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WO2018136884A1 - Compositions et procédés de traitement de l'obésité et d'induction de perte de poids - Google Patents

Compositions et procédés de traitement de l'obésité et d'induction de perte de poids Download PDF

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Publication number
WO2018136884A1
WO2018136884A1 PCT/US2018/014722 US2018014722W WO2018136884A1 WO 2018136884 A1 WO2018136884 A1 WO 2018136884A1 US 2018014722 W US2018014722 W US 2018014722W WO 2018136884 A1 WO2018136884 A1 WO 2018136884A1
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WIPO (PCT)
Prior art keywords
bacterial strain
subject
genus
belongs
weight loss
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Ceased
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English (en)
Inventor
Emeran A. MAYER
Claudia P. SANMIGUEL
Jonathan Patrick JACOBS
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University of California Berkeley
University of California San Diego UCSD
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University of California Berkeley
University of California San Diego UCSD
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Publication of WO2018136884A1 publication Critical patent/WO2018136884A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Bariatric surgery includes a variety of procedures performed on people who have obesity. Weight loss is achieved by reducing the size of the stomach with a gastric band or through removal of a portion of the stomach (sleeve gastrectomy or
  • the present invention is based, at least in part, on the discovery that some bacteria, as well as some metabolites, were associated with better outcomes of bariatric surgery (e.g., measured by, e.g., weight loss at six months post-surgery).
  • a probiotic and/or symbiotic product containing such bacteria or metabolites may thus be used to enrich or alter abundance of gut microbiota before the surgery or after the surgery to improve outcome, such as weight loss.
  • Such bacteria include at least one of Sutterella, Megasphaera, Fusobacterium, Veillonella, Succiniclastitcum, Dialister, Butyricimonas, catenibacterium, Butyrivibrio, Prevotella, CF231, RF39, Bacteroidales, etc.
  • Other bacteria include at least some phenol-producing bacteria (such asMorganella morganii, Bacteroides fragilis, Bad. Ovatus, Bad. Thetaiotuomicron,
  • Escherichia coli Escherichia coli, Peptostreptococcus asaccharolyticus, Proteus spp.,
  • Streptococcus faecalis Clostridium limosum, Clostridium malenominatum, CI. lentoputrescens, CI. Tetani, CI. Tetanomorphum, CI. Cochlearium., etc.), some bacteria producing
  • phenylpropionate such as Clostridium sporogenes, Clostridum sordelbii, etc.
  • some bacteria producing Indole-3 -lactate such as Clostridium botulinum, Clostridium sporogenes, CI.
  • IP A 3-indolepropionic acid
  • metabolites include at least one of phenol, phenylpropionate, indole-3 -lactate, 3-indolepropionic acid (IP A), and others described herein (e.g., in Figure 7).
  • a composition comprising at least one of these or other related bacteria and/or metabolites may be administered via oral ingestion or other delivery systems to the distal bowel (e.g., through enema) prior to or after the surgery.
  • the probiotic based on gut microbial assessment in obese subjects may be used to improve outcomes of non-surgical weight loss regimens using at least one of the beneficial bacteria and/or metabolites described herein.
  • These metabolites including those derived from fermentation of amino acids and/or from gut microbiome, could be used to modify appetite and/or enhance weight loss. They may be used alone as treatments or to improve weight loss after bariatric surgery or non-surgical weight loss interventions.
  • compositions are for promoting weight loss and/or treating a metabolic disorder in a subject, comprising administering a composition comprising one or more such bacteria and/or metabolites.
  • bacteria or metabolites include at least one of a bacterial strain of a phylum selected from Firmicutes, Fusobacteria,
  • IP A 3-indolepropionic acid
  • the at least one bacterial strain belongs to a phylum of Firmicutes, Fusobacteria, Tenericutes, Bacteroidetes, or Proteobacteria.
