentum strains can be formulated into physiological acceptable compositions by combination with appropriate, physiologically acceptable carriers.
- Additional components of a composition can include trehalose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium hyaluronate, sodium alginate, chitosan and its derivatives, polyethylene glycol, glycerin, propylene glycol, Triacetin, N,N-Dimethylacetamide, pyrrolidone, dimethyl sulfoxide, ethanol, N-(-beta-Hydroxyethyl)-lactamide, 1-Methyl-2-pyrrolidinone, triglycerides, monothioglycerol, sorbitol, lecithin, methylparaben, propylparaben, polysorbates, block copolymers of ethylene oxide and propylene oxide, di-block polymers or tri-block copolymers of polyethylene oxide and polypropylene oxide, ethoxylated emulsifiers, polyethylene glycol esters, sucrose la
- Lactobacillus fermentum strains may be formulated into preparations including, e.g., tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols and topical compositions.
- the formulations may be designed for administration via a number of different routes, including, e.g., oral, buccal, sublingual, rectal, parenteral, intraperitoneal, intradermal, transdermal, or intracheal administration.
- the composition is a food product.
- Food products of interest include a disclosed Lactobacillus fermentum strain in combination with a food delivery vehicle.
- food delivery vehicle is meant a delivery vehicle that is a nourishing substance that is eaten, drunk, or otherwise taken into the body to sustain life, provide energy, promote growth, etc.
- Examples of food delivery vehicles or food products of interest include, but are not limited to: baby or infant formula, baby food (e.g., pureed food suitable for infant or toddler consumption), chips, cookies, breads, spreads, creams, yogurts, liquid drinks, chocolate containing products, candies, ice creams, cereals, coffees, pureed food products, water, fluid milk products, milk, concentrated milk, fermented milk, yogurt, sour milk, frozen yogurt, lactic acid bacteria-fermented beverages, milk powder, ice cream, cream cheeses, dry cheeses, soybean milk, fermented soybean milk, vegetable-fruit juices, juices, sports drinks, confectionery, jellies, candies, infant formulas, health foods, and/or animal feeds.
- the composition is a food supplement.
- a food supplement may further include, e.g., a sweetener, a stabilizer, a flavoring, an emulsifier, and/or a colorant.
- the composition (e.g., pharmaceutical composition) and/or the edible product of the present disclosure include about 0.01 mg, about 0.05 mg, about 0.1 mg, about 1 mg, about 5 mg, 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, or about 250 mg of one or more Lactobacillus fermentum strains that shares at least 80% to 100% genome sequence identity with Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060.
- the composition e.g., pharmaceutical composition
- the edible product of the present disclosure include about 0.01% (w/w or w/v)) to about 50% (w/w or w/v) of a bioactive agent, an additive, an excipient, an emulsifier, a therapeutic agent, a pharmaceutically acceptable carrier, and/or a preservative.
- compositions can be used to treat or prevent various medical indications.
- Treating includes any effect, e.g., lessening, reducing, modulating, preventing, or eliminating, that results in the improvement of the condition, disease, disorder, etc.
- Treating” or “treatment” of a disease state includes: (1) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms; (2) relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms; (3) reducing or lessening the symptoms of the disease state; or (4) preventing the disease state, e.g., causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state.
- preventing or “prevent” describes reducing or eliminating the onset of the symptoms or complications of the disease, condition or disorder.
- the term “preventing,” when used in relation to a condition, is art-recognized, and refers to formulation, composition and/or device which reduces the frequency of, or delays the onset of, signs and/or symptoms of a medical condition in a subject relative to a subject which does not receive the composition.
- reduce or other forms of the word, such as “reducing” or “reduction,” is meant lowering of an event or characteristic. It is understood that this is typically in relation to some standard or expected value, in other words it is relative, but that it is not always necessary for the standard or relative value to be referred to.
- the term “prevent” does not require that the disease state be completely thwarted. Rather, as used herein, the term preventing refers to the ability of the skilled artisan to identify a population that is susceptible to disorders, such that administration of the compounds of the present disclosure may occur prior to onset of a disease. The term does not imply that the disease state be completely avoided.
- ameliorating a symptom or other forms of the word such as “ameliorate a symptom” is used herein to mean that administration of a therapeutic agent of the present disclosure mitigates one or more symptoms of a disease or a disorder in a host and/or reduces, inhibits, or eliminates a particular symptom associated with the disease or disorder prior to and/or post-administration of the therapeutic agent.
- a disclosed compositions e.g., a composition including a Lactobacillus fermentum strain, bioactive dairy product, bioactive dairy product fraction, or bioactive compounds
- a method treat an immune system deficiency, e.g., a deficiency in the secretion of cytokines, e.g., IL-10, IL-6 and/or IL-2.
- cytokines e.g., IL-10, IL-6 and/or IL-2.
- Such a method includes administering an effective amount of a disclosed composition thereby to treat the subject.
- Effective amount refers to the amount of an agent that is sufficient to at least partially treat a condition when administered to a patient.
- the therapeutically effective amount will vary depending on the condition, the route of administration of the component, and the age, weight, etc. of the patient being treated. Accordingly, an effective amount of a specific inhibitor of composition/edible product is the amount of the composition/edible product necessary for the needed purpose in a patient.
- An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.
- a “patient,” as described herein, refers to any animal suffering from or diagnosed for a disease or disorder, including, but not limited to, mammals, primates, and humans.
- the patient may be a non-human mammal such as, for example, a cat, a dog, or a horse.
- the patient is a human subject.
- a “subject” is meant an individual.
- the “subject” can include domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), laboratory animals (e.g., mouse, rabbit, rat, guinea pig, etc.), and birds.
- “Subject” can also include a mammal, such as a primate or a human.
- the terms “subject” and “patient” may be used interchangeably, however, in some embodiments a subject may not be diagnosed with or is suffering from a disease or disorder, though may be in need of therapy.
- administering means administration as a suppository, topical contact (e.g., a spray), parenteral, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration to a subject.
- Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal).
- Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
- “sequential administration” includes that the administration of two agents (e.g., compositions described in this disclosure) occurs separately on the same day or do not occur on a same day (e.g., occurs on consecutive days).
- “concurrent administration” includes overlapping in duration at least in part.
- two agents e.g., any compositions described in this disclosure that has bioactivity
- their administration occurs within a certain desired time.
- the agents' administration may begin and end on the same day.
- the administration of one agent can also precede the administration of a second agent by day(s) as long as both agents are taken on the same day at least once.
- the administration of one agent can extend beyond the administration of a second agent as long as both agents are taken on the same day at least once.
- the compositions/agents do not have to be taken at the same time each day to include concurrent administration.
- “intermittent administration” includes the administration of an agent for a period of time (which can be considered a “first period of administration”), followed by a time during which the agent is not taken or is taken at a lower maintenance dose (which can be considered “off-period”) followed by a period during which the agent is administered again (which can be considered a “second period of administration”).
- first period of administration a period of time
- second period of administration a period during which the agent is administered again
- the dosage level of the agent will match that administered during the first period of administration but can be increased or decreased as medically necessary.
- compositions described in this disclosure are administered at the same time, just prior to, or just after the administration of additional therapies.
- the composition of the disclosure can be administered alone or can be co-administered to the patient.
- Co-administration is meant to include simultaneous or sequential administration of the composition individually or in combination (more than one composition or agent).
- the preparations can also be combined, when desired, with other active substances (e.g. for wound healing).
- administration of a disclosed composition stimulates secretion of interleukin-10 (IL-10) and/or immunoglobulin A (IgA) antibodies immunoglobulin.
- administration of a disclosed composition does not induce a pro-inflammatory responses, e.g., as measured by interleukin-2 (IL-2) or interleukin-6 (IL-6) levels.
- a disclosed composition e.g., a composition including a Lactobacillus fermentum strain, bioactive dairy product, bioactive dairy product fraction, or bioactive compound, stimulates secretion of the anti-inflammatory cytokine IL-10.
- a disclosed composition is used to treat an inflammatory condition.
- an inflammatory condition is a disease or condition characterized, in whole or in part, by inflammation or an inflammatory response in the patient. Inflammatory may be characterized, for example, based on the primary tissue affected, the mechanism of action underlying the condition, or the portion of the immune system that is misregulated or overactive.
- examples of inflammatory conditions that may be treated include inflammation of the lungs (e.g., asthma, adult respiratory distress syndrome, bronchitis, pulmonary inflammation, pulmonary fibrosis, and cystic fibrosis), joints (e.g., rheumatoid arthritis, rheumatoid spondylitis, juvenile rheumatoid arthritis, osteoarthritis, gouty arthritis and other arthritic conditions), connective tissue, eyes (e.g., uveitis (including crizis), conjunctivitis, scleritis, and keratoconjunctivitis sicca), nose, bowel (e.g., Crohn's disease, ulcerative colitis, inflammatory bowel disease, inflammatory bowel syndrome, and distal proctitis), kidney (e.g., glomerulonephritis, interstitial nephritis, lupus nephritis, nephritis secondary to
- eczematous dermatitides g., topic and seborrheic dermatitis, allergic or irritant contact dermatitis, eczema craquelee, photoallergic dermatitis, phototoxicdermatitis, phytophotodermatitis, radiation dermatitis, and stasis dermatitis
- central nervous system e.g., multiple sclerosis and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease or dementia associated with HIV infection
- vascular system e.g.
- endocrine system e.g., autoimmune thyroiditis (Hashimoto's disease), Type I diabetes, inflammation in liver and adipose tissue associated with Type II diabetes, and acute and chronic inflammation of the adrenal cortex
- endocrine system e.g., autoimmune thyroiditis (Hashimoto's disease), Type I diabetes, inflammation in liver and adipose tissue associated with Type II diabetes, and acute and chronic inflammation of the adrenal cortex
- adipose tissue e.g., autoimmune thyroiditis (Hashimoto's disease), Type I diabetes, inflammation in liver and adipose tissue associated with Type II diabetes, and acute and chronic inflammation of the adrenal cortex
- the disclosure contemplates that some inflammatory conditions involve inflammation in multiple tissues. Moreover, the disclosure contemplates that some inflammatory conditions may fall into multiple categories. In certain embodiments, the inflammatory condition is an autoimmune disease.
- Exemplary autoimmune diseases include, but are not limited to, rheumatoid arthritis, psoriasis (including plaque psoriasis), psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, multiple sclerosis, lupus, alopecia, autoimmune pancreatitis, Celiac disease, Behcet's disease, Cushing syndrome, and Grave's disease.
