WO2011069860A1 - Nouvelle utilisation pour le traitement de l'endotoxémie métabolique - Google Patents

Nouvelle utilisation pour le traitement de l'endotoxémie métabolique Download PDF

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WO2011069860A1
WO2011069860A1 PCT/EP2010/068460 EP2010068460W WO2011069860A1 WO 2011069860 A1 WO2011069860 A1 WO 2011069860A1 EP 2010068460 W EP2010068460 W EP 2010068460W WO 2011069860 A1 WO2011069860 A1 WO 2011069860A1
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strain
lps
expression
genes
bacillus
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PCT/EP2010/068460
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Jens Kildsgaard
Thomas Dyrmann Leser
Thomas Gunnarsson
Ondrej Valina
Bénédicte Flambard
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Chr. Hansen A/S
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • TITLE NOVEL USE FOR THE TREATMENT OF METABOLIC ENDOTOXEMIA
  • the invention relates to the use of at least two bacterial strains for the prevention and/or treatment of metabolic endotoxemia and disorders related thereto.
  • One of the strains is a strain that produces a phosphatase able to desphosphorylate endotoxin (LPS) and the at least one other strain is a strain which is able to induce the expression of one or more genes positively associated with the intestinal barrier function (tightness of the intestinal epithelium) of a mammal.
  • LPS desphosphorylate endotoxin
  • Metabolic endotoxemia is a condition recently described by Cani et al. (1 ). Whereas endotoxemia in general is associated with acute, high levels of endotoxins in the blood that can lead to septic shock, ME is characterized by chronic, but only moderately increased levels of plasma lipopolysaccharide (LPS) and is associated with a low-grade inflammatory status. Lipopolysaccharides are large (MW 200.000 to 1.000.000), heat stable molecules found in the cell walls of Gram-negative bacteria. Circulating lipopolysaccharides or endotox- ins are extremely toxic to the mammalian organism and may induce septic shock. In a mammal suffering from ME the concentration of circulating LPS is typically only 2-3 times higher than normal. This increase is 10-50 times lower than values reached during septicemia or septic shock.
  • LPS plasma lipopolysaccharide
  • LPS circulates in the plasma of healthy human subjects at low concentrations ranging be- tween 1 and 10 pg/ml, with transient increases rarely exceeding 80 pg/ml.
  • Plasma LPS is derived mainly from the gut, which is a reservoir of ⁇ 1 g of LPS (2).
  • the sources of LPS in the gut are the Gram-negative fraction of the gut microflora and LPS and/or bacteria ingested with the food.
  • Cani et al. (1 ) showed that a four-week, high-fat diet chronically increased plasma LPS by 2- 3 times in mice, and further, that continuous subcutaneous infusion of LPS for four weeks caused increased fasted glycemia, insulinemia, whole body, liver, and adipose tissue weight gain similar to that of the high-fat diet.
  • Adipose tissue F4/80 positive cells and markers of inflammation (IL-6, TNF-a, IL-1 , and PAI-1 ), and liver triglyceride content were increased.
  • Obesity is a condition in which the natural energy reserve, stored in the fatty tissue, is increased to a point where it is associated with certain adverse health conditions or increased mortality.
  • the term overweight is generally used to indicate that a human has more body fat than is considered useful for the optimal functioning of the body.
  • the term overweight is used to describe humans with a Body Mass Index (BMI) of 25 to 29.9.
  • BMI Body Mass Index
  • the number of overweight and obese people (BMI of 30 and above) in the developed countries is increasing at an epidemic rate.
  • Overweight and obesity is the result of eating habits frequently involving a diet rich in fat.
  • One major metabolic consequence of high-fat feeding is that insulin action and the regulatory mechanisms of body weight are impaired.
  • obesity/obesity and insulin resistance is associated with a low-grade systemic inflammation.
  • Elevated plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-a), which are markers of inflammation were observed (8-10).
  • CRP C-reactive protein
  • IL-6 interleukin-6
  • TNF-a tumor necrosis factor-alpha
  • cytokines and chemokines are up-regulated. These mediators are associated with a number of autoimmune diseases including: Acute disseminated encephalomyelitis (ADEM), Addison's disease, Ankylosing spondylitis (chronic back pain), Antiphospholipid antibody syndrome (APS), Aplastic anemia, Autoimmune hepatitis, Autoimmune Oophoritis, Celiac disease, Crohn's disease, Diabetes mellitus type 1 , Gestational pemphigoid, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, Idiopathic thrombocytopenic purpura, Kawasaki's Disease, Lupus erythematosus, Multiple sclerosis, Myasthenia gravis, Opsoclonus myoclonus syndrome (OMS), Optic neuritis, Ord's thyroid
  • ADAM Acute disseminated encephalomyelitis
  • metabolic endotoxemia is linked to a number of diseases by chronic low level inflammation including: Alopecia universalis, Behget's disease, Chagas' disease, Chronic fatigue syndrome, Dysautonomia, Endometriosis, Hidradenitis suppurativa, Interstitial cystitis, Lyme disease, Morphea, Neuromyotonia, Narcolepsy, Psoriasis, Sarcoidosis, Schizophrenia, Scleroderma, Ulcerative colitis, Vitiligo, Vulvodynia, Depression (mood), Clinical depression, including: Melancholic depression, Atypical depression, Psychotic depression, Postnatal de- pression.
  • EP 1 ,359,924 B1 (Schiffrin and Kociubinski) describe that bacteria with hydrophobic surface properties bind LPS and can be used to reduce the momentary very high LPS values asso- ciated with endotoxic shock, sepsis of gut origin, necrotising enterocolitis etc.