  • the bacterial strain belongs to a class of Clostridia, Fusobacteriia, RF3, Bacteroidia, Erysipelotrichi, Bacilli, or Betaproteobacteria, e.g., belonging to an order of Clostridiales, Fusobacteriales, ML615J-28, Bacteroidales, Erysipelotrichales, Lactobacillales, or Burkholderiales, and/or belonging to a family of Veillonellaceae, Fusobacteriaceae, Porphyromonadaceae,
  • the at least one bacterial strain belongs to a genus of Veillonella, Megasphaera, Dialister, Succiniclasticum, Fusobacetrium, Butyricimonas, Catenibacterium, Butyrivibrio, Prevotella, CF231, RF39, or Sutterella.
  • the bacterial strain is capable of metabolizing an amino acid (e.g., tyrosine or tryptophan) in a subject, regulating the levels of indolelactate and/or kynurenine in a subject, and/or increasing the levels of phenol sulfate and/or 3-indoxyl sulfate in a subject.
  • an amino acid e.g., tyrosine or tryptophan
  • amino acid selected from tyrosine and tryptophan, such as phenol sulfate, indole propionate, kynuranate, or 3-indoxyl sulfate.
  • the metabolic product may be (4-hydroxyphenyl) lactate, indolelactate, kynuranate or kynurenine.
  • the methods may further comprise measuring the level of the at least one bacterial strain in the subject prior to administration. In certain embodiments, the methods may comprise comparing the measured level to a control or pre-determined level, and optionally administering the composition if the measured level is below the control or predetermined level and/or not administering the composition if the measured level is below the control or pre-determined level. In another embodiment, the level of at least one bacterial strain is measured after administration and compared to a control or pre-determined level.
  • the administration of the bacteria or metabolites results in decreased brain connectivity, at regions of the reward system (e.g., thalamus, pallidum, and/or putamen of the subject), change in appetite (e.g., decrease), increased satiety after a meal, and/or decreased fat mass in the subject.
  • regions of the reward system e.g., thalamus, pallidum, and/or putamen of the subject
  • change in appetite e.g., decrease
  • increased satiety after a meal e.g., decreased fat mass in the subject.
  • Outcomes of the methods described herein can be assessed by BMI change in 6 months, hunger (fasting), Yale Food Addiction Scale (YFAS), excess weight loss (%EWL), and/or desire for high-calorie or low-calorie food.
  • the methods further comprise administering an additional therapy (e.g., a reduced-amino acid diet) capable of promoting weight loss and/or treating a metabolic disorder.
  • an additional therapy e.g., a reduced-amino acid diet
  • the subject has obesity, or has undergone or expected to undergo bariatric surgery.
  • the bacteria and/or metabolites are administered prior to bariatric surgery.
  • the bacteria and/or metabolites may be administered after bariatric surgery.
  • the bacteria may be administered to the GI tract of the subject (e.g., the stomach and/or distal bowel), e.g., orally and/or anally.
  • the subject may be a mammal, e.g., a non-human mammal, or preferably a human.
  • the metabolic disorder may be selected from obesity, diabetes, impaired glucose tolerance, impaired fasting glucose or insulin resistance, dyslipidemia, microalbuminuria, and hypertension.
  • the subject may have raised triglycerides, reduced HDL cholesterol, rasised blood pressure (BP), and/or raised fasting plasma glucose (FPG).
  • the bacteria or metabolites may be formulated in a food product for promoting weight loss and/or treating a metabolic disorder for a subject, e.g., the subject has decreased levels of at least one bacterial strain relative to a control or pre-determined level.
  • a pharmaceutical composition comprising at least one bacterial strain.
  • the bacterial strain is selected from Sutterella, Megasphaera, Fusobacterium, Veillonella, Succiniclastitcum, Dialister, Butyricimonas, catenibacterium, Butyrivibrio, Prevotella, CF231, RF39, Bacteroidales, Morganella morganii, Bacteroides fragilis, Bad. Ovatus, Bact. Thetaiotuomicron, Escherichia coli,
  • Peptostreptococcus asaccharolyticus Proteus spp., Streptococcus faecalis, Clostridium limosum, Clostridium malenominatum, CI. lentoputrescens, CI. Tetani, CI. Tetanomorphum, CI.