- the inflammatory condition is a rheumatoid disorder.
- rheumatoid disorders include, but are not limited to, rheumatoid arthritis, juvenile arthritis, bursitis, spondylitis, gout, scleroderma, Still's disease, and vasculitis. It is noted that certain categories of conditions overlap.
- rheumatoid arthritis is an inflammatory rheumatoid disorder, an inflammatory joint disorder, and an autoimmune disorder.
- the present disclosure provides a method of treating a disease or disorder, e.g., a dietary disease or disorder, an inflammatory disease or disorder, and an autoimmune disease or disorder in a subject in need thereof, the method including administering to the subject an effective amount of the composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% genome sequence identity with Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060.
- the composition described in any of its forms as described in the present disclosure is administered to the subject for treating a disease or disorder.
- the present disclosure provides a method of modulating the immune system and/or response in a subject in need thereof, the method including administering to the subject an effective amount of the composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% genome sequence identity with Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060.
- the composition described in any of its forms as described in the present disclosure is administered to the subject for modulating the immune system and/or response in the subject.
- the present disclosure provides a method of modulating the immune system and/or response in a subject in need thereof, the method including administering to the subject an effective amount of a composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% sequence identity with the partial 16S rRNA gene sequence of SEQ ID NO: 1 or SEQ ID NO: 2.
- the present disclosure provides a method of improving immune system in a subject in need thereof, the method including administering to the subject an effective amount of a composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% genome sequence identity with Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060.
- the present disclosure provides a method of improving immune system in a subject in need thereof, the method including administering to the subject an effective amount of a composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% sequence identity with the partial 16S rRNA gene sequence of SEQ ID NO: 1 or SEQ ID NO: 2.
- the present disclosure provides a method of treating and/or ameliorating an immunodeficiency disorder in a subject in need thereof, the method including administering to the subject an effective amount of a composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% sequence identity with the partial 16S rRNA gene sequence of SEQ ID NO: 1 or SEQ ID NO: 2.
- An immunodeficiency disorder involves malfunction of the immune system, resulting in infections that develop and recur more frequently, are more severe, and last longer than usual.
- Immunodeficiency disorders usually result from use of a drug or from a long-lasting serious disorder (such as cancer) but occasionally are inherited. People usually have frequent, unusual, or unusually severe or prolonged infections and may develop an autoimmune disorder or cancer.
- Immunodeficiency disorders impair the immune system's ability to defend the body against foreign or abnormal cells that invade or attack it (such as bacteria, viruses, fungi, and cancer cells). As a result, unusual bacterial, viral, or fungal infections or lymphomas or other cancers may develop.
- Another problem is that up to 25% of people who have an immunodeficiency disorder also have an autoimmune disorder (such as immune thrombocytopenia).
- an autoimmune disorder such as immune thrombocytopenia
- the immune system attacks the body's own tissues.
- the autoimmune disorder develops before the immunodeficiency causes any symptoms.
- immunodeficiency disorders There are two types of immunodeficiency disorders: primary and secondary.
- Primary disorders are usually present at birth and are usually hereditary. They typically become evident during infancy or childhood. However, some primary immunodeficiency disorders (such as common variable immunodeficiency) are not recognized until adulthood. There are more than 100 primary immunodeficiency disorders, all of which are relatively rare. Secondary disorders generally develop later in life and often result from use of certain drugs or from another disorder, such as diabetes or human immunodeficiency virus (HIV) infection. They are more common than primary immunodeficiency disorders. Some immunodeficiency disorders shorten life span. Others persist throughout life but do not affect life span, and a few resolve with or without treatment.
- HIV human immunodeficiency virus
- the present disclosure provides a method of improving health in a subject in need thereof, the method including administering to the subject an effective amount of the composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% genome sequence identity with Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060.
- the present disclosure provides a method of improving health in a subject in need thereof, the method including administering to the subject an effective amount of a composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% sequence identity with the partial 16S rRNA gene sequence of SEQ ID NO: 1 or SEQ ID NO: 2.
- composition described in any of its forms as described in the present disclosure is administered to the subject for improving health of the subject.
- the improving health of the subject is achieved by modulating the immune system of the subject.
- composition of the present disclosure use in the methods described herein is prepared as a dairy bioactive fraction before administering to the subject.
- the present disclosure provides a method of preparing a food product, a food supplement, or a pharmaceutical composition including a dairy bioactive fraction of one or more Lactobacillus fermentum strains that shares at least 80% to 100% genome sequence identity with Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060, where in the method the bioactive fraction is obtained by a bioguided procedure and used for preparing a food product, a food supplement, or a pharmaceutical composition.
- the present disclosure provides a process for preparing an edible product, the method including fermenting a protein-containing starting material with one or more Lactobacillus fermentum strains that shares at least 80% to 100% genome sequence identity with Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060.
- the starting material is milk or a milk-based product.
- the process for preparing an edible product involves removing unhydrolyzed protein from milk or a milk-based starting material.
- the process for preparing an edible product includes a starting material, which includes one or more dairy bioactive fractions.
- the one or more dairy bioactive fractions may have immunomodulatory activity.
- the process for preparing an edible product includes a starting material, which includes one or more bioactive compounds.
- the one or more bioactive compounds may have immunomodulatory activity.
- the present disclosure provides a method of modulating the immune system in a subject in need thereof, the method including administering to the subject an effective amount of the edible product prepared by a process disclosed herein.
- the present disclosure provides a method of treating, preventing, and/or ameliorating inflammation in a subject in need thereof, the method including administering to the subject an effective amount of the edible product prepared by a process disclosed herein.
- the edible product of the present disclosure is or may be suitable for use in the dairy industry, the beverage industry, the processed food industry, the processed meat industry, the baking industry, and/or the confectionary industry.
- the edible product of the present disclosure is or may be a fermented milk product.
- the edible product of the present disclosure is or may be a beverage.
- the edible product of the present disclosure is or may be a pharmaceutical composition.
- the present disclosure provides a method of improving immune system in a subject in need thereof, the method including administering to the subject an effective amount of a composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% genome sequence identity with Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060.
- the present disclosure provides a method of enhancing secretion of cytokines in a subject in need thereof including administering the subject an effective amount of the composition described in this disclosure.
- composition for improving the immune system and/or enhancing secretion of cytokines in a subject in need thereof is or may be a food product.
- composition for improving the immune system and/or enhancing secretion of cytokines in a subject in need thereof is or may be a pharmaceutical composition.
- the one or more Lactobacillus fermentum strains is/are concentrated to provide enhanced efficacy.
- compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
- an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.
- a weight percent of a component is based on the total weight of the formulation or composition in which the component is included.
- the term “about” refers to any minimal alteration in the concentration or amount of an agent that does not change the efficacy of the agent in preparation of a formulation and in treatment of a disease or disorder.
- concentration range of the agents (e.g., therapeutic/active agents) of the current disclosure also refers to any variation of a stated amount or range which would be an effective amount or range.
- the term “about” may include ⁇ 15% of a specified numerical value or data point. Ranges can be expressed in this disclosure as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it is understood that the particular value forms another aspect.
- each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed in this disclosure, and that each value is also disclosed as “about” that particular value in addition to the value itself. It is also understood that throughout the application, data are provided in a number of different formats and that this data represent endpoints and starting points and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point “15” are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.
- Sequence identity may be determined in various ways that are within the skill in the art, e.g., using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software.
- BLAST Basic Local Alignment Search Tool
- analysis using the algorithm employed by the programs blastp, blastn, blastx, tblastn and tblastx (Karlin et al., (1990) P ROC . N ATL . A CAD . S CI. USA 87:2264-2268; Altschul, (1993) J. M OL . E VOL . 36, 290-300; Altschul et al., (1997) N UCLEIC A CIDS R ES.
- lactic acid production is a feature common to all LAB, the production of other compounds depends on the bacterial strains and on the conditions of the fermentation process. Additionally, some LAB have received special attention in recent decades for their use as probiotic microorganisms. Probiotics have traditionally been defined as “live microorganisms that, when being administered in appropriate dose provide health benefits to the host” (FAO/WHO 2001). Nevertheless, scientific evidence has shown that inactivated microorganisms (heat-killed) may also positively affect human health (Taverniti and Guglielmetti 2011, Genes Nutr 6:261-274).
- bioactive fermented dairy product that can produce a bioactive fermented dairy product, and have remarkable capacity to modulate the immune system in humans or mammals were isolated.
- Such bioactive fermented dairy product or its isolated biologically active fractions provides a method for inducing, increasing or stimulating the secretion of cytokines, such as interleukin-10 (IL-10).
- IL-6 interleukin-6
- the bioactive fermented dairy product or its isolated fractions included in this invention is a viable option to modulate the immune system without secondary effects which are produced by some drugs. Additionally, such bioactive fermented dairy product or its isolated fractions induces anti-inflammatory effect at the systemic level. Therefore, the isolated Lactobacillus fermentum strains, NRRL B-67059 or NRRL B-67060, disclosed herein, and the bioactive compounds produced by them, included in this disclosure may be used in pharmaceutical preparations as well as in food products.
- This disclosure includes the generation of bioactive compounds by the action of novel Lactobacillus fermentum NRRL B-67059 or NRRL B-67060 during the fermentation of dairy substrates.
- One objective of the present disclosure is the manufacture of food products with bioactive compounds, for the production of functional foods as a consequence of the action of specific Lactobacillus fermentum NRRL B-67059 or NRRL B-67060 on a substrate within the food.
- these bioactive compounds could be used in an edible product such as a food supplement or as a pharmaceutical composition.
- NRRL B-67059 and NRRL B-67060 Novel strains of Lactobacillus fermentum , hereafter referred to as NRRL B-67059 and NRRL B-67060.
- NRRL B-67059 and NRRL B-67060 were isolated and were then deposited at the National Center for Agricultural Utilization Research, United States Department of Agriculture, United States of America, in Apr. 17, 2015.
- This invention is related to specific Lactobacillus strains, NRRL B-67059 or NRRL B-67060, that can produce a bioactive fermented dairy product, mainly that have remarkable capacity to modulate the immune system in humans or mammals.
- L. fermentum strains were assessed by evaluating their resistance (percentage of survival) under conditions of low pH and enzyme treatment (Maragkoudakis et al., 2006, International Dairy Journal, 16, 189-199) and tolerance to bile salts (Thirabunyanon et al., 2009, Biotechnology Letters, 31, 571-576). In general, L. fermentum strains showed high viability to different gastrointestinal conditions with percentage ranges of cell survival at pH 3.0, enzyme treatment and bile salts of 94-99%, 71-99% and 79-96%, respectively (Table 2).