  • the inventors of the present invention have realized that a two-string strategy has to be applied. Accordingly the solution implies a product comprising a combination of bacterial strains wherein the at least one of the strains is a strain that detoxifies LPS by dephosphorylation and the at least one other strain reduces the uptake of LPS into the circulating system from the intestinal lumen by inducing the expression of one or more genes that are positively as- sociated with the tightness of the intestinal epithelium of a mammal.
  • the invention pertains to the use of at least two strains of bacteria for the preparation of a composition for lowering concentrations of plasma LPS that characterize metabolic endotoxemia wherein the at least one strain is a strain that detoxifies LPS by dephosphorylation and the at least one other strain is characterized by being capable of inducing the expression of one or more genes that are positively associated with the tightness (or barrier function) of the intestinal epithelium of a mammal.
  • the invention pertains to the use of the composition prepared according to the first aspect for the preparation of a composition intended for the prevention, alleviation or treatment of metabolic endotoxemia and disorders related thereto.
  • a further important aspect of the invention is the provision of a human or pet food composition or dietary supplement dosage form containing at least one strain that is able to detoxify LPS by dephosphorylation and least one other strain that is able to induce the expression of one or more genes that are positively associated with the tightness (or barrier function) of the intestinal epithelium of a mammal.
  • ME metabolic endotoxemia
  • LPS plasma lipopolysaccharide
  • the concentration of circulat- ing LPS varies considerably depending on the time difference between food intake and time of LPS assessment. Plasma LPS concentration is also subjected to diurnal variations. Thus in a mammal suffering from ME the concentration of circulating LPS may transiently be lower, e.g. 1.5 times or even close to normal, as well as significantly higher, e.g. 4-8 times higher than normal.
  • concentration of plasma LPS that characterize metabolic endotoxemia is referred to the observation by Cani et al. (1 ) and others that subjects suffering from ME is characterized by a concentration of circulating LPS that moderately increased.
  • modified- ately increased is referred to an increase in the concentrations of plasma LPS between 1 .5 and 8 times the normal, more typically between 2-4 and most typically between 2-3 times the normal.
  • phosphatase is referred to any phosphoric ester hydrolases that is capable of catalyzing the reaction: a phosphate monoester + H 2 0 -> an alcohol + phosphate.
  • alkaline phosphatase also referred to as EC 3.1.3.1 according to the International Union of Biochemistry and Molecular Biology (IUBMB) Enzyme Nomenclature
  • acid phosphatase also referred to as EC 3.1.3.2 according to the IUBMB Enzyme Nomenclature.
  • genes that are positively associated with intestinal barrier function are synonymous with genes that are positively associated with tightness of the intestinal epithelium.
  • genes that are positively associated with the tightness or barrier function of the intestinal epithelium of a mammal is referred to genes that code for proteins that are positively associated with the intestinal barrier or tightness function of the intestinal epithelium of a mammal.
  • proteins are occludin and junctional adhesion molecule 1 (JAM-1 or F1 1 R), which have been described as proteins that are essential for the function of the tight junctions of the epithelia.
  • OCLN designates the gene coding for occludin, a tight junction structural protein.
  • F1 1 R or “JAM1” designate the gene coding for Junctional Adhesion Molecule 1 , a tight junction structural protein.
  • disorders related to metabolic endotoxemia designates disorders which comprise metabolic syndrome also known as metabolic syndrome X, syndrome X, insulin resistance syndrome, Reaven's syndrome or CHAOS (Australia). The symptoms of these disorders are: 1 .
  • Fasting hyperglycemia diabetes mellitus type 2 or impaired fasting glucose, impaired glucose tolerance, or insulin resistance
  • High blood pressure 3.
  • Cen- tral obesity 4. Decreased HDL cholesterol, and 5. Elevated triglycerides.
  • Metabolic endotoxemia is associated with the up-regulation of several biological mediators, e.g. specific cytokines and chemokines. These mediators are associated with a number of autoimmune diseases including: Acute disseminated encephalomyelitis (ADEM), Addison's disease, Ankylosing spondylitis (chronic back pain), Antiphospholipid antibody syndrome (APS), Aplastic anemia, Autoimmune hepatitis, Autoimmune Oophoritis, Celiac disease, Crohn's disease, Diabetes mellitus type 1 , Gestational pemphigoid, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, Idiopathic thrombocytopenic purpura, Kawasaki's Disease, Lupus erythematosus, Multiple sclerosis, Myasthenia gravis, Opsoclonus myoclonus syndrome (OMS), Optic neuritis, Or
  • the chronic low level inflammation imposed by metabolic endotoxemia is linked to a number of diseases e.g.: Alopecia universalis, Behget's disease, Chagas' disease, Chronic fatigue syndrome, Dysautonomia, Endometriosis, Hidradenitis suppurativa, Interstitial cystitis, Lyme disease, Morphea, Neuromyotonia, Narcolepsy, Psoriasis, Sarcoidosis, Schizophrenia, Scleroderma, Ulcerative colitis, Vitiligo, Vulvodynia, Depression (mood), Clinical depression, including: Melancholic depression, Atypical depression, Psychotic depression, Postnatal depression.”
  • strain producing alkaline phosphatase EC 3.1 .3.1
  • strain producing alkaline phosphatase designates any bacterial strain that is able to produce a phosphatase (EC 3.1 .3. 1 ) that catalyzes the chemical reaction: A phosphate monoester + H 2
  • CFU colony forming units
  • BMI body mass index
  • ⁇ designates body mass index.
  • BMI is a measure of the weight of a person scaled according to height. It is defined as the individual's body weight divided by the square of their height (weight measured in kilograms, height in meters).
  • the formula universally used in medicine produce a unit of measure of kg/m 2 . According to the US Department of Health & Human Services a BMI below 18.5 indicates underweight, 18.5 - 24.9 normal weight, 25 - 29.9 overweight and a BMI of 30 and above indicates obesity.