  • Clostridium sporogenes CI. mangenoti, CI. ghoni, CI. bifermentans, CI. sordellii,
  • the pharmaceutical composition comprises at least one bacterial strain of a phylum selected from Firmicutes, Fusobacteria, Tenericutes, Bacteroidetes,
  • Proteobacteria and the bacterial strains in Figures 3 and 4, e.g., belonging to a genus of Veillonella, Megasphaera, Dialister, Succiniclasticum, Fusobacetrium, Butyricimonas, Catenibacterium, Butyrivibrio, Prevotella, CF231, RF39, or Sutterella.
  • a pharmaceutical composition comprising at least one metabolite selected from phenol, phenylpropionate, indole-3-lactate, 3-indolepropionic acid (IP A), phenylacetylglutamine, 4- hydroxyphenylpyruvate, 3 -(4-hydroxyphenyl) lactate, p-cresol sulfate, phenol sulfate, indolelactate, indolacetate, 3-indoxyl sulfate, and indolepropionate.
  • IP A 3-indolepropionic acid
  • Such pharmaceutical compositions can be used for promoting weight loss and/or treating a metabolic disorder in a subject, such as where the subject has decreased levels of the at least one bacterial strain relative to a control or pre-determined level, e.g., as described in greater detail herein. .
  • Figure 1 compares the effects of gut bacteria to patient BMI change at Month 6, used as a predictor of weight loss in these patients.
  • Figure 2 compares the effects of gut bacteria to patient BMI change at Month 6, used as a predictor of weight loss in these patients.
  • Figure 3 compares the effects of different gut bacteria genera to patients, in factors such as BMI change at Month 6, hunger (fasting), YFAS, and desire for high calorie foods.
  • Figure 4 shows gut microbiota associated with obesity and feeding behaviors after surgery.
  • Figure 5 depicts the relationship between fermentation of amino acids (such as tyrosine) by gut microbiome and patient health (such as weight loss, appetite change, etc.).
  • amino acids such as tyrosine
  • Figure 6 depicts the relationship between fermentation of amino acids (such as tryptophan) by gut microbiome and patient health (such as weight loss, etc.).
  • amino acids such as tryptophan
  • patient health such as weight loss, etc.
  • Figure 7 depicts the effect of some microbial metabolic products on outcomes of bariatric surgery.
  • Probiotic bacterial compositions described herein may be administered alone, or in combination with other therapies, to improve weight loss.
  • the bacteria and metabolites including those from fermentation of amino acids (such as tyrosine and tryptophan), can result in improved satiety after meals and/or a change of appetite and/or enhanced weight loss.
  • the present invention relates, in part, to compositions of probiotic bacteria and/or amino acid metabolites, and methods for promoting weight loss or treating a metabolic disorder with such composition.
  • the present invention provides methods of promoting weight loss with such composition in subjects, especially for those subjects having obesity and/or having or being planned to have bariatic surgery.
  • an element means one element or more than one element.
  • administering is intended to include routes of administration which allow an agent (such as the compositions described herein) to perform its intended function.
  • routes of administration for treatment of a body which can be used include injection
  • injection subcutaneous, intravenous, parenterally, intraperitoneally, intrathecal, etc.
  • oral inhalation, and transdermal routes.
  • the injection can be bolus injections or can be continuous infusion.
  • the agent can be coated with or disposed in a selected material to protect it from natural conditions which may detrimentally affect its ability to perform its intended function.
  • the agent may be administered alone, or in conjunction with a pharmaceutically acceptable carrier.
  • the agent also may be administered as a prodrug, which is converted to its active form in vivo.
  • the agent is orally administered.
  • the agent is administered through anal and/or colorectal route.
  • the term "increased/decrased amount” or “increased/decreased level” refers to increased or decreased absolute and/or relative amount and/or value of a biomarker (e.g., at leat one of bacterial strains and/or at least one amino acid metabolites and/or metabolic index paramenters of a subject, as described herein) in a subject, as compared to the amount and/or value of the same biomarker in the same subject in a prior time and/or in a normal and/or control subject.