- antibiotic susceptibility testing Multidisc Gram positives II, BIO-RAD
- BIO-RAD BIO-RAD
- Lactobacillus fermentum strains NRRL B-67059 and NRRL B-67060
- Table 3 antibiotic susceptibility testing
- probiotics may be susceptible to the majority of antibiotics, their resistance can be beneficial for people with an unbalanced intestinal microbiota due to the administration of various antimicrobial agents, so that the probiotics can be administered with antibiotics to prevent the gastrointestinal side effects (Courvalin, 2006, Digestive Liver Diseases, 38, S261-S26).
- Lactobacillus fermentum strains, NRRL B-67059 and NRRL B-67060 presented important technological characteristics such as high acidifying and proteolytic activities when they were inoculated in reconstituted nonfat dry milk. In fact lactic acid production was significantly (p ⁇ 0.05) higher at 48 h of fermentation for both strains ( FIG. 2 ). Also, these strains presented high acidifying activity (pH ⁇ 4.0 in 48 h) ( FIG. 3 ) and high proteolytic activity (Abs 340>0.20 in 48 h) ( FIG. 4 ) according to the OPA (o-phtaldialdehyde method) (Church et al., 1983, J. Dairy Sci. 66:1219-1227).
- OPA o-phtaldialdehyde method
- Lactobacillus fermentum NRRL B-67059 and NRRL B-67060 were activated in MRS broth (De Man, Rogosa and Sharpe, Difco) in three consecutive sub-cultures, these were inoculated at 1% level and incubated at 37° C. for 24, 18 and 12 h, respectively. Fresh cultures were obtained by repeating the same procedure. Initial starter cultures were prepared by allowing L. fermentum strains to reach 10 6 -10 7 colony-forming units (CFU) mL ⁇ 1 as enumerated on MRS agar.
- CFU colony-forming units
- Reconstituted nonfat dry milk (10%, w/v) was sterilized at 110° C. for 10 min.
- the pre-culture (10 7 CFU mL ⁇ 1 ) of Lactobacillus fermentum NRRL B-67059 or NRRL B-67060 was inoculated into sterilized milk at 1% level and incubated for 12 h. Then, milk (20 mL) was inoculated with 3% of pre-culture. Samples were incubated at 37° C. for 48 h to obtain the different fermented milk batches (10 9 CFU mL ⁇ 1 ). For fermented-pasteurized milk preparation, fermented milk was subjected to 75° C. for 15 min.
- Samples (1 mL, 10 9 CFU mL ⁇ 1 ) of specific fermented milk were administered via canula to female Wistar rats (6-8 week-old, weighing 140 ⁇ 20 g) obtained from Harlan Laboratories, INC, (Indianapolis, Ind., USA, through their Mexico city representative).
- the control groups were administered unfermented milk. Rats were randomly assigned to groups of six and housed in pairs per cage at 23 ⁇ 2° C. with 12 h light/dark cycles, 52 ⁇ 6% relative humidity, with ad libitum intake of a standard diet (Teklad, Harlan Laboratories, USA) and purified water. Blood samples were obtained from each group after 7 and 21 d of treatment administration, before animals were sacrificed.
- the concentration of cytokines was evaluated by a commercial ELISA kit (BD, Invitrogen). The results were expressed as concentration of each cytokine (pg mL-1).
- milk fermented by specific lactic acid bacteria Lactobacillus fermentum NRRL B-67059 or NRRL B-67060 may be considered as a co-adjuvant for the improvement of health by modulating the immune system.
- dairy products fermented with Lactobacillus fermentum NRRL B-67059 or NRRL B-67060 may be used as functional foods with potential benefits.
- a process for preparing an edible product, the process including fermenting a protein-containing starting material with one or more Lactobacillus fermentum strains that shares at least 80% to 100% genome sequence identity with Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060.
- the starting material is milk or a milk-based product.
- the method includes removing unhydrolyzed protein.
- the edible product includes a bioactive fraction.
- the starting material may include one or more bioactive compounds.
- a subject is administered with a composition, pharmaceutical composition, and/or an edible product of the present disclosure for treating a dietary disease or disorder, an inflammatory disease or disorder, and/or an immune disease or disorder.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Nutrition Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Physiology (AREA)
- Molecular Biology (AREA)
- Zoology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Transplantation (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Bakery Products And Manufacturing Methods Therefor (AREA)
- Meat, Egg Or Seafood Products (AREA)
- Non-Alcoholic Beverages (AREA)
- Dairy Products (AREA)
Abstract
Description
- This application claims the benefit of, and priority to, U.S. provisional patent application Ser. No. 62/387,474, filed Dec. 24, 2015, which is incorporated by reference herein in its entirety.
- The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Dec. 23, 2016, is named UGD-001-Sequence-Listing.txt and is 1,839 bytes in size.
- Lactic acid bacteria, including those of the genera Lactococcus, Lactobacillus, Streptococcus, Bifidobacterium, and Pediococcus, have long been utilized as fermenting agents for the preservations of food and for preparing from milk a variety of different foodstuff such as cheese, yogurt and other fermented dairy products. More recently, some lactic acid bacteria strains have been found to exhibit beneficial properties for humans and animals including, e.g., the enhancement of immune system function.
- Despite the advances made to date, there is still ongoing need for additional lactic acid bacteria strains for use in the enhancement of immune system function.
- This disclosure relates to new Lactobacillus fermentum strains, NRRL B-67059 or NRRL B-67060, and a bacterial preparation containing the same, that can produce a bioactive fermented dairy product, particularly one that modulates the immune system for better health.
- In one aspect the present disclosure provides a composition or edible product including one or more Lactobacillus fermentum strains that shares at least 80% to 100% genome sequence identity with Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060. In embodiments, the present disclosure provides a composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% sequence identity with the partial 16S rRNA gene sequence of SEQ ID NO: 1 or SEQ ID NO: 2. For example, the composition includes Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060.
- According to one aspect, the modulation of the immune system is the modulation of systemic IgA and the anti-inflammatory cytokine interleukin-10 (IL-10). According to another aspect, the modulation of the immune system is the modulation of the pro inflammatory cytokines interleukin-6 (IL-6) and interleukin-2 (IL-2). This biologically active fermented dairy product can be manufactured for the production of a functional food. Another aspect relates to the isolation of biologically active fractions from this fermented dairy product and their addition to a food as part of the formulation or as part of a food supplement or a pharmaceutical preparation.
- Lactobacillus fermentum strains, NRRL B-67059 or NRRL B-67060, can be used to produce a bioactive fermented dairy product that has remarkable capacity to modulate the immune system in humans or mammals. Such bioactive fermented dairy product or its isolated biologically active fractions, provides a method for inducing, increasing or stimulating the secretion of cytokines, such as interleukin-10 (IL-10) and antibodies immunoglobulin A (IgA). On the other hand, such bioactive fermented dairy product or its active fractions did not induce a pro-inflammatory response, such as that shown by interleukin-2 (IL-2) or interleukin-6 (IL-6).
- The bioactive fermented dairy product or its isolated fractions described herein is a viable option to modulate the immune system without secondary effects which are produced by some drugs. Additionally, such bioactive fermented dairy product or its isolated fractions induces anti-inflammatory effect at the systemic level. Therefore, the mentioned Lactobacillus fermentum strains, NRRL B-67059 or NRRL B-67060, and the bioactive compounds produced by them, may be used in pharmaceutical preparations as well as in food products.
- The novel Lactobacillus fermentum NRRL B-67059 or NRRL B-67060 and bioactive products incorporating or derived from the novel Lactobacillus fermentum NRRL B-67059 or NRRL B-67060 can be administered to persons suffering from immune system deficiencies and, in particular, deficiencies in the secretion of cytokines to modulate and improve the functioning of their immune system and the secretion of cytokines.
- Bioactive compounds can be generated by the action of novel Lactobacillus fermentum NRRL B-67059 or NRRL B-67060 during the fermentation of dairy substrates. One objective is the manufacture of food products with bioactive compounds, for the production of functional foods as a consequence of the action of specific Lactobacillus fermentum NRRL B-67059 or NRRL B-67060 on a substrate within the food. Also, these bioactive compounds could be used in an edible product such as a food supplement or as a pharmaceutical composition. The novel Lactobacillus fermentum NRRL B-67059 or NRRL B-67060 can be concentrated in manufactured food products to provide enhanced efficacy.
-
FIG. 1 is a graph showing cell growth of Lactobacillus fermentum NRRL B-67059 and NRRL B-67060. Optical density (OD600) was measured after incubation of cells in basal medium with mucin or glucose for 24 hours. Depicted values are means (n=3), and means for each value without a common letter differ significantly (p<0.05). -
FIG. 2 is a graph showing lactic acid production in milk fermented by Lactobacillus fermentum NRRL B-67059 or NRRL B-67060 for the indicated time points. Depicted values are means (n=3), and means for each value without a common letter differ significantly (p<0.05). -
FIG. 3 is a graph showing the pH of milk fermented by Lactobacillus fermentum NRRL B-67059 or NRRL B-67060 for the indicated time points. Depicted values are means (n=3), and means for each value without a common letter differ significantly (p<0.05). -
FIG. 4 is a graph showing the proteolyic activity, as measured by absorbance at 340 nm) in milk fermented by Lactobacillus fermentum NRRL B-67059 or NRRL B-67060 at different times of incubation. Depicted values are means (n=3), and means for each value without a common letter differ significantly (p<0.05). -
FIG. 5 is a graph showing the effect of oral administration of milk fermented with with Lactobacillus fermentum NRRL B-67059 or NRRL B-67060 on anti-inflammatory cytokine IL-10 production in rats. Depicted values are means (n=6), and means for each value without a common letter differ significantly (p<0.05). -
FIG. 6 is a graph showing the effect of oral administration of milk fermented with with Lactobacillus fermentum NRRL B-67059 or NRRL B-67060 on pro-inflammatory cytokine IL-6 production in rats. Depicted values are means (n=6), and means for each value without a common letter differ significantly (p<0.05). - This disclosure provides, in part, novel strains of Lactobacillus fermentum, hereafter referred to as NRRL B-67059 and NRRL B-67060. NRRL B-67059 and NRRL B-67060 have been deposited at the National Center for Agricultural Utilization Research, United States Department of Agriculture, United States of America, on Apr. 17, 2015.