  • the invention aims at preventing, reducing or treating metabolic endotoxemia (ME) and disorders, conditions or diseases associated with ME by a two-string process.
  • ME metabolic endotoxemia
  • This process raises two levels of defence mechanisms against the translocation of toxic LPS from the gut to systemic circulation by: 1 ) detoxifying intestinal LPS by providing bacteria that express and secrete alkaline phosphatase and thus inactivate part of the gut flora derived LPS by dephosphorylation, and 2) further reducing the flux of LPS from the gut lumen into the circulating system by providing bacteria which improve the gastro-intestinal barrier function by stimulating expression of genes which are central to the maintenance or enhancement of the intestinal barrier integrity (i.e. the barrier function of the epithelium). It is contemplated that by maintaining the level of circulating LPS at the normal level the low level inflammatory response that characterizes ME is avoided and a condition of low-level chronic inflammation associated with the intake of a high-fat, western type diet is prevented.
  • LPS LPS is a major component of the outer membrane of Gram-negative bacteria, contributing greatly to the structural integrity of the bacteria, and protecting the membrane from certain kinds of chemical attack.
  • the gastro-intestinal tract contains 10 to 10 bacteria. About one third of these are Gram-negative, containing LPS in the cell membrane. Thus, the gut lumen holds ⁇ 1 g of LPS and is the major source of plasma LPS.
  • LPS is extremely toxic with LD50 by i.v. or i.p. administration ranges between 250-500 ⁇ g pr. 20 g mice (a typical laboratory mouse weighs 18-22 g). LD50 in humans has not been determined, but is anticipated to be within the same ranges.
  • LPS is a very potent stimulator of the cells of the immune system, (monocyte/macrophages, B cells, polymorph nuclear cells) and vascular endothelial cells. LPS binds the cells of the immune system.
  • CD14/TLR4/MD2 receptor complex which promotes the secretion of pro-inflammatory cytokines in many cell types.
  • LPS induces a pro-inflammatory response in human adipocytes and is, thus, a link between an unhealthy diet and systemic low-grade inflammation.
  • Lipid A contains two phosphate groups attached to diglu- cosamine, which are crucial for the toxicity of LPS. Alkaline phosphatase from vertebrates is able to dephosphorylate LPS and generate monophosphoryl lipid A (13). Monophosphoryl lipid A is virtually non-toxic (14).
  • Intestinal alkaline phosphatase is expressed on the intestinal lumen brush border side of all vertebrates. Zebra fish raised under germ-free conditions do not express intestinal alkaline phosphatase. Adding back LPS or a typical gut microflora restores intestinal alkaline phosphatase production of the zebra fish (15). After oral administration of LPS to rats, serum LPS was increased 2-fold when the rats were given an inhibitor of intestinal alkaline phosphatase compared to rats that were not given the inhibitor (16). Furthermore, disruption of the gene that encodes for mouse intestinal alkaline phosphatase, Akp3, induces visceral fat accumulation and hepatic steatosis (17;18).
  • This phenotype corresponds to the phenotype observed upon continuous subcutaneous infusion of LPS for four weeks in normal mice, i.e. whole body, liver, and adipose tissue weight gain (1 ).
  • alkaline phosphatases in response to changes in living conditions, e.g. when phosphate concentration is low and limiting for growth, or when bacteria are cultivated in conditions that trigger sporulation (19). Aligning the sequences from a selection of bacterial alkaline phosphatases shows that the enzymes are well conserved, especially at the active site (20). However, when comparing alkaline phosphatase from Homo sapiens and E. coli, the amino acid sequence homology is only 26.5%. Whereas the active site of alkaline phosphatase from H. sapiens and E. coli requires Zn 2+ and Mg 2+ ' most bacterial alkaline phosphatases require Co 2+ at the active site (20).
  • the invention pertains to the use of at least two strains of bacteria for the preparation of a composition for lowering concentrations of plasma LPS that characterize metabolic endotoxemia wherein the at least one strain is characterized by producing a phosphatase that is able to able to dephosphorylate LPS, such as e.g. alkaline phosphatase (EC 3.1 .3.1 ).
  • Intestinal barrier function regulates transport and host defense mechanisms at the mucosal interface with the outside world.
  • Transcellular and paracellular fluxes are tightly controlled by membrane pumps, ion channels and tight junctions, adapting permeability to physiological needs. Disturbance at any level, but particularly bacterial translocation due to increased permeability and breakdown of oral tolerance due to compromised epithelial and T cell interac- tion, can result in inflammation and tissue damage.
  • Tight junctions or zonula occludens, are the closely associated areas of two epithelial cells whose membranes join together forming a virtual impermeable barrier to fluid, which separates the vascular system from the lumen of the digestive tract.
  • tight junction bar- rier function has been demonstrated to result in an increased invasion of undesirable substances such as LPS from intestinal lumen into the circulating system.
  • induction of the tight junction barrier function is expected to result in a decreased invasion of undesirable substances such as LPS.
  • Tight junctions are composed of a branching network of sealing strands, each strand acting independently from the others. Therefore, the efficiency of the junction in preventing pas- sage increases exponentially with the number of strands.
  • the tight junction strands are composed by a number of proteins, one of the major types are the occludins. The other major constituents of tight junctions are claudins and junctional adhesion molecules (JAMs).
  • Occludin is a 65-kDa (504-amino acid polypeptide) which is coded by the OCLN gene.
  • Oc- cludin is a transmembrane protein that appears to pass the plasma membrane four times, forming two extracellular loops and exposing its NH 2 and COOH terminus to the cytosol. Interaction of occludin with several cytoplasmic proteins of the junctional plaque has been found to occur via its COOH terminus, while the extracellular loops are thought to be involved in the regulation of paracellular permeability and cell adhesion (22).