  • a biomarker e.g., at leat one of bacterial strains and/or at least one amino acid metabolites and/or metabolic index paramenters of a subject, as described herein
  • the amount of a biomarker (e.g., at least one of bacterial strains and/or at least one amino acid metabolites and/or metabolic index parameters of a subject, as described herein) in a subject is "significantly" higher or lower than the normal amount of the biomarker, if the amount of the biomarker is greater or less, respectively, than the normal level by an amount greater than the standard error of the assay employed to assess amount, and preferably at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 350%, 400%, 500%, 600%, 700%, 800%, 900%, 1000% or than that amount.
  • a biomarker e.g., at least one of bacterial strains and/or at least one amino acid metabolites and/or metabolic index parameters of a subject, as described herein
  • the amount of the biomarker in the subject can be considered “significantly” higher or lower than the normal amount if the amount is at least about two, and preferably at least about three, four, or five times, higher or lower, respectively, than the normal amount of the biomarker.
  • Such "significance” can also be applied to any other measured parameter described herein, such as for expression, inhibition, cytotoxicity, cell growth, and the like.
  • the term "assigned score” refers to the numerical value designated for each of the biomarkers after being measured in a patient sample.
  • the assigned score correlates to the absence, presence or inferred amount of the biomarker in the sample.
  • the assigned score can be generated manually (e.g., by visual inspection) or with the aid of instrumentation for image acquisition and analysis.
  • the assigned score is determined by a qualitative assessment, for example, detection of a fluorescent readout on a graded scale, or quantitative assessment.
  • an "aggregate score” which refers to the combination of assigned scores from a plurality of measured biomarkers, is determined.
  • the aggregate score may be a summation of assigned scores.
  • combination of assigned scores may involve performing mathematical operations on the assigned scores before combining them into an aggregate score.
  • the aggregate score is also referred to herein as the "predictive score.”
  • biomarker refers to a measurable parameter of the present invention that has been determined to be predictive of the effects of the probiotic bacteria therapy described herein, either alone or in combination with at least one other therapies, on a target disease or disorder (e.g., obesity, and/or bariatric surgery).
  • Biomarkers can include, without limitation, bacteria, amino acid metabolites, and metabolic index parameters of a subject, including those shown in the Tables, the Examples, the Figures, and otherwise described herein.
  • a bacterial biomarker such as at least one type of bacteria and/or metabolites described in
  • Examples may be detected and analyzed by any known methods, such as detecting and/or quantifying the bacteria and/or metabolites by in vivo or in vitro assays or detecting bacterial- originated polynucleotides, polypeptides, and/or metabolites , tec.
  • a metabolite biomarker e.g., fermentation products of amino acids, such as tyrosine and tryptophan, phenol sulfate, 3-indoxyl sulfate, and others in e.g., Figure 7
  • a metabolic biomarker e.g., body mass index (BMI), Yale Food Addiction Scale (YFAS), hunger (fasting), desire for high calorie food, etc.
  • BMI body mass index
  • YFAS Yale Food Addiction Scale
  • hunger fasting
  • desire for high calorie food, etc. may be measured by any suitable methods known.
  • body fluid refers to fluids that are excreted or secreted from the body as well as fluids that are normally not (e.g. amniotic fluid, aqueous humor, bile, blood and blood plasma, cerebrospinal fluid, cerumen and earwax, cowper's fluid or pre-ejaculatory fluid, chyle, chyme, stool, female ejaculate, interstitial fluid, intracellular fluid, lymph, menses, breast milk, mucus, pleural fluid, pus, saliva, sebum, semen, serum, sweat, synovial fluid, tears, urine, vaginal lubrication, vitreous humor, vomit).
  • any body fluid may be taken to detect and/or measure at least one biomarker described herein.
  • control refers to any reference standard suitable to provide a comparison to the expression products in the test sample.
  • the control comprises obtaining a "control sample” from which expression product levels are detected and compared to the expression product levels from the test sample.
  • a control sample may comprise any suitable sample, including but not limited to a sample from a control subject (can be stored sample or previous sample measurement) with a known outcome; normal tissue or cells isolated from a subject, such as a normal subject or the subject with obesity or undergone bariatric surgery, cultured primary cells/tissues isolated from a subject such as a normal subject or the subject with obesity or that has undergone bariatric surgery, adjacent normal cells/tissues obtained from the same organ or body location of the normal subject or the subject with obesity or undergone bariatric surgery, a tissue or cell sample isolated from a normal subject, or a primary cells/tissues obtained from a depository.