- As used herein, NRRL B-67059 and NRRL B-67060 are understood to refer to the deposited strains of Lactobacillus fermentum as well as progeny obtained from the subculture of the isolated strains or their mutants that maintain the biological properties of the deposited NRRL B-67059 and NRRL B-67060 strains. In embodiments, Lactobacillus fermentum of the present disclosure shares at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% genome sequence identity with the deposited NRRL B-67059 and NRRL B-67060. In embodiments, a Lactobacillus fermentum of the present disclosure shares at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the partial 16S rRNA gene sequence of SEQ ID NO: 1 or SEQ ID NO: 2, respectively.
- The following abbreviations are used through the present invention:
- L. fermentum, Lactobacillus fermentum; LAB, Lactic acid bacteria; cfu, colony-forming units.
- In one aspect the present disclosure provides a composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% genome sequence identity with Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060. In embodiments, the present disclosure provides a composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% sequence identity with the partial 16S rRNA gene sequence of SEQ ID NO: 1 or SEQ ID NO: 2. For example, the composition includes Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060. In embodiments, Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060 are purified. In embodiments, the composition does or may include a bioactive agent, an additive, an excipient, an emulsifier, a therapeutic agent, and/or a preservative.
- In certain embodiments, the composition of the present disclosure is formulated as a pharmaceutical composition or an edible product. For example, the pharmaceutical composition is or may be a solid dosage form, a semisolid dosage form, or a liquid dosage form. In embodiments, the solid dosage form is or may be a tablet, a lozenge, or a capsule.
- In embodiments, the tablet or the capsule includes microtablets, minitablets, pellets, or granulates comprising lyophilized powder of the strain. In embodiments, the semisolid dosage form is a gel, a cream, an ointment, or a chewable lozenge. In embodiments, the liquid is or may be an emulsion or a solution.
- In embodiments, the composition or the pharmaceutical composition of the present disclosure may be or is formulated for oral, rectal, or parenteral administration to a subject in need thereof.
- In embodiments, the edible product of the present disclosure is a food product or a food supplement. The food product or a food supplement includes or may include a food delivery vehicle. The food product or food supplement includes or may include a dairy product.
- In embodiments, the edible product of the present disclosure is a dairy product.
- In embodiments, the edible product of the present disclosure is a beverage.
- In one aspect, the present disclosure provides an edible product or a pharmaceutical composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% genome sequence identity with Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060. For example, the edible product and/or the pharmaceutical composition includes Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060. In embodiments, the present disclosure provides an edible product and/or a pharmaceutical composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% sequence identity with the partial 16S rRNA gene sequence of SEQ ID NO: 1 or SEQ ID NO: 2. In embodiments, Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060 are purified.
- In embodiments, the edible product or the pharmaceutical composition of the present disclosure does or may include a bioactive agent, an additive, an excipient, an emulsifier, a therapeutic agent, and/or a preservative. In certain embodiments, the edible product is a food product or a food supplement. In certain embodiments, the food product or a food supplement includes a food delivery vehicle. In certain embodiments, the food product or food supplement includes a dairy product. In certain embodiments, the edible product is prepared as a dairy product. In certain embodiments, the edible product is prepared as a beverage.
- Also provided are physiological acceptable compositions that include Lactobacillus fermentum strains, e.g., the deposited NRRL B-67059 and NRRL B-67060 strains, and a physiologically acceptable delivery vehicle.
- As used herein, “physiologically acceptable carrier” or “pharmaceutically acceptable carrier” means buffers, carriers, and excipients suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. The carrier(s) should be “acceptable” in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient. A physiologically acceptable carrier can be administered to an individual along with the relevant active compound without causing clinically unacceptable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Physiologically acceptable carriers include buffers, solvents, dispersion media, coatings, isotonic and absorption-delaying agents, and the like, that are compatible with pharmaceutical administration. Physiologically acceptable carriers include any of the standard carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers and adjuvants, see, e.g., Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, Pa. [1975]. Physiologically acceptable carriers include buffers, solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is known in the art.
- The use of such media and/or agents for pharmaceutically active substances is known in the art. In certain embodiments the composition is administered orally and includes an enteric coating suitable for regulating the site of absorption of the encapsulated substances within the digestive system or gut. For example, an enteric coating can include an ethylacrylate-methacrylic acid copolymer. The term “vehicle” as used herein refers to a medium used to carry an active agent. Vehicles of the present invention typically comprise components such as polymers and solvents.
- Also provided are fermented dairy products produced using Lactobacillus fermentum strains, e.g., the deposited NRRL B-67059 or NRRL B-67060 strains. As used herein, the term “fermented dairy product” refers to products which are obtained by the multiplication of lactic acid bacteria, e.g., Lactobacillus fermentum, in a milk base leading to a milk coagulum. The milk preparation used as raw material for the fermentation may be skimmed or non-skimmed milk, optionally concentrated or in the form of powder. Furthermore, this milk preparation may have been subjected to a thermal processing operation which is at least as efficient as pasteurization. The particular characteristics of the various fermented dairy products depend upon various factors, such as the composition of milk base, the incubation temperature, the lactic acid flora and/or non-lactic acid flora. Thus, fermented dairy products manufactured herein include, for instance, various types of regular yogurt, low fat yogurt, non-fat yogurt, kefir, ymer, buttermilk, butterfat, sour cream and sour whipped cream as well as fresh cheeses. Processes for making fermented dairy products are well known in the art. As used herein, the term “bioactive dairy product” refers to a fermented dairy product that can affect a biological function. The biological activity of a bioactive dairy product may, e.g., result from particular compounds generated by Lactobacillus fermentum strains during the fermentation of dairy products. Accordingly, also provided herein are isolated fractions of a bioactive dairy product, i.e., bioactive dairy product fractions, or isolated compounds of a bioactive dairy product, i.e., bioactive compounds, that possess the same biological properties as the bioactive diary product. Methods for fractionating fermented dairy products or isolating compounds from fermented dairy products are well known in the art.
- Disclosed Lactobacillus fermentum strains, bioactive dairy products, bioactive dairy product fractions, or bioactive compounds, can be formulated into physiological acceptable compositions by combination with appropriate, physiologically acceptable carriers.
- Additional components of a composition can include trehalose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium hyaluronate, sodium alginate, chitosan and its derivatives, polyethylene glycol, glycerin, propylene glycol, Triacetin, N,N-Dimethylacetamide, pyrrolidone, dimethyl sulfoxide, ethanol, N-(-beta-Hydroxyethyl)-lactamide, 1-Methyl-2-pyrrolidinone, triglycerides, monothioglycerol, sorbitol, lecithin, methylparaben, propylparaben, polysorbates, block copolymers of ethylene oxide and propylene oxide, di-block polymers or tri-block copolymers of polyethylene oxide and polypropylene oxide, ethoxylated emulsifiers, polyethylene glycol esters, sucrose laurate, Tocopherol-PEG-succinate, phospholipids and their derivatives, and/or other non-ionic self-emulsifying agents. Additional components of a composition can include triacetine, L-Lysine, ammonium acetate.
- Disclosed Lactobacillus fermentum strains, bioactive dairy products, bioactive dairy product fractions, or bioactive compounds, may be formulated into preparations including, e.g., tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols and topical compositions. The formulations may be designed for administration via a number of different routes, including, e.g., oral, buccal, sublingual, rectal, parenteral, intraperitoneal, intradermal, transdermal, or intracheal administration.
- In embodiments the composition is a food product. Food products of interest include a disclosed Lactobacillus fermentum strain in combination with a food delivery vehicle. By food delivery vehicle is meant a delivery vehicle that is a nourishing substance that is eaten, drunk, or otherwise taken into the body to sustain life, provide energy, promote growth, etc. Examples of food delivery vehicles or food products of interest include, but are not limited to: baby or infant formula, baby food (e.g., pureed food suitable for infant or toddler consumption), chips, cookies, breads, spreads, creams, yogurts, liquid drinks, chocolate containing products, candies, ice creams, cereals, coffees, pureed food products, water, fluid milk products, milk, concentrated milk, fermented milk, yogurt, sour milk, frozen yogurt, lactic acid bacteria-fermented beverages, milk powder, ice cream, cream cheeses, dry cheeses, soybean milk, fermented soybean milk, vegetable-fruit juices, juices, sports drinks, confectionery, jellies, candies, infant formulas, health foods, and/or animal feeds. In embodiments, the composition is a food supplement. A food supplement may further include, e.g., a sweetener, a stabilizer, a flavoring, an emulsifier, and/or a colorant.
- In embodiments, the composition (e.g., pharmaceutical composition) and/or the edible product of the present disclosure include about 0.01 mg, about 0.05 mg, about 0.1 mg, about 1 mg, about 5 mg, 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, or about 250 mg of one or more Lactobacillus fermentum strains that shares at least 80% to 100% genome sequence identity with Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060.
- In embodiments, the composition (e.g., pharmaceutical composition) and/or the edible product of the present disclosure include about 0.01% (w/w or w/v)) to about 50% (w/w or w/v) of a bioactive agent, an additive, an excipient, an emulsifier, a therapeutic agent, a pharmaceutically acceptable carrier, and/or a preservative.
- Methods of Treatment and/or Prevention
- The foregoing compositions can be used to treat or prevent various medical indications.
- “Treating,” includes any effect, e.g., lessening, reducing, modulating, preventing, or eliminating, that results in the improvement of the condition, disease, disorder, etc. “Treating” or “treatment” of a disease state includes: (1) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms; (2) relieving the disease state, i.e., causing temporary or permanent regression of the disease state or its clinical symptoms; (3) reducing or lessening the symptoms of the disease state; or (4) preventing the disease state, e.g., causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state. As used herein, “preventing” or “prevent” describes reducing or eliminating the onset of the symptoms or complications of the disease, condition or disorder. The term “preventing,” when used in relation to a condition, is art-recognized, and refers to formulation, composition and/or device which reduces the frequency of, or delays the onset of, signs and/or symptoms of a medical condition in a subject relative to a subject which does not receive the composition.
- By “reduce” or other forms of the word, such as “reducing” or “reduction,” is meant lowering of an event or characteristic. It is understood that this is typically in relation to some standard or expected value, in other words it is relative, but that it is not always necessary for the standard or relative value to be referred to.
- Insofar as the methods of the present disclosure are directed to preventing disorders, it is understood that the term “prevent” does not require that the disease state be completely thwarted. Rather, as used herein, the term preventing refers to the ability of the skilled artisan to identify a population that is susceptible to disorders, such that administration of the compounds of the present disclosure may occur prior to onset of a disease. The term does not imply that the disease state be completely avoided.