  • junctional adhesion molecule 1 also known as the F1 1 receptor, F1 1 R, is a member of the immunoglobulin superfamily and is an important regulator of tight junction assembly in epithelia and endothelia. Its extracellular domain can dimerize to form homodimers, while the intracellular domain interacts with structural and signaling proteins (22). Recently, polymorphisms in the F1 1 R have been directly linked to ME-related conditions such as obesity and increased blood pressure (23).
  • the invention pertains to use of at least two strains of bacteria for the preparation of a composition for lowering concentrations of plasma LPS that characterize metabolic en- dotoxemia wherein the at least one strain is a strain that detoxifies LPS by dephosphoryla- tion and the at least one other strain is able to induce the expression of one or more genes that are positively associated with the tightness of the intestinal epithelium of a mammal. While a number of such genes have been identified a strain that is able to induce the ex- pression the expression of at least one of the genes selected from the group consisting of OCLN and F1 1 R is preferred.
  • the at least one phosphatase producing strain is se- lected from the group consisting of Bacillus sp, such as Bacillus subtilis, Bacillus licheniformis, Bacillus coagulans, Bacillus cereus, Bacillus natto, Bacillus clausii, Bacillus indicus and Enterococcus faecium; and the at least one other strain is selected from the group consisting of Lactobacillus sp. and Bifidobacterium sp. in particular Lactobacillus paracasei ssp. paracasei, Bifidobacterium animalis subsp. lactis and Lactobacillus acidophilus.
  • Bacillus sp such as Bacillus subtilis, Bacillus licheniformis, Bacillus coagulans, Bacillus cereus, Bacillus natto, Bacillus clausii, Bacillus indicus and Enterococcus faecium
  • the phosphatase producing strain is selected from the group consisting of Bacillus sp, such as Bacillus subtilis, Bacillus licheniformis, Bacillus coagulans, Bacillus cereus, Bacillus natto, Bacillus clausii, Bacillus indicus and Enterococcus faecium.
  • Bacillus subtilis such as Bacillus subtilis, Bacillus licheniformis, Bacillus coagulans, Bacillus cereus, Bacillus natto, Bacillus clausii, Bacillus indicus and Enterococcus faecium.
  • the phosphatase producing strain is selected form the group of Bacillus subtilis (CHCC3810/DSM 17231 ), Bacillus licheniformis (CHCC3809/DSM 17236) and Bacillus licheniformis (CHCC5019/LMG6934/DSM394) is pre- ferred.
  • these Bacillae produce
  • the strain Bacillus subtilis (CHCC3810/DSM17231 ) was deposited on 07 April 2005 according to the Budapest Treaty on the International Recognition of the Deposit of Microorgan- isms for the Purposes of Patent Procedure with the Deutsche Sammlung von Mikroorganis- men und Zellkulturen (DSMZ) under accession number DSM17231 .
  • the strain Bacillus licheniformis (CHCC3809/DSM 17236) was deposited according to the Budapest Treaty with the DSMZ on 07 April 2005 under accession number DSM17236, and Bacillus licheniformis (CHCC5019/LMG6934/DSM394) was deposited in the publicly available section of DSMZ under accession number DSM394.
  • Bacillus licheniformis (CHCC5019/LMG6934/DSM394) is also available from the Belgian Coordinated Collections of Microorganisms, BCCM/LMG under the accession number LMG 6934.
  • the two probiotic strains Bifidobacterium ani- malis subsp. lactis strain BB-12 and Lactobacillus paracasei subsp. paracasei strain CRL- 431 are able to induce genes that enhance intestinal barrier function (tightness of the intestinal epithelium) in vivo.
  • the at least one other strain is selected from the group consisting of Lactobacillus paracasei subsp. paracasei (CRL431 , ATCC 55544) and Bifidobacterium animalis subsp. lactis (BB-12®, DSM15954). The strain Lactobacillus paracasei subsp.
  • CRL431 ATCC 55544
  • ATCC 55544 accession number ATCC 55544
  • the CRL431 strain is commercially available from Chr. Hansen A S, 10-12 Boege Alle, DK-2970 Hoersholm, Denmark, under the product name Probio-Tec® F-DVS L.casei-431®, Item number 501749, and under the product name Probio-Tec® C-Powder-30, Item number 687018.
  • Bifidobacterium animalis subspecies lactis strain CHCC5445 (BB-12®) was deposited on 30 September 2003 according to the Budapest Treaty with the DSMZ under accession number DSM15954. This strain is also commercially available from Chr. Hansen A S, 10-12 Boege Alle, DK-2970 Hoersholm, Denmark.
  • strains that are directly derived from these two probiotic strains are likely to retain the ability to induce the expression of one or more genes that are positively associated with the tightness of the intestinal epithelium of a mammal.
  • the BB-12® strain contains an active tetW gene that endows the BB-12 strain with resistance to tetracycline (EP 1.724.340 [Stroeman]).
  • EP 1.724.340 [Stroeman] tetracycline-sensitive BB-12 mutants which contain an inactivated tetW.
  • the at least one other strain is selected from the group consisting of Bifidobacterium animalis subsp.
  • lactis (BB-12®, DSM15954) and a tetracycline-sensitive strain derived directly from BB-12 or its very close tetracycline-resistant relative NH019 (DR10TM, DSM17280): strain BB12Tet-S139 (DSM17281 ), strain DR10Tet-S9X (DSM17282), strain BB12Tet-S70 (DSM18735) and strain BB12Tet-S705 (DSM18776).