  • control may comprise a reference standard expression product level from any suitable source, including but not limited to housekeeping genes, an expression product level range from normal tissue (or other previously analyzed control sample), a previously determined expression product level range within a test sample from a group of patients, or a set of patients with a certain outcome (for example, survival for one, two, three, four years, etc.) or receiving a certain treatment.
  • a certain outcome for example, survival for one, two, three, four years, etc.
  • control samples and reference standard expression product levels can be used in combination as controls in the methods of the present invention.
  • the specific expression product level of each patient can be assigned to a percentile level of expression, or expressed as either higher or lower than the mean or average of the reference standard expression level.
  • control may comprise normal cells, cells from patients treated with combination chemotherapy.
  • control may also comprise a measured value for example, average level of expression of a particular gene in a population compared to the level of expression of a housekeeping gene in the same population.
  • kits are any manufacture (e.g., a package or container) comprising at least one reagent, e.g. a probe or small molecule, for specifically detecting and/or affecting the expression of a marker of the present invention.
  • the kit may be promoted, distributed, or sold as a unit for performing the methods of the present invention.
  • the kit may comprise one or more reagents necessary to express a composition useful in the methods of the present invention.
  • the kit may further comprise a reference standard.
  • One skilled in the art can envision many such controls, including, but not limited to, common molecules.
  • Reagents in the kit may be provided in individual containers or as mixtures of two or more reagents in a single container.
  • instructional materials which describe the use of the compositions within the kit can be included.
  • the term "neoadjuvant therapy” refers to a treatment given before the primary treatment.
  • the "normal" level of expression and/or activity of a biomarker is the level of expression and/or activity of the biomarker in cells of a subject, e.g., a human patient, not afflicted with obesity or bariatric surgery.
  • an "over-expression” or “significantly higher level of expression” of a biomarker refers to an expression level in a test sample that is greater than the standard error of the assay employed to assess expression, and is preferably at least 10%, and more preferably 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1 , 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20 times or more higher than the expression activity or level of the biomarker in a control sample (e.g., sample from a healthy subject not having the biomarker associated disease) and preferably, the average expression level of the biomarker in several control samples.
  • a control sample e.g., sample from a healthy subject not having the biomarker associated disease
  • a "significantly lower level of expression" of a biomarker refers to an expression level in a test sample that is at least 10%, and more preferably 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 times or more lower than the expression level of the biomarker in a control sample (e.g., sample from a healthy subject not having the biomarker associated disease) and preferably, the average expression level of the biomarker in several control samples. The same determination can be made to determine overactivity or underactivity.
  • the instant invention is drawn to a therapeutic composition for improving weight loss in a subject, comprising at least one bacterial strain of a phylum selected from Firmicutes, Fusobacteria, Tenericutes, Proteobacteria, Bacteroidetes, and, and the bacterial strains described herein (e.g., in Figure 3).
  • a bacterial strain may belong to a phlyum of Firmicutes, Fusobacteria, Tenericutes, Bacteroidetes, or Proteobacteria.
  • the bacterial strain described herein belongs to a phylum of Firmicutes.
  • the bacterial strain described herein belongs to a phylum of Fusobacteria. In some embodiments, the bacterial strain described herein belongs to a phylum of Tenericutes. In other embodiments, the bacterial strain described herein belongs to a phylum of Proteobacteria. In some embodiments, the bacterial strain described herein belongs to a phylum of Bacteroidetes. Such bacterial strain may belong to a class of Clostridia, Fusobacteriia, RF3, Bacteroidia, Erysipelotrichi, Bacilli, or Betaproteobacteria. In some embodiments, the bacterial strain described herein belongs to a class of Clostridia.
  • the bacterial strain described herein belongs to a class of Fusobacteriia. In some embodiments, the bacterial strain described herein belongs to a class of RF3. In other embodiments, the bacterial strain described herein belongs to a class of Betaproteobacteria. In some embodiments, the bacterial strain described herein belongs to a class of Bacteroidia. In other embodiments, the bacterial strain described herein belongs to a class of Erysipelotrichi. In some embodiments, the bacterial strain described herein belongs to a class of Bacilli.