- The term “ameliorating a symptom” or other forms of the word such as “ameliorate a symptom” is used herein to mean that administration of a therapeutic agent of the present disclosure mitigates one or more symptoms of a disease or a disorder in a host and/or reduces, inhibits, or eliminates a particular symptom associated with the disease or disorder prior to and/or post-administration of the therapeutic agent.
- In embodiments, a disclosed compositions, e.g., a composition including a Lactobacillus fermentum strain, bioactive dairy product, bioactive dairy product fraction, or bioactive compounds, can used in a method treat an immune system deficiency, e.g., a deficiency in the secretion of cytokines, e.g., IL-10, IL-6 and/or IL-2. Such a method includes administering an effective amount of a disclosed composition thereby to treat the subject.
- “Effective amount” or “therapeutically effective amount” as used herein, refers to the amount of an agent that is sufficient to at least partially treat a condition when administered to a patient. The therapeutically effective amount will vary depending on the condition, the route of administration of the component, and the age, weight, etc. of the patient being treated. Accordingly, an effective amount of a specific inhibitor of composition/edible product is the amount of the composition/edible product necessary for the needed purpose in a patient. An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.
- A “patient,” as described herein, refers to any animal suffering from or diagnosed for a disease or disorder, including, but not limited to, mammals, primates, and humans. In certain embodiments, the patient may be a non-human mammal such as, for example, a cat, a dog, or a horse. In a preferred embodiment, the patient is a human subject.
- As used herein, by a “subject” is meant an individual. Thus, the “subject” can include domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), laboratory animals (e.g., mouse, rabbit, rat, guinea pig, etc.), and birds. “Subject” can also include a mammal, such as a primate or a human. The terms “subject” and “patient” may be used interchangeably, however, in some embodiments a subject may not be diagnosed with or is suffering from a disease or disorder, though may be in need of therapy.
- As used in this disclosure, the term “administering” means administration as a suppository, topical contact (e.g., a spray), parenteral, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
- As used in this disclosure, “sequential administration” includes that the administration of two agents (e.g., compositions described in this disclosure) occurs separately on the same day or do not occur on a same day (e.g., occurs on consecutive days).
- As used in this disclosure, “concurrent administration” includes overlapping in duration at least in part. For example, when two agents (e.g., any compositions described in this disclosure that has bioactivity) are administered concurrently, their administration occurs within a certain desired time. The agents' administration may begin and end on the same day. The administration of one agent can also precede the administration of a second agent by day(s) as long as both agents are taken on the same day at least once. Similarly, the administration of one agent can extend beyond the administration of a second agent as long as both agents are taken on the same day at least once. The compositions/agents do not have to be taken at the same time each day to include concurrent administration.
- As used in this disclosure, “intermittent administration includes the administration of an agent for a period of time (which can be considered a “first period of administration”), followed by a time during which the agent is not taken or is taken at a lower maintenance dose (which can be considered “off-period”) followed by a period during which the agent is administered again (which can be considered a “second period of administration”). Generally, during the second phase of administration, the dosage level of the agent will match that administered during the first period of administration but can be increased or decreased as medically necessary.
- By “co-administer” it is meant that a composition described in this disclosure is administered at the same time, just prior to, or just after the administration of additional therapies. The composition of the disclosure can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the composition individually or in combination (more than one composition or agent). The preparations can also be combined, when desired, with other active substances (e.g. for wound healing).
- In embodiments, administration of a disclosed composition stimulates secretion of interleukin-10 (IL-10) and/or immunoglobulin A (IgA) antibodies immunoglobulin. In embodiments, administration of a disclosed composition does not induce a pro-inflammatory responses, e.g., as measured by interleukin-2 (IL-2) or interleukin-6 (IL-6) levels.
- In embodiments, administration of a disclosed composition, e.g., a composition including a Lactobacillus fermentum strain, bioactive dairy product, bioactive dairy product fraction, or bioactive compound, stimulates secretion of the anti-inflammatory cytokine IL-10. Accordingly, in embodiments, a disclosed composition is used to treat an inflammatory condition. As used herein, an inflammatory condition is a disease or condition characterized, in whole or in part, by inflammation or an inflammatory response in the patient. Inflammatory may be characterized, for example, based on the primary tissue affected, the mechanism of action underlying the condition, or the portion of the immune system that is misregulated or overactive. In certain embodiments, examples of inflammatory conditions that may be treated include inflammation of the lungs (e.g., asthma, adult respiratory distress syndrome, bronchitis, pulmonary inflammation, pulmonary fibrosis, and cystic fibrosis), joints (e.g., rheumatoid arthritis, rheumatoid spondylitis, juvenile rheumatoid arthritis, osteoarthritis, gouty arthritis and other arthritic conditions), connective tissue, eyes (e.g., uveitis (including iritis), conjunctivitis, scleritis, and keratoconjunctivitis sicca), nose, bowel (e.g., Crohn's disease, ulcerative colitis, inflammatory bowel disease, inflammatory bowel syndrome, and distal proctitis), kidney (e.g., glomerulonephritis, interstitial nephritis, lupus nephritis, nephritis secondary to Wegener's disease, acute renal failure secondary to acute nephritis, Goodpasture's syndrome, postobstructive syndrome and tubular ischemia), liver (e.g., hepatitis (arising from viral infection, autoimmune responses, drug treatments, toxins, environmental agents, or as a secondary consequence of a primary disorder), obesity, biliary atresia, primary biliary cirrhosis and primary sclerosing cholangitis), skin (e.g., psoriasis, eczema, and dermatitis, e. g., eczematous dermatitides, topic and seborrheic dermatitis, allergic or irritant contact dermatitis, eczema craquelee, photoallergic dermatitis, phototoxicdermatitis, phytophotodermatitis, radiation dermatitis, and stasis dermatitis), central nervous system (e.g., multiple sclerosis and neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease or dementia associated with HIV infection), vascular system (e.g. coronary infarct damage, peripheral vascular disease, myocarditis, vasculitis, revascularization of stenosis, atherosclerosis, and vascular disease associated with Type II diabetes), endocrine system (e.g., autoimmune thyroiditis (Hashimoto's disease), Type I diabetes, inflammation in liver and adipose tissue associated with Type II diabetes, and acute and chronic inflammation of the adrenal cortex) heart, or adipose tissue. The disclosure contemplates that some inflammatory conditions involve inflammation in multiple tissues. Moreover, the disclosure contemplates that some inflammatory conditions may fall into multiple categories. In certain embodiments, the inflammatory condition is an autoimmune disease. Exemplary autoimmune diseases include, but are not limited to, rheumatoid arthritis, psoriasis (including plaque psoriasis), psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, multiple sclerosis, lupus, alopecia, autoimmune pancreatitis, Celiac disease, Behcet's disease, Cushing syndrome, and Grave's disease. In certain embodiments, the inflammatory condition is a rheumatoid disorder. Exemplary rheumatoid disorders include, but are not limited to, rheumatoid arthritis, juvenile arthritis, bursitis, spondylitis, gout, scleroderma, Still's disease, and vasculitis. It is noted that certain categories of conditions overlap. For example, rheumatoid arthritis is an inflammatory rheumatoid disorder, an inflammatory joint disorder, and an autoimmune disorder.
- In one aspect, the present disclosure provides a method of treating a disease or disorder, e.g., a dietary disease or disorder, an inflammatory disease or disorder, and an autoimmune disease or disorder in a subject in need thereof, the method including administering to the subject an effective amount of the composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% genome sequence identity with Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060. In embodiments, the composition described in any of its forms as described in the present disclosure is administered to the subject for treating a disease or disorder.
- In one aspect, the present disclosure provides a method of modulating the immune system and/or response in a subject in need thereof, the method including administering to the subject an effective amount of the composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% genome sequence identity with Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060. In embodiments, the composition described in any of its forms as described in the present disclosure is administered to the subject for modulating the immune system and/or response in the subject. In embodiments, the present disclosure provides a method of modulating the immune system and/or response in a subject in need thereof, the method including administering to the subject an effective amount of a composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% sequence identity with the partial 16S rRNA gene sequence of SEQ ID NO: 1 or SEQ ID NO: 2.
- In one aspect, the present disclosure provides a method of improving immune system in a subject in need thereof, the method including administering to the subject an effective amount of a composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% genome sequence identity with Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060. In embodiments, the present disclosure provides a method of improving immune system in a subject in need thereof, the method including administering to the subject an effective amount of a composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% sequence identity with the partial 16S rRNA gene sequence of SEQ ID NO: 1 or SEQ ID NO: 2.
- In one aspect, the present disclosure provides a method of treating and/or ameliorating an immunodeficiency disorder in a subject in need thereof, the method including administering to the subject an effective amount of a composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% sequence identity with the partial 16S rRNA gene sequence of SEQ ID NO: 1 or SEQ ID NO: 2. An immunodeficiency disorder involves malfunction of the immune system, resulting in infections that develop and recur more frequently, are more severe, and last longer than usual. Immunodeficiency disorders usually result from use of a drug or from a long-lasting serious disorder (such as cancer) but occasionally are inherited. People usually have frequent, unusual, or unusually severe or prolonged infections and may develop an autoimmune disorder or cancer. Doctors suspect immunodeficiency based on symptoms and do blood tests to identify the particular disorder. People may be given antimicrobial drugs (such as antibiotics) to prevent and treat infections. Immune globulin may be given if there are too few antibodies (immunoglobulins) or they are not functioning normally. If the disorder is severe, stem cell transplantation is sometimes done. Immunodeficiency disorders impair the immune system's ability to defend the body against foreign or abnormal cells that invade or attack it (such as bacteria, viruses, fungi, and cancer cells). As a result, unusual bacterial, viral, or fungal infections or lymphomas or other cancers may develop. Another problem is that up to 25% of people who have an immunodeficiency disorder also have an autoimmune disorder (such as immune thrombocytopenia). In an autoimmune disorder, the immune system attacks the body's own tissues. Sometimes the autoimmune disorder develops before the immunodeficiency causes any symptoms.
- There are two types of immunodeficiency disorders: primary and secondary. Primary disorders are usually present at birth and are usually hereditary. They typically become evident during infancy or childhood. However, some primary immunodeficiency disorders (such as common variable immunodeficiency) are not recognized until adulthood. There are more than 100 primary immunodeficiency disorders, all of which are relatively rare. Secondary disorders generally develop later in life and often result from use of certain drugs or from another disorder, such as diabetes or human immunodeficiency virus (HIV) infection. They are more common than primary immunodeficiency disorders. Some immunodeficiency disorders shorten life span. Others persist throughout life but do not affect life span, and a few resolve with or without treatment.