  • the Bifidobacterium animalis subsp. lactis strain BB12Tet-S139 (DSM17281 ) was deposited on 28 April 2005 according to the Budapest Treaty with the DSMZ under accession number DSM17281 .
  • the Bifidobacterium lactis strain DR10Tet-S9X (DSM17282) was deposited on 28 April 2005 according to the Budapest Treaty with the DSMZ under accession number DSM17282. Based on DNA fingerprints it appears to us that this Bifidobacterium strain correctly should be designated as B. animalis subsp. lactis.
  • the Bifidobacterium animalis subsp. lactis strain BB12Tet-S70 (DSM18735) was deposited on 26 October 2006 according to the Budapest Treaty with the DSMZ under accession number DSM18735.
  • the Bifidobacterium animalis subsp. lactis strain BB12Tet-S705 (DSM18776) was deposited on 9 November 2006 according to the Budapest Treaty with the DSMZ under accession number DSM18776.
  • the phosphatase producing strain is selected from the group consisting of Bacillus subtilis (CHCC3810/DSM17231 ), Bacillus licheniformis (CHCC3809/DSM 17236) and Bacillus licheniformis
  • the at least one other strain is selected from the group consisting of Lactobacillus paracasei subsp. paracasei (CRL431 , ATCC 55544) and Bifidobacterium animalis subsp. lactis (BB-12®, DSM 15954).
  • Probiotic microorganisms have been defined as "Live microorganisms which when administered in adequate amounts confer a health benefit on the host" (FAO/WHO 2002).
  • BB- 12, Crl431 Bacillus subtilis (DSM17231 ) and Bacillus licheniformis (DSM17236) are probiotic bacteria according to this definition. From the definition it is clear that in order to exert their beneficial effects adequate amounts of the living probiotics must be present. In general it is considered beneficial that the ingestible material comprise live probiotic bacteria in an amount from about 10 5 CFU/g to about 10 12 CFU/g ingestible material, since living cells are a prerequisite for obtaining the probiotic effect.
  • the amount available for the individual corresponds to an amount of each of the at least two strains of about 10 3 -10 14 CFU per day, such as 10 6 -10 13 CFU per day including 10 8 -10 12 CFU per day or even 10 9 -10 11 CFU per day.
  • the CFU numbers are to be understood as the total or accumulative number of CFU, i.e. as the sum of CFU's provided by the phosphatase producing strain(s) and the strain(s) being able to induce genes that are positively associ- ated with intestinal barrier function (tightness of the intestinal epithelium).
  • an important embodiment of the present invention is the use of the composi- tion comprising at least two strains of bacteria according to the present invention for the preparation of a composition intended for the prevention, alleviation or treatment of metabolic endotoxemia and disorders related thereto.
  • metabolic endotoxemia is associated with the up-regulation of several biologi- cal mediators that are indicative of a low-grade systemic inflammation, such as C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-1 (IL-1 ), plasminogen activator inhibitor- 1 (PAI- 1 ), and tumor necrosis factor-alpha (TNF-a), which are markers of inflammation (8-10) as well as other cytokines and chemokines.
  • CRP C-reactive protein
  • IL-6 interleukin-6
  • IL-1 interleukin-1
  • PAI- 1 plasminogen activator inhibitor- 1
  • TNF-a tumor necrosis factor-alpha
  • Acute disseminated encephalomyelitis ADAM
  • Addison's disease Ankylosing spondylitis (chronic back pain)
  • Antiphospholipid antibody syndrome APS
  • Aplastic anemia Autoimmune hepatitis
  • Autoimmune Oophoritis Celiac disease, Crohn's disease
  • Diabetes mellitus type 1 Gestational pemphigoid
  • Goodpasture's syndrome Graves' disease, Guillain-Barre syndrome (GBS)
  • GBS Guillain-Barre syndrome
  • Hashimoto's disease Idiopathic thrombocytopenic purpura
  • Kawasaki's Disease Lupus erythematosus
  • Multiple sclerosis Myasthenia gravis
  • Opsoclonus myoclonus syndrome OMS
  • Optic neuritis Ord's thyroiditis
  • Pemphigus Pernicious anaemia
  • Polyarthritis in dogs Primary biliary cirrhosis
  • two strain composition to prepare a composition directed to the prevention, treatment or alleviation of any of these diseases or syndromes.
  • a number of diseases or syndromes are associated with a general, chronic, low level of inflammation similar to what is seen in metabolic endotoxemia.
  • a non-exhaustive list of such diseases or syndromes mentions: Alopecia universalis, Behget's disease, Chagas' disease, Chronic fatigue syndrome, Dysautonomia, Endometriosis, Hidradenitis suppurativa, Interstitial cystitis, Lyme disease, Morphea, Neuromyotonia, Narcolepsy, Psoriasis, Sarcoidosis, Schizophrenia, Scleroderma, Ulcerative colitis, Vitiligo, Vulvodynia, Depression (mood), Clinical depression, including: Melancholic depression, Atypical depression, Psychotic depression and Postnatal depression.
  • the "two strain composition" of the invention can be used to prepare a composition directed to the treatment or alleviation of these diseases or syndromes also.
  • the present invention relates to a human or pet food composition or dietary supplement dosage form containing at least one strain that is able to detoxify LPS by dephosphorylation and least one other strain that is able to induce the expression of one or more genes that are positively associated with the tightness of the intestinal epithelium of a mammal.
  • the bacteria may be administered as a supplement to the normal diet or as a component of a nutritionally complete human or pet food.
  • the dosage form may be liquid or solid.
  • the product may be powdered and formed into tablets, granules or capsules or simply mixed with other food ingredients to form a functional food.