  • Such bacterial strain may belongs to an order of Clostridiales, Fusobacteriales, ML615J- 28, Bacteroidales, Erysipelotrichales, Lactobacillales, or Burkholderiales .
  • the bacterial strain described herein belongs to an order of Clostridiales.
  • the bacterial strain described herein belongs to an order of Fusobacteriales.
  • the bacterial strain described herein belongs to an order oiML615J-28.
  • the bacterial strain described herein belongs to an order of Burkholderiales.
  • the bacterial strain described herein belongs to an order of Bacteroidales.
  • the bacterial strain described herein belongs to an order of Erysipelotrichales. In some embodiments, the bacterial strain described herein belongs to an order of Bacteroidales. In other embodiments, the bacterial strain described herein belongs to an order of Lactobacillales. Such bacterial strain may belongs to a family of Veillonellaceae , Fusobacteriaceae , Porphyromonadaceae, Erysipelotrichidae , Lachnospiraceae , Prevotellaceae , Paraprevotellaceae, Enterococcaceae, or Alcaligenaceae . In some embodiments, the bacterial strain described herein belongs to a family of Veillonellaceae.
  • the bacterial strain described herein belongs to a family of Fusobacteriaceae. In some embodiments, the bacterial strain described herein belongs to a family of Alcaligenaceae. In other embodiments, the bacterial strain described herein belongs to a family of Porphyromonadaceae. In some embodiments, the bacterial strain described herein belongs to a family of Erysipelotrichidae. In other embodiments, the bacterial strain described herein belongs to a family of Lachnospiraceae. In some embodiments, the bacterial strain described herein belongs to a family of Prevotellaceae. In other embodiments, the bacterial strain described herein belongs to a family of Paraprevotellaceae.
  • the bacterial strain described herein belongs to a family of Enterococcaceae. Such bacterial strain may belongs to a genus of Veillonella, Megasphaera, Dialister, Succiniclasticum, Fusobacetrium, Butyricimonas, Catenibacterium, Butyrivibrio, Prevotella, CF231, RF39, or Sutterella. In some embodiments, the bacterial strain described herein belongs to a genus of Veillonella. In other embodiments, the bacterial strain described herein belongs to a genus of Megasphaera. In some embodiments, the bacterial strain described herein belongs to a genus of Dialister.
  • the bacterial strain described herein belongs to a genus of Succiniclasticum. In some embodiments, the bacterial strain described herein belongs to a genus of Fusobacetrium. In other embodiments, the bacterial strain described herein belongs to a genus of Butyricimonas. In some embodiments, the bacterial strain described herein belongs to a genus of Sutterella. In other embodiments, the bacterial strain described herein belongs to a genus of Catenibacterium. In some embodiments, the bacterial strain described herein belongs to a genus of Butyrivibrio. In other embodiments, the bacterial strain described herein belongs to a genus of Prevotella.
  • the bacterial strain described herein belongs to a genus of CF231. In other embodiments, the bacterial strain described herein belongs to a genus of RF39. In some embodiments, two or more of the bacterial strains described herein may be combined together in a composition for use. Such combinations may include bacterial strains of the same or different phylum, class, order, family, and/or genus.
  • IPA binds to pregnane X receptors (PXR) in intestinal cells, thereby facilitating mucosal homeostasis and barrier function.
  • PXR pregnane X receptors
  • IPA confers a neuroprotective effect against cerebral ischemia and Alzheimer's disease.
  • Lactobacillus species metabolize tryptophan into indole-3 -aldehyde (13 A) which acts on the aryl hydrocarbon receptor (AhR) in intestinal immune cells, in turn increasing interleukin-22 (IL-22) production.
  • Indole itself acts as a glucagon-like peptide- 1 (GLP-1) secretagogue in intestinal L cells and as a ligand for AhR.
  • GLP-1 glucagon-like peptide- 1
  • Indole can also be metabolized by the liver into indoxyl sulfate, a compound that is toxic in high concentrations and associated with vascular disease and renal dysfunction.