- In one aspect, the present disclosure provides a method of improving health in a subject in need thereof, the method including administering to the subject an effective amount of the composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% genome sequence identity with Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060. In embodiments, the present disclosure provides a method of improving health in a subject in need thereof, the method including administering to the subject an effective amount of a composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% sequence identity with the partial 16S rRNA gene sequence of SEQ ID NO: 1 or SEQ ID NO: 2.
- In embodiments, the composition described in any of its forms as described in the present disclosure is administered to the subject for improving health of the subject. In embodiments, the improving health of the subject is achieved by modulating the immune system of the subject.
- In embodiments, the composition of the present disclosure use in the methods described herein is prepared as a dairy bioactive fraction before administering to the subject.
- In one aspect, the present disclosure provides a method of preparing a food product, a food supplement, or a pharmaceutical composition including a dairy bioactive fraction of one or more Lactobacillus fermentum strains that shares at least 80% to 100% genome sequence identity with Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060, where in the method the bioactive fraction is obtained by a bioguided procedure and used for preparing a food product, a food supplement, or a pharmaceutical composition.
- In one aspect, the present disclosure provides a process for preparing an edible product, the method including fermenting a protein-containing starting material with one or more Lactobacillus fermentum strains that shares at least 80% to 100% genome sequence identity with Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060. In embodiments, the starting material is milk or a milk-based product. In embodiments, the process for preparing an edible product involves removing unhydrolyzed protein from milk or a milk-based starting material.
- In embodiments, the process for preparing an edible product includes a starting material, which includes one or more dairy bioactive fractions. The one or more dairy bioactive fractions may have immunomodulatory activity.
- In embodiments, the process for preparing an edible product includes a starting material, which includes one or more bioactive compounds. The one or more bioactive compounds may have immunomodulatory activity.
- In one aspect, the present disclosure provides a method of modulating the immune system in a subject in need thereof, the method including administering to the subject an effective amount of the edible product prepared by a process disclosed herein.
- In one aspect, the present disclosure provides a method of treating, preventing, and/or ameliorating inflammation in a subject in need thereof, the method including administering to the subject an effective amount of the edible product prepared by a process disclosed herein.
- The edible product of the present disclosure is or may be suitable for use in the dairy industry, the beverage industry, the processed food industry, the processed meat industry, the baking industry, and/or the confectionary industry.
- The edible product of the present disclosure is or may be a fermented milk product. The edible product of the present disclosure is or may be a beverage. The edible product of the present disclosure is or may be a pharmaceutical composition.
- In one aspect, the present disclosure provides a method of improving immune system in a subject in need thereof, the method including administering to the subject an effective amount of a composition including one or more Lactobacillus fermentum strains that shares at least 80% to 100% genome sequence identity with Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060.
- In one aspect, the present disclosure provides a method of enhancing secretion of cytokines in a subject in need thereof including administering the subject an effective amount of the composition described in this disclosure.
- In embodiments, composition for improving the immune system and/or enhancing secretion of cytokines in a subject in need thereof is or may be a food product.
- In embodiments, composition for improving the immune system and/or enhancing secretion of cytokines in a subject in need thereof is or may be a pharmaceutical composition.
- In the composition, the edible product, the method, and the process of the present disclosure the one or more Lactobacillus fermentum strains is/are concentrated to provide enhanced efficacy.
- Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
- In the application, where an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.
- Further, it should be understood that elements and/or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present invention, whether explicit or implicit herein. For example, where reference is made to a particular compound, that compound can be used in various embodiments of compositions of the present invention and/or in methods of the present invention, unless otherwise understood from the context. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and invention(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the invention(s) described and depicted herein.
- The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present disclosure. As used throughout this disclosure, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to “a composition” includes a plurality of such compositions, as well as a single composition, and a reference to “a therapeutic agent” is a reference to one or more therapeutic and/or pharmaceutical agents and equivalents thereof known to those skilled in the art, and so forth. All percentages and ratios used herein, unless otherwise indicated, are by weight.
- Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the case of conflict, the present specification will control. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed disclosure. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting.
- A weight percent of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.
- The term “about” refers to any minimal alteration in the concentration or amount of an agent that does not change the efficacy of the agent in preparation of a formulation and in treatment of a disease or disorder. The term “about” with respect to concentration range of the agents (e.g., therapeutic/active agents) of the current disclosure also refers to any variation of a stated amount or range which would be an effective amount or range. In embodiments, the term “about” may include ±15% of a specified numerical value or data point. Ranges can be expressed in this disclosure as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it is understood that the particular value forms another aspect.
- It is further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed in this disclosure, and that each value is also disclosed as “about” that particular value in addition to the value itself. It is also understood that throughout the application, data are provided in a number of different formats and that this data represent endpoints and starting points and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point “15” are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.
- It should be understood that the expression “at least one of” includes individually each of the recited objects after the expression and the various combinations of two or more of the recited objects unless otherwise understood from the context and use. The expression “and/or” in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context.
- The use of the term “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context.
- Sequence identity may be determined in various ways that are within the skill in the art, e.g., using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. BLAST (Basic Local Alignment Search Tool) analysis using the algorithm employed by the programs blastp, blastn, blastx, tblastn and tblastx (Karlin et al., (1990) P
ROC . NATL . ACAD . SCI. USA 87:2264-2268; Altschul, (1993) J. MOL . EVOL . 36, 290-300; Altschul et al., (1997) NUCLEIC ACIDS RES. 25:3389-3402, incorporated by reference) are tailored for sequence similarity searching. For a discussion of basic issues in searching sequence databases see Altschul et al., (1994) NATURE GENETICS 6:119-129, which is fully incorporated by reference. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. The search parameters for histogram, descriptions, alignments, expect (i.e., the statistical significance threshold for reporting matches against database sequences), cutoff, matrix and filter are at the default settings. The default scoring matrix used by blastp, blastx, tblastn, and tblastx is the BLOSUM62 matrix (Henikoff et al., (1992) PROC . NATL . ACAD . SCI . USA 89:10915-10919, fully incorporated by reference). Four blastn parameters may be adjusted as follows: Q=10 (gap creation penalty); R=10 (gap extension penalty); wink=1 (generates word hits at every wink.sup.th position along the query); and gapw=16 (sets the window width within which gapped alignments are generated). The equivalent Blastp parameter settings may be Q=9; R=2; wink=1; and gapw=32. Searches may also be conducted using the NCBI (National Center for Biotechnology Information) BLAST Advanced Option parameter (e.g.: -G, Cost to open gap [Integer]: default=5 for nucleotides/11 for proteins; -E, Cost to extend gap [Integer]: default=2 for nucleotides/1 for proteins; -q, Penalty for nucleotide mismatch [Integer]: default=−3; -r, reward for nucleotide match [Integer]: default=1; -e, expect value [Real]: default=10; -W, wordsize [Integer]: default=11 for nucleotides/28 for megablast/3 for proteins; -y, Dropoff (X) for blast extensions in bits: default=20 for blastn/7 for others; -X, X dropoff value for gapped alignment (in bits): default=15 for all programs, not applicable to blastn; and -Z, final X dropoff value for gapped alignment (in bits): 50 for blastn, 25 for others). ClustalW for pairwise protein alignments may also be used (default parameters may include, e.g., Blosum62 matrix and Gap Opening Penalty=10 and Gap Extension Penalty=0.1). A Bestfit comparison between sequences, available in the GCG package version 10.0, uses DNA parameters GAP=50 (gap creation penalty) and LEN=3 (gap extension penalty) and the equivalent settings in protein comparisons are GAP=8 and LEN=2. - The following Examples are merely illustrative and are not intended to limit the scope or content of the invention in any way.
- The relationship between diet and health is now well known to be one of the keys to preventing disease and promoting wellbeing. This is the reason why there has been major growth in the market of functional foods that are foods that provide a positive influence on human health over and above their nutritive value. Dairy products hold a major share of this market, due partly to the fact that manufacturing process of fermented dairy products involves the addition of lactic acid bacteria (LAB), many of which are known to possess probiotic properties or which themselves produce secondary metabolites with associated health-promoting effects (Mills et al., 2011, Int. Dairy J. 21:377-401). Although, the transformation of lactose into lactic acid is the most significant phenomenon associated to LAB, fermented milks also contain a wide range of potentially active components, still not comprehensively characterized. These compounds, usually present in small amounts, are thought to exhibit specific properties, mostly in the area of immunostimulation (Granier et al., 2013, Pediatric Research 74:238-244).
- Whereas lactic acid production is a feature common to all LAB, the production of other compounds depends on the bacterial strains and on the conditions of the fermentation process. Additionally, some LAB have received special attention in recent decades for their use as probiotic microorganisms. Probiotics have traditionally been defined as “live microorganisms that, when being administered in appropriate dose provide health benefits to the host” (FAO/WHO 2001). Nevertheless, scientific evidence has shown that inactivated microorganisms (heat-killed) may also positively affect human health (Taverniti and Guglielmetti 2011, Genes Nutr 6:261-274).
- There is still a great need for finding new effective LAB which are useful, both as starters in fermented dairy foods and for the production of bioactive compounds with immunomodulatory and anti-inflammatory activities, that could be used as a food supplement or as a pharmaceutical composition.
- Specific Lactobacillus fermentum strains, NRRL B-67059 or NRRL B-67060, that can produce a bioactive fermented dairy product, and have remarkable capacity to modulate the immune system in humans or mammals were isolated. Such bioactive fermented dairy product or its isolated biologically active fractions, provides a method for inducing, increasing or stimulating the secretion of cytokines, such as interleukin-10 (IL-10). On the other hand, such bioactive fermented dairy product or its active fractions did not induce a pro-inflammatory response, such as that shown by interleukin-6 (IL-6).
- The bioactive fermented dairy product or its isolated fractions included in this invention is a viable option to modulate the immune system without secondary effects which are produced by some drugs. Additionally, such bioactive fermented dairy product or its isolated fractions induces anti-inflammatory effect at the systemic level. Therefore, the isolated Lactobacillus fermentum strains, NRRL B-67059 or NRRL B-67060, disclosed herein, and the bioactive compounds produced by them, included in this disclosure may be used in pharmaceutical preparations as well as in food products.
- This disclosure includes the generation of bioactive compounds by the action of novel Lactobacillus fermentum NRRL B-67059 or NRRL B-67060 during the fermentation of dairy substrates. One objective of the present disclosure is the manufacture of food products with bioactive compounds, for the production of functional foods as a consequence of the action of specific Lactobacillus fermentum NRRL B-67059 or NRRL B-67060 on a substrate within the food. Also, these bioactive compounds could be used in an edible product such as a food supplement or as a pharmaceutical composition.