  • the food composition of the present invention can be any ingestible material selected from the group consisting of milk, curd, milk based fermented products, acidified milk, yoghurt, frozen yoghurt, milk powder, milk based powders, milk concentrate, cheese, cheese spreads, dressings beverages, ice-creams, fermented cereal based products, infant formu- lae, tablets, liquid bacterial suspensions, dried oral supplement, wet oral supplement, dry tube feeding or wet tube feeding that is produced by use of the "two strain composition" of this invention.
  • the composition further comprises a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier means one or more solid or liquid filler diluents or encapsulating substances which are suitable for administration to a human or an animal and which is/are compatible with the probiotically active organisms.
  • compatible relates to components of the pharmaceutical composition which are capable of being commingled with the "two strain composition” in a manner enabling no in- teraction because it would substantially reduce the probiotic efficacy of the organisms selected for the invention under ordinary use conditions.
  • Pharmaceutically acceptable carriers must be of a sufficiently high purity and a sufficiently low toxicity to render them suitable for administration to humans and animals being treated.
  • a solid composition as described herein is preferably a tablet, a capsule or a granulate (comprising a number of granules).
  • the solid composition is an oral dosage form.
  • the tablets may be prepared by methods known in the art and can be compressed, enterically coated, sugar coated, film coated or multiply compressed, containing suitable binders, lubricants, diluents, disintegrating agents, colouring agents, flouring agents, flow-inducing agents and melting agents.
  • Capsules both soft and hard capsules, having liquid or solid contents, may be prepared according to conventional techniques that are well known in the pharmaceutical industry.
  • the probiotically active organisms may be filled into gela- tine capsules, using a suitable filling machine.
  • a solid composition as described herein may also be a pellet.
  • the human or pet food composition or dosage form should comprise the at least two bacteria, as described above, so that the amount of each of the two strains that is available for the individual is of about 10 3 -10 14 CFU per day, such as 10 6 -10 13 CFU per day including 10 8 - 10 12 CFU per day or even 10 9 -10 11 CFU per day. This amount depends on the individual weight, and it is preferably of about 10 9 -10 12 CFU /day for humans and 10 7 -10 10 CFU /day for pets.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound em- ployed, the age, body weight, general health, sex, diet, time of administration, route of ad- ministration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
  • the human food may be in the form of a nutritional formula, an infant formula, milk-based products, dairy products, cereal-based products, for example.
  • a food product or composition the bacterial strains as described above can be incorporated into a food, such as cereal powder, milk powder, a yoghurt, during its manufacture, for example.
  • a nutritional formula comprising a source of protein and the at least two bacterial strains according to the invention can be prepared.
  • Dietary proteins are preferably used as a source of protein.
  • the dietary proteins may be any suitable dietary protein; for example animal proteins (such as milk proteins, meat proteins and egg proteins), vegetable proteins (such as soy, wheat, rice or pea proteins), mixtures of free amino acids, or combination thereof. Milk proteins such as casein, whey proteins and soy proteins are particularly preferred.
  • the composition may also contain a source of carbohydrates and a source of fat.
  • strains are used in their viable form, but embodiments wherein the strains are in an inactivated form are contemplated.
  • the "inactivated form” does not necessary refer to dead bacteria.
  • a number of bacteria e.g. Bacillus subtilis or Bacillus licheniformis may enter into a particular spore form wherein the physiological expressions normally associated with "life" is almost absent. The Bacillae are nevertheless able to generate normal bacterial cells from their spores.
  • spores may be considered as one example of a bacterium in which may be considered an "inactivated form" which is not dead.
  • the human or pet food composition or dietary supplement dosage form further comprise one or more prebiotic substances.
  • suitable prebiotic substances are Fructo-oligosaccharides (FOS) and Inulin.
  • FOS Fructo-oligosaccharides
  • GOS galacto-oligosaccharides
  • MOS mannan-oligosaccharides
  • strain that detoxify LPS by dephosphorylation is characterized by producing alkaline phosphatase (EC 3.1 .3.1 ).
  • the at least one phosphatase producing strain is selected from the group consisting of Bacillus subtilis, Bacillus licheniformis, Bacillus co- agulans, Bacillus cereus and Enterococcus faecium.
  • the at least one other strain that, is able to induce the expression of one or more genes that are positively associated with the tightness of the intestinal epithelium of a mammal is selected from the group consisting of Lactobacillus paracasei ssp. paracasei, Bifidobacterium animalis subsp. lactis and Lactobacillus acidophilus.
  • the at least one phosphatase producing strain is selected from the group consisting of Bacillus subtilis (CHCC3810/DSM 17231 ), Bacillus licheniformis (CHCC3809/DSM 17236) and Bacillus licheniformis
  • the at least one other strain that is able to induce the expression of one or more genes that are positively associated with the tightness of the intestinal epithelium of a mammal is selected from the group consisting of Lactobacillus paracasei subsp. paracasei strain CRL431 (ATCC 55544), Bifidobacterium animalis subsp. lactis strain BB-12® (DSM15954), strain BB12Tet-S139 (DSM17281 ), strain DR10Tet-S9X (DSM17282), strain BB12Tet-S70 (DSM18735) and strain BB12Tet-S705 (DSM18776).
  • compositions for lowering the plasma LPS concentration that characterizes metabolic endotoxemia according to any of the preceding claims wherein the composition is used for the preparation of a composition intended for the prevention, alleviation or treatment of metabolic endotoxemia and disorders related thereto.