  • AST- 120 activated charcoal
  • an intestinal sorbent that is taken by mouth, adsorbs indole, in turn decreasing the concentration of indoxyl sulfate in blood plasma.
  • IPA indole to indole-3 -propionic acid
  • Phenol and phenolic derivatives are produced by the intestinal microbiota, in particular, Clostridium, Bifidobacterium, Bacteroides fragilis, and Escherichia coli, from tyrosine. Around 50-100 mg of volatile phenols are excreted in humans per day, mainly in the form of glucuronide and sulphate conjugates of phenol or 4-cresol. Altered levels of volatile phenols in human urine have been linked to a large array of physiological and pathological conditions, including weight loss and inflammatory bowel disease (IBD). 4-Cresol produced by Clostridia was detected at significantly higher concentrations in the urine samples of children with autism spectrum disorders (ASD) and in schizophrenia.
  • IBD inflammatory bowel disease
  • 4EPS was dramatically elevated in serum levels of offspring of maternal immune activation (MIA), a mouse model which exhibits features of ASD.
  • MIA maternal immune activation
  • 4EPS is proposed to be produced by Lachnospiraceae family of Clostridia and ingestion of Bacteroides fragilis was shown to restore the serum levels of 4EPS to normal.
  • Indole is exclusively produced by the intestinal microbiota, which converts tryptophan into indole, pyruvate and ammonia by the bacterial tryptophanase enzyme. Indole regulates gut immune cells and is proposed as a potential treatment of IBD via its immunomodulatory and antiinflammatory effects on intestinal epithelial cells, which are central regulators of gut homeostasis. Indole can be further modified into indole-2-acetic acid (IAA) and the neuro-protective molecule; indole-3 -propionic acid (IP A). Incubation of human large intes-tinal content with tryptophan and indolelactate resulted in the production of IP A in vitro.
  • IAA indole-2-acetic acid
  • IP A neuro-protective molecule
  • IPA In vivo, IPA was detected in the plasma and cerebrospinal fluid. Intriguingly, IPA was shown to completely protect primary neurons and neuroblastoma cells against oxidative damage and death caused by exposure to Alzheimer Beta-amyloid protein, via inhibition of superoxide dismutase, or by treatment with hydrogen peroxide.
  • the gut microbiota appear to sequester tryptophan from the diet and alter its metabolites in the host, resulting eventually in altered brain levels of neuropeptide that affect the brain function.
  • tryptophan decarboxylase which converts dietary tryptophan to the neuropeptide tryptamine, has been recently identified.
  • the enzyme was found to be present in several bacteria that colonize about 10 % of the human population. Altered levels of tryptamine in urine have been used in diagnosis, where low levels of tryptamine in urine were detected in patients with severe depression. Tryptamine also stimulates the release of serotonin from enterochromaffin epithelial cells and is a key regulator of the gut motility and secretion.
  • the probiotic bacteria described herein may be capable of metabolizing amino acids, such as tyrosine and/or tryptophan, in the subject. In some embodiments, the probiotic bacteria described herein may be capable of increasing levels of phenol sulfate and/or 3-indoxul sulfate in the subject.
  • the instant invention is drawn to a therapeutic composition for improving weight loss in a subject, comprising at least one metabolic product from metabolism of at least one amino acid.
  • at least one amino acid may be tyrosine or tryptophan.
  • the at least one metabolic products may comprise phenol sulfate and/or 3-indoxul sulfate.
  • the therapeutic composition described herein may promote decreased brain connectivity, change (e.g., decrease) in appetite, increased satiety after a meal, and/or decreased fat mass in the subject.
  • decreased brain connectivity may include decreased brain connectivity in the thalamus, pallidum, and/or putamen of the subject.
  • the weigh loss may be measured by BMI change in 6 months, hunger (fasting), Yale Food Addiction Scale (YFAS), excess weight loss (%EWL), and/or desire for high calorie.
  • the therapeutic composition described herein further comprises another agent capable of improving weight loss.
  • the subject has no obesity. In other embodiments, the subject described herein has obesity.