- Novel strains of Lactobacillus fermentum, hereafter referred to as NRRL B-67059 and NRRL B-67060. NRRL B-67059 and NRRL B-67060 were isolated and were then deposited at the National Center for Agricultural Utilization Research, United States Department of Agriculture, United States of America, in Apr. 17, 2015.
- This invention is related to specific Lactobacillus strains, NRRL B-67059 or NRRL B-67060, that can produce a bioactive fermented dairy product, mainly that have remarkable capacity to modulate the immune system in humans or mammals.
- These bacteria were isolated from raw milk products and were Gram positive, catalase negative and bacilli-shaped organisms. These bacteria were identified as Lactobacillus fermentum by partially amplifying the 16S rRNA gene and sequencing (Table 1). These strains were characterized for their probiotic potential. Thus, L. fermentum strains were assessed by evaluating their resistance (percentage of survival) under conditions of low pH and enzyme treatment (Maragkoudakis et al., 2006, International Dairy Journal, 16, 189-199) and tolerance to bile salts (Thirabunyanon et al., 2009, Biotechnology Letters, 31, 571-576). In general, L. fermentum strains showed high viability to different gastrointestinal conditions with percentage ranges of cell survival at pH 3.0, enzyme treatment and bile salts of 94-99%, 71-99% and 79-96%, respectively (Table 2).
-
TABLE 1 Identification of Lactobacillus fermentum strains by the partial sequence of gene 16S rRNA. Strain Sequence NRRL GGATGAACGCCGGCGGTGTGCCTAATACATGCAAGTC B-67059 GAACGCGTTGGCCCAATTGATTGATGGTGCTTGCACC TGATTGATTTTGGTCGCCAACGAGTGGCGGACGGGTG AGTAACACGTAGGTAACCTGCCCAGAAGCGGGGGACA ACATTTGGAAACAGATGCTAATACCGCATAACAGCGT TGTTCGCATGAACAACGCTTAAAAGATGGCTTCTCGC TATCACTTCTGGATGGACCTGCGGTGCATTAGCTTGT TGGTGGGGTAATGGCCTACCAAGGCGATGATGCATAG CCGAGTTGAGAGACTGATCGGCCACAATGGGACTGAG ACACGGCCCATACTCCTACGGGAGGCAGCAGTAGGGA ATCTTCCACAATGGGCGCAAGCCTGATGGAGCAACAC CGCGTGAGTGAAGAAGGGTTTCGGCTCGTAAAGCTCT GTTGTTAAAGAAGAACACGTATGAGAGTAACTGTTCA TACGTTGACGGTATTTAACCAGAAAGTCACGGCTAAC TAC [SEQ ID NO: 1] NRRL GGATGAACGCCGGCGGTGTGCCTAATACATGCAAGTC B-67060 GAACGCGTTGGCCCAATTGATTGATGGTGCTTGCACC TGATTGATTTTGGTTGCCAACGAGTGGCGGACGGGTG AGTAACACGTAGGTAACCTGCCCAGAAGCGGGGGACA ACATTTGGAAACAGATGCTAATACCGCATAACAGCGT TGTTCGCATGAACAACGCTTAAAAGATGGCTTCTCGC TATCACTTCTGGATGGACCTGCGGTGCATTAGCTTGT TGGTGGGGTAACGGCCTACCAAGGCGATGATGCATAG CCGAGTTGAGAGACTGATCGGCCACAATGGGACTGAG ACACGGCCCATACTCCTACGGGAGGCAGCAGTAGGGA ATCTTCCACAATGGGCGCAAGCCTGATGGAGCAACAC CGCGTGAGTGAAGAAGGGTTTCGGCTCGTAAAGCTCT GTTGTTAAAGAAGAACACGTATGAGAGTAACTGTTCA TACGTTTACGGTATTTAACCAGAAAGTCACGGCTAAC TACGTGC [SEQ ID NO: 2] -
TABLE 2 Characterization of Lactobacillus fermentum NRRL B67059 and NRRL B67060 for the evaluation of their probiotic potential. Viability (%) Autoaggregation Strains pH 3.0 Pepsin Pancreatin Lysozyme Bile salts (%) Hydrophobicity L. fermentum 94.96 ± 0.31a 96.65 ± 0.03a 98.88 ± 0.36a 98.73 ± 0.34a 96.95 ± 0.10a 31.85 ± 0.05a 20.1 ± 1.11a NRRL B67059 L. fermentum 99.76 ± 0.06b 71.56 ± 0.69b 94.68 ± 0.15a 99.21 ± 0.14a 78.99 ± 0.10b 10.57 ± 0.03b 5.10 ± 1.59b NRRL B67060 Values are means for n = 3. Means for each value without a common letter differ significantly (p < 0.05). -
TABLE 3 Lactobacillus fermentum sensitivity to different antibiotics (n = 3). Cephalotin Dicloxacilin Erythromicn Gentamicin Penicillin Ampicilin Cefepime Cefuroxime Tetracycline L. fermentum NRRL B67059 R R R R R R R R R L. fermentum NRRL B67060 R R R I R R R R R R = Resistant I = Intermediate - Auto-aggregation (Collado et al. 2008, European Food Research and Technology, 226, 1065-1073) and hydrophobicity (Marin et al., 1997) were evaluated. In general, low levels of both parameters were observed (Table 2). These are properties of adhesion to epithelial cells and mucosal surfaces and may be a desirable feature for probiotics. Both strains of L. fermentum did not present hemolytic activity when grown on blood agar medium (Thirabunyanon, et al., 2009, Biotechnology Letters, 31, 571-576). The absence of hemolytic activity is an important property of selection for probiotics. Similarly, L. fermentum strains were unable to degrade mucin (
FIG. 1 ). Mucin degradation has been regarded as a non-desirable characteristic for probiotics. - In general, antibiotic susceptibility testing (Multidisc Gram positives II, BIO-RAD) of Lactobacillus fermentum strains, NRRL B-67059 and NRRL B-67060, showed resistance to all antibiotics tested (Table 3). Although probiotics may be susceptible to the majority of antibiotics, their resistance can be beneficial for people with an unbalanced intestinal microbiota due to the administration of various antimicrobial agents, so that the probiotics can be administered with antibiotics to prevent the gastrointestinal side effects (Courvalin, 2006, Digestive Liver Diseases, 38, S261-S26).
- Additionally, Lactobacillus fermentum strains, NRRL B-67059 and NRRL B-67060 presented important technological characteristics such as high acidifying and proteolytic activities when they were inoculated in reconstituted nonfat dry milk. In fact lactic acid production was significantly (p<0.05) higher at 48 h of fermentation for both strains (
FIG. 2 ). Also, these strains presented high acidifying activity (pH<4.0 in 48 h) (FIG. 3 ) and high proteolytic activity (Abs 340>0.20 in 48 h) (FIG. 4 ) according to the OPA (o-phtaldialdehyde method) (Church et al., 1983, J. Dairy Sci. 66:1219-1227). - The bacterial strains Lactobacillus fermentum NRRL B-67059 and NRRL B-67060 were activated in MRS broth (De Man, Rogosa and Sharpe, Difco) in three consecutive sub-cultures, these were inoculated at 1% level and incubated at 37° C. for 24, 18 and 12 h, respectively. Fresh cultures were obtained by repeating the same procedure. Initial starter cultures were prepared by allowing L. fermentum strains to reach 106-107 colony-forming units (CFU) mL−1 as enumerated on MRS agar.
- Reconstituted nonfat dry milk (10%, w/v) was sterilized at 110° C. for 10 min. The pre-culture (107 CFU mL−1) of Lactobacillus fermentum NRRL B-67059 or NRRL B-67060 was inoculated into sterilized milk at 1% level and incubated for 12 h. Then, milk (20 mL) was inoculated with 3% of pre-culture. Samples were incubated at 37° C. for 48 h to obtain the different fermented milk batches (109 CFU mL−1). For fermented-pasteurized milk preparation, fermented milk was subjected to 75° C. for 15 min.
- Samples (1 mL, 109 CFU mL−1) of specific fermented milk (prepared as previously described) were administered via canula to female Wistar rats (6-8 week-old, weighing 140±20 g) obtained from Harlan Laboratories, INC, (Indianapolis, Ind., USA, through their Mexico city representative). The control groups were administered unfermented milk. Rats were randomly assigned to groups of six and housed in pairs per cage at 23±2° C. with 12 h light/dark cycles, 52±6% relative humidity, with ad libitum intake of a standard diet (Teklad, Harlan Laboratories, USA) and purified water. Blood samples were obtained from each group after 7 and 21 d of treatment administration, before animals were sacrificed. Blood samples were centrifuged (1800×g, 10 min, 4° C.) and serum samples were stored −20° C. until cytokine analysis. The animal experimental procedures were done following the guidelines and supervision of the CIAD, A.C. Committee of Ethics for scientific research.
- The concentration of cytokines (IL-10 and IL-6) was evaluated by a commercial ELISA kit (BD, Invitrogen). The results were expressed as concentration of each cytokine (pg mL-1).
- All groups administered with fermented milk containing Lactobacillus fermentum NRRL B-67059 or NRRL B-67060 presented significantly (p<0.05) higher anti-inflammatory cytokine IL-10 than the control group after 7 days of treatment (
FIG. 5 ). Furthermore, the concentration of IL-10 was maintained at higher levels than the control at 21 d, although only treatment with milk fermented with Lactobacillus fermentum NRRL B-67059 was highly significant (p<0.05) (FIG. 5 ). Furthermore, the concentration of the pro-inflammatory cytokine IL-6 decreased significantly (p<0.05) in the group that consumed fermented-pasteurized milk with Lactobacillus fermentum NRRL B-67059 with respect to the control group (FIG. 6 ). Therefore, the beneficial effect on the immune system may be attributed to bioactive compounds produced during fermentation (postbiotics) and/or live or heat-killed bacteria. - Thus, the use of milk fermented by specific lactic acid bacteria Lactobacillus fermentum NRRL B-67059 or NRRL B-67060, may be considered as a co-adjuvant for the improvement of health by modulating the immune system. Thus, dairy products fermented with Lactobacillus fermentum NRRL B-67059 or NRRL B-67060, may be used as functional foods with potential benefits.