  • the metabolic endotoxemia syndrome mediated and/or associated disorder is selected for the group consisting of Acute disseminated en- cephalomyelitis (ADEM), Addison's disease, Ankylosing spondylitis (chronic back pain), An- tiphospholipid antibody syndrome (APS), Aplastic anemia, Autoimmune hepatitis, Autoimmune Oophoritis, Celiac disease, Crohn's disease, Diabetes mellitus type 1 , Gestational pemphigoid, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, Idiopathic thrombocytopenic purpura, Kawasaki's Disease, Lupus ery- thematosus, Multiple sclerosis, Myasthenia gravis, Opsoclonus myoclonus syndrome (OMS), Optic neuritis, Ord's thyroiditis, Pemphigu
  • a human or pet food composition or dietary supplement dosage form comprising the composition for lowering concentrations of plasma LPS that characterize metabolic endotoxemia of any of the preceding claims.
  • the composition according to any of claims 12 to 14 which reduces, prevents or treats endotoxin mediated and/or associated disorders.
  • the metabolic endotoxemia syndrome mediated and/or associated disorder is selected for the group consisting of Acute dissemi- nated encephalomyelitis (ADEM), Addison's disease, Ankylosing spondylitis (chronic back pain), Antiphospholipid antibody syndrome (APS), Aplastic anemia, Autoimmune hepatitis, Autoimmune Oophoritis, Celiac disease, Crohn's disease, Diabetes mellitus type 1 , Gestational pemphigoid, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, Idiopathic thrombocytopenic purpura, Kawasaki's Disease, Lu- pus erythematosus, Multiple sclerosis, Myasthenia gravis, Opsoclonus myoclonus syndrome (OMS), Optic neuritis, Ord's thyroiditis, Pemphigus, Pernicious
  • the invention provides:
  • a composition comprising at least one strain that is able detoxify LPS by dephosphorylation and at least one other strain which is characterized by being capable of inducing the expres- sion of one or more genes that are positively associated with the tightness (or barrier function) of the intestinal epithelium of a mammal.
  • the strain that detoxifies LPS by dephosphorylation is characterized by producing alkaline phosphatase (EC 3.1 .3.1 ) and the at least one other strain, that is able to induce the expression of one or more genes that are positively associated with the tightness of the intestinal epithelium of a mammal, induce the expression of at least one of the genes selected from the group consisting of OCLN and F1 1 R.
  • the at least one phosphatase producing strain is selected from the group consisting of Bacillus subtilis, Bacillus licheniformis, Bacillus coagulans, Bacillus cer- eus and Enterococcus faecium and the at least one other strain, that is able to induce the expression of one or more genes that are positively associated with the tightness of the intestinal epithelium of a mammal, is selected from the group consisting of Lactobacillus para- casei ssp. paracasei, Bifidobacterium animalis subsp. lactis and Lactobacillus acidophilus.
  • the at least one phosphatase producing strain is selected from the group consisting of Bacillus subtilis (CHCC3810/DSM 17231 ), Bacillus licheniformis
  • CHCC3809/DSM 17236) and Bacillus licheniformis (CHCC5019/LMG6934/DSM394) and the at least one other strain, that is able to induce the expression of one or more genes that are positively associated with the tightness of the intestinal epithelium of a mammal, is selected from the group consisting of Lactobacillus paracasei subsp. paracasei strain CRL431 (ATCC 55544), Bifidobacterium animalis subsp.
  • lactis strain BB-12® (DSM15954), strain BB12Tet-S139 (DSM17281 ), strain DR10Tet-S9X (DSM17282), strain BB12Tet-S70 (DSM18735) and strain BB12Tet-S705 (DSM18776).
  • the invention also provides a composition according to the above for use as a medicament, preferably for use in the treatment of metabolic endotoxemia.
  • FIG. 1 B. subtilis (CHCC3810/DSM 17231 ), Bacillus licheniformis (CHCC3809/DSM17236) and Bacillus licheniformis (CHCC5019/LMG6934/DSM394) were cultivated in minimal medium (24) overnight at 37°C. The cultures were centrifuged and the supernatant sterile filtered through 0.22 ⁇ filters. The cultivation medium was analyzed for phosphatase activity by measuring the conversion of p-nitrophenol phosphate (PNPP) to p-nitrophenol (Pierce, Rockford, IL). The phosphatase activity was measured by spectrophotometry at A405. Error bars represent ⁇ 1 x S.D.
  • PNPP p-nitrophenol phosphate
  • FIG. 1 B. subtilis (CHCC3810/DSM 17231 ), Bacillus licheniformis
  • Figure 3 Gene expression in intestinal tissues from pigs.
  • the tissue comprised 75% of the full length of the small intestine (i.e. the ileum or terminal part of the small intestine).
  • Upper panel shows effect of BB-12 and CRL-431 on the expression of F1 1 R/JAM-1 ; lower panel shows effect of BB-12 and CRL-431 on the expression of OCLN.
  • EXAMPLE 1 Bacillus subtilis (CHCC3810/DSM17231 ) and Bacillus licheniformis (CHCC3809/DSM17236 and CHCC5019/LMG6934/DSM394) produce phosphatase
  • Bacillus subtilis produces a vegetative phosphatase when cultured in a medium which reaches Pi levels limiting for growth, but which does not trigger sporulation (19).
  • B. subtilis CHCC3810/DSM17231
  • Bacillus licheniformis B. subtilis (CHCC3810/DSM17231 ) and Bacillus licheniformis
  • B. subtilis (CHCC3810/DSM17231 ) and Bacillus licheniformis (CHCC3809/DSM 17236 and CHCC5019/LMG6934/DSM394) secrete a phosphatase. Compared to the control (fresh cultivation broth), spend cultivation broth contains significant levels of phosphatase (figure 1 ).
  • EXAMPLE 2 Spend cultivation medium from Bacillus subtilis (CHCC3810/DSM17231 ) and Bacillus licheniformis (CHCC3809/DSM 17236 and CHCC5019/LMG6934/DSM394) dephosphorylate LPS
  • the inorganic phosphate (Pi) released was measured as a colored complex of phosphomolybdate and malachite green at 610 nm. This procedure allows the detection of free inorganic phosphate without the disturbance of LPS- bound phosphate groups. As a control spend cultivation medium was mixed with LPS free water (Pyroclear LRW, Associates of Cape Cod Inc.) to identify carry-over of phosphate from the medium.