- A method is performed for preparing a food product, a food supplement, or a pharmaceutical composition including a dairy bioactive fraction of one or more Lactobacillus fermentum strains that shares at least 80% to 100% genome sequence identity with Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060, where the bioactive fraction is obtained by a bioguided procedure and used for preparing the food product, the food supplement, or the pharmaceutical composition.
- A process is described for preparing an edible product, the process including fermenting a protein-containing starting material with one or more Lactobacillus fermentum strains that shares at least 80% to 100% genome sequence identity with Lactobacillus fermentum strain NRRL B-67059 and/or Lactobacillus fermentum strain NRRL B-67060. The starting material is milk or a milk-based product. The method includes removing unhydrolyzed protein. The edible product includes a bioactive fraction. In the process, the starting material may include one or more bioactive compounds.
- A subject is administered with a composition, pharmaceutical composition, and/or an edible product of the present disclosure for treating a dietary disease or disorder, an inflammatory disease or disorder, and/or an immune disease or disorder.
- The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes.
- The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting on the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and the range of equivalency of the claims are intended to be embraced therein.
Claims (21)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17/350,102 US20220000950A1 (en) | 2015-12-24 | 2021-06-17 | Compositions and Methods of Use of Novel Strains of Lactobacillus Fermentum |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562387474P | 2015-12-24 | 2015-12-24 | |
US15/390,108 US11071760B2 (en) | 2015-12-24 | 2016-12-23 | Compositions and methods of use of novel strains of Lactobacillus fermentum |
US17/350,102 US20220000950A1 (en) | 2015-12-24 | 2021-06-17 | Compositions and Methods of Use of Novel Strains of Lactobacillus Fermentum |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/390,108 Division US11071760B2 (en) | 2015-12-24 | 2016-12-23 | Compositions and methods of use of novel strains of Lactobacillus fermentum |
Publications (1)
Publication Number | Publication Date |
---|---|
US20220000950A1 true US20220000950A1 (en) | 2022-01-06 |
Family
ID=59088233
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/390,108 Active 2037-11-08 US11071760B2 (en) | 2015-12-24 | 2016-12-23 | Compositions and methods of use of novel strains of Lactobacillus fermentum |
US17/350,102 Abandoned US20220000950A1 (en) | 2015-12-24 | 2021-06-17 | Compositions and Methods of Use of Novel Strains of Lactobacillus Fermentum |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/390,108 Active 2037-11-08 US11071760B2 (en) | 2015-12-24 | 2016-12-23 | Compositions and methods of use of novel strains of Lactobacillus fermentum |
Country Status (13)
Country | Link |
---|---|
US (2) | US11071760B2 (en) |
EP (1) | EP3393484A4 (en) |
JP (2) | JP7121996B2 (en) |
CN (1) | CN108495643A (en) |
BR (1) | BR112018013052A2 (en) |
CA (1) | CA3008175A1 (en) |
CL (2) | CL2018001680A1 (en) |
CO (1) | CO2018007607A2 (en) |
CR (1) | CR20180376A (en) |
EA (1) | EA201891508A1 (en) |
IL (1) | IL260181B (en) |
MX (1) | MX2018007780A (en) |
WO (1) | WO2017112945A1 (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114774302B (en) * | 2022-03-09 | 2023-06-16 | 善恩康生物科技(苏州)有限公司 | Application of lactobacillus plantarum CQPC02 in preparation of product for preventing and/or treating lupus nephritis |
CN114517171B (en) * | 2022-03-17 | 2023-11-28 | 江南大学 | Lactobacillus fermentum CCFM1225 capable of promoting intestinal tract secretion of IgA and application thereof |
CN114540247B (en) * | 2022-03-17 | 2023-11-28 | 江南大学 | Lactobacillus fermentum CCFM1226 capable of improving intestinal IgA level and relieving enteritis and application thereof |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6066343A (en) | 1998-05-13 | 2000-05-23 | Nutribiotech, Llc | Methods and compositions for making fermented cereal products |
EP1541673B1 (en) * | 2000-05-25 | 2007-04-04 | Société des Produits Nestlé S.A. | Probiotics for pet food applications |
AU2003224355A1 (en) | 2003-04-02 | 2004-10-25 | Axcel Photonics, Inc. | Lactobacillus fermentum strain and uses thereof |
EP1997499A1 (en) * | 2007-05-31 | 2008-12-03 | Puleva Biotech, S.A. | Mammalian milk microorganisms, compositions containing them and their use for the treatment of mastitis |
TWI383798B (en) * | 2010-04-27 | 2013-02-01 | Syngen Biotech Co Ltd | Lactobacillus fermentum sg-a95 for improving oral bacterial groups and health care compositions thereof |
JP5887062B2 (en) | 2011-03-30 | 2016-03-16 | 国立研究開発法人海洋研究開発機構 | New useful deep-sea bacteria |
US8906668B2 (en) | 2012-11-23 | 2014-12-09 | Seres Health, Inc. | Synergistic bacterial compositions and methods of production and use thereof |
-
2016
- 2016-12-23 EP EP16880154.6A patent/EP3393484A4/en active Pending
- 2016-12-23 MX MX2018007780A patent/MX2018007780A/en unknown
- 2016-12-23 CA CA3008175A patent/CA3008175A1/en active Pending
- 2016-12-23 JP JP2018553045A patent/JP7121996B2/en active Active
- 2016-12-23 EA EA201891508A patent/EA201891508A1/en unknown
- 2016-12-23 CR CR20180376A patent/CR20180376A/en unknown
- 2016-12-23 US US15/390,108 patent/US11071760B2/en active Active
- 2016-12-23 BR BR112018013052A patent/BR112018013052A2/en not_active Application Discontinuation
- 2016-12-23 WO PCT/US2016/068557 patent/WO2017112945A1/en active Application Filing
- 2016-12-23 CN CN201680076158.4A patent/CN108495643A/en active Pending
-
2018
- 2018-06-20 CL CL2018001680A patent/CL2018001680A1/en unknown
- 2018-06-20 IL IL260181A patent/IL260181B/en unknown
- 2018-07-23 CO CONC2018/0007607A patent/CO2018007607A2/en unknown
-
2020
- 2020-07-29 CL CL2020001975A patent/CL2020001975A1/en unknown
-
2021
- 2021-06-17 US US17/350,102 patent/US20220000950A1/en not_active Abandoned
-
2022
- 2022-08-01 JP JP2022122628A patent/JP2022140607A/en not_active Withdrawn
Non-Patent Citations (2)
Title |
---|
Cárdenas et al. "Relationships between the genome and some phenotypical properties of Lactobacillus fermentum CECT 5716, a probiotic strain isolated from human milk." Applied microbiology and biotechnology 99 (2015): 4343-4353. (Year: 2015) * |
Sharma et al. "Dietary supplementation of milk fermented with probiotic Lactobacillus fermentum enhances systemic immune response and antioxidant capacity in aging mice." Nutrition research 34.11 (2014): 968-981. (Year: 2014) * |
Also Published As
Publication number | Publication date |
---|---|
BR112018013052A2 (en) | 2018-12-04 |
US20170182101A1 (en) | 2017-06-29 |
CN108495643A (en) | 2018-09-04 |
EA201891508A1 (en) | 2019-03-29 |
CL2018001680A1 (en) | 2018-11-30 |
IL260181A (en) | 2018-07-31 |
CA3008175A1 (en) | 2017-06-29 |
CO2018007607A2 (en) | 2018-11-13 |
MX2018007780A (en) | 2019-05-23 |
WO2017112945A1 (en) | 2017-06-29 |
JP2022140607A (en) | 2022-09-26 |
EP3393484A1 (en) | 2018-10-31 |
EP3393484A4 (en) | 2019-06-12 |
JP7121996B2 (en) | 2022-08-19 |
JP2019506448A (en) | 2019-03-07 |
CR20180376A (en) | 2018-11-09 |
IL260181B (en) | 2022-03-01 |
CL2020001975A1 (en) | 2020-12-04 |
US11071760B2 (en) | 2021-07-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20220000950A1 (en) | Compositions and Methods of Use of Novel Strains of Lactobacillus Fermentum | |
KR102569754B1 (en) | Use of pasteurized akkermansia for treating metabolic disorders | |
JP5031249B2 (en) | Bacteria-containing composition having anti-inflammatory effect | |
JP2021522867A (en) | Lactobacillus paracasei strain and its use | |
EP2889371A1 (en) | Bacteroides cect 7771 and the use thereof in the prevention and treatment of excess weight, obesity and metabolic and immunological alterations | |
KR20140147656A (en) | Bifidobacterium cect 7765 and use thereof in the prevention and/or treatment of excess weight, obesity and related pathologies | |
JP2002534113A (en) | Bifidobacterium in the treatment of inflammatory diseases | |
KR101640744B1 (en) | Macromolecular polysaccharide binder conjugated Lactobacillus rhamnosus RHT-3201, and use thereof in prevention and treatment of atopic dermatitis | |
CN110643541B (en) | Lactobacillus casei capable of adjusting Th2/Th1 balance of allergic asthma and application thereof | |
EP2220210B1 (en) | Strains of lactobacillus plantarum as probiotics with immunomodulatory specific effect | |
CA3174352A1 (en) | Compositions for metabolic health | |
KR102224072B1 (en) | Bifidobacterium longum subsp. longum having both abilities of reducing total cholesterol in serum and immune regulation and its application | |
KR101987678B1 (en) | Bifidobacterium longum KACC 91563 and cheese comprising the same for treatment of dermatitis | |
JP2020162479A (en) | Composition for improving eye trouble and use thereof | |
EA041936B1 (en) | PHARMACEUTICAL COMPOSITION AND FOOD PRODUCT CONTAINING NEW LACTOBACILLUS FERMENTUM STRAINS | |
JP6016326B2 (en) | Screening method for lactic acid bacteria | |
JP6029242B2 (en) | Clostridium difficile growth inhibitor | |
CN118020946A (en) | Nutritional composition for protecting intestinal barrier and/or preventing central nervous system diseases and application thereof | |
JP2021101645A (en) | Composition for regulating immune balance | |
KR20240137695A (en) | Use of pasteurized akkermansia for preventing cancer |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
AS | Assignment |
Owner name: DAIRY A DAY INC., TEXAS Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:GALLAND, BELINDA VALLEJO;CORDOVA, AARON FERNANDO GONZALEZ;QUEZADA, JOSE ANTONIO FEREGRINO;AND OTHERS;REEL/FRAME:065407/0128 Effective date: 20161229 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NOTICE OF ALLOWANCE MAILED -- APPLICATION RECEIVED IN OFFICE OF PUBLICATIONS |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO PAY ISSUE FEE |