  • EXAMPLE 3 Probiotic strains (BB-12 and CRL-431 ) enhance intestinal barrier function in vivo.
  • probiotic bacteria i.e. Bifidobacterium animalis subsp. lactis strain BB-12® (DSM15954) and Lactobacillus paracasei subsp. paracasei strain CRL431 ,(ATCC 55544).
  • probiotic bacteria i.e. Bifidobacterium animalis subsp. lactis strain BB-12® (DSM15954) and Lactobacillus paracasei subsp. paracasei strain CRL431 ,(ATCC 55544).
  • Pigs fed with the same standard diet but not sup- plemented with probiotic bacteria served as control. Each group consisted of 8 piglets. At weaning at 4 weeks the animals were moved to pens where they were housed individually and assigned to the corresponding treatments for 14 days. Littermates were assigned to each of the treatments. The number of barrows and gilts in each treatment was the same. The pigs were fed twice daily, receiving an amount of feed corresponding to 4% of their body weight. The probiotic
  • the pigs were killed and tissues comprising 75% of the full length of the small intestine (i.e. the ileum or terminal part of the small intestine) were sampled and snap-frozen in liquid nitrogen.
  • Gene expression analysis on the distal ileum was performed by quantitative PCR analysis using primers specific for F1 1 R (also known as JAM-1 , junctional adhesion molecule 1 ) and OCLN (occludin, a tight junction structural protein).
  • IEC Intestinal epithelial cell cultures will be grown as monolayers in cell culture medium. To qualitatively determine whether the IEC have reached confluence, formed tight junctions, and established cell polarity, the electrical conductance and the spontaneous potential across the monolayer will be determined using an EVOM voltmeter and ENDOHM electrode set (World Precision Instruments). To determine the effect of probiotic strains on the IEC function, monolayers will be exposed to the compounds for varying lengths of time and per- meability of macromolecules measured. The macromolecules will e.g. be FITC-labeled dex- tran. The cross-epithelial transport of LPS will also be measured with unlabeled LPS or FITC-labeled LPS. The integrity of the IEC monolayers will be challenged by addition of en- teropathogenic bacterial strains or specific compounds (e.g. proteases or chemical absorption enhancers) to study the protective capacity of probiotic strains.
  • specific compounds e.g. proteases or
  • TEER transepithelial electrical resistance
  • Quantitative PCR will be carried out for the measurements relative expression levels of selected markers of the zonula occludens, e.g. OCLN (occludin). These measurements will be performed before and after cell culture exposure to probiotic strains.
  • OCLN occludin
  • EXAMPLE 5 Preclinical animal model to indicate that elevated circulating levels of LPS may be decreased by a strain producing phosphatase and one or more probiotic strains that increase expression of OCLN and/or JAM-1.
  • HF diet high fat
  • mice are sacrificed after a 5 hour fasting period.
  • Caecum full and empty
  • adipose tissues epididymal, subcutaneous, and vis- ceral
  • Oral glucose tolerance tests will be performed after 13 weeks of treatment in mice that have been fasted for 6 hours.
  • Glucose will be orally administered (3 g/kg body weight, 660 g/l glucose solution) and blood glucose determined through a glucose meter using blood collected from the tip of the tail vein 30 min before administration and at administration of the glucose load as well as after the glucose load (at 15, 30, 60, 90, and 120 min).
  • blood glucose determined through a glucose meter using blood collected from the tip of the tail vein 30 min before administration and at administration of the glucose load as well as after the glucose load (at 15, 30, 60, 90, and 120 min).
  • 20 microliters of blood were sampled 30 min before and 15 min after the glucose load.
  • Plasma LPS determination will be carried out using a Limulus amoebocyte extract (LAL kit; Lonza Corporation). Samples will be diluted 1 :50 and heated for 10 min at 70°C. Plasma insulin concentration will be determined in 5 ⁇ of plasma using an ELISA kit (Mercodia, Sweden).

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Abstract

La présente invention concerne un nouveau procédé pour la prévention et/ou le traitement de l'endotoxémie métabolique et de troubles associés à celle-ci. Le procédé concerne l'utilisation d'au moins une souche bactérienne qui produit une phosphatase et d'au moins une autre souche bactérienne qui induit l'expression d'un ou plusieurs gènes associés à la fonction de barrière intestinale d'un mammifère.
PCT/EP2010/068460 2009-12-08 2010-11-30 Nouvelle utilisation pour le traitement de l'endotoxémie métabolique WO2011069860A1 (fr)

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US20150057343A1 (en) * 2012-05-15 2015-02-26 Thesan Pharmaceuticals, Inc. AGONISTS OF THE AhR RECEPTOR PATHWAY HAVING SEBOSUPPRESSIVE ACTIVITY AND A METHOD FOR IDENTIFYING SAID AGONISTS
US9480674B2 (en) * 2012-05-15 2016-11-01 Thesan Pharmaceuticals, Inc. Method and composition for treating acne
US20190321341A1 (en) * 2018-04-06 2019-10-24 Ovid Therapeutics, Inc. Use of gaboxadol in the treatment of substance use disorders
CN114423442A (zh) * 2019-09-16 2022-04-29 诺维信公司 在狗中的基于孢子的益生菌补充和内毒素血症的控制
EP4031153A4 (fr) * 2019-09-16 2023-11-22 Novozymes A/S Supplémentation probiotique à base de spores chez les chiens et contrôle de l'endotoxémie

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