  • the term "obesity" refers to any condition in which the subject is overweight than a control subject or the same subject in a prior time. Obesity is generally defined by measuring the body mass index (BMI), defined as the body mass divided by the square of the body height, and is universally expressed in units of kg/m 2 , resulting from mass in kilograms and height in meters. Excess body weight (EBW) is defined as the amount of weight that is in excess of the ideal body weight (IBW). Ideal body weight is conventionally determined by the Metropolitan Life Tables, or as a BMI of 25 kg/m 2 .
  • BMI body mass index
  • IBW ideal body weight
  • a BMI of about 25.0-29.9 is referred to overweight.
  • a BMI value of about 30-34.9 is referred to obesity (class 1).
  • a BMI value of about 35-39.9 is referred to severe obesity (class 2).
  • a BMI value of about 40-49.9 is referred to severe obesity (class 3).
  • a BMI value above about 50 is referred to superobesity.
  • the term "obesity" described herein includes the status of at least being overweight, for example, when the BMI value of a subject is at least about 25.0, or above.
  • the subject has not experienced or is not expected to have gastrointestinal surgery, e.g., bariatric surgery.
  • the subject described herein has or is expected to have gastrointestinal surgery, e.g., bariatric surgery.
  • the term "bariatric surgery" refers to any type or combination of weight loss surgery, including a variety of procedures performed on people who have or another metabolic condition. For example, weight loss may be achieved by reducing the size of the stomach with a gastric band or through removal of a portion of the stomach (sleeve gastrectomy or biliopancreatic diversion with duodenal switch) or by resecting and re-routing the small intestine to a small stomach pouch (gastric bypass surgery).
  • the therapeutic composition described herein may be administered, alone or in combination with a therapeutically acceptable carrier, to the subject through any known systemic or topical routes.
  • the composition may be administered to the stomach and/or the distal bowel of the subject. It may be administered by oral and/or anal/colorectal administration (in any format and by any assisting device, such as emema). Such administration may be systemically or locally (e.g., directly to intestines) performed.
  • a preferable administration route is oral administration. Other routes (e.g., rectal) may be also used.
  • the bacteria e.g., in a wet, sonicated, grounded, or dried form or formula
  • a bacterial culture medium containing the bacteria e.g., in a wet, sonicated, grounded, or dried form or formula
  • the bacterial culture medium supernatant not containing the bacteria
  • the administration may be prior to or after any gastrointestinal surgery, such as bariatric surgery.
  • the subject described herein may be a mammal, a non-human mammal, or a human.
  • the term "pre-determined" biomarker amount and/or activity measurement(s) may be a biomarker amount and/or activity measurement(s) used to, by way of example only, evaluate a subject that may be selected for a particular treatment, evaluate a response to a treatment such as using a composition described herein, alone or in combination with other therapy to improve weight loss.
  • a pre-determined biomarker amount and/or activity measurement(s) may be determined in populations of patients with or without a disease (e.g., obesity or overweight) or with or without a surgery (e.g., bariatric surgery).
  • the pre-determined biomarker amount and/or activity measurement(s) can be a single number, equally applicable to every patient, or the predetermined biomarker amount and/or activity measurement s) can vary to reflect differences among specific subpopulations of patients. Age, weight, height, and other factors of a subject may affect the pre-determined biomarker amount and/or activity measurement(s) of the individual. Furthermore, the pre-determined biomarker amount and/or activity can be determined for each subject individually. In certain embodiments, the amounts determined and/or compared in a method described herein are based on absolute measurements.
  • the amounts determined and/or compared in a method described herein are based on relative measurements, such as ratios (e.g., serum biomarker normalized to the expression of housekeeping or otherwise generally constant biomarker).
  • the pre-determined biomarker amount and/or activity measurement(s) can be any suitable standard.
  • the predetermined biomarker amount and/or activity measurement s) can be obtained from the same or a different subject for whom a subject selection is being assessed.
  • the pre-determined biomarker amount and/or activity measurement(s) can be obtained from a previous assessment of the same subject. In such a manner, the progress of the selection of the patient can be monitored over time.
  • control can be obtained from an assessment of another subject or multiple subjects, e.g., selected groups of subjects.
  • the extent of the selection of the subject for whom selection is being assessed can be compared to suitable other subjects, e.g., other subjects who are in a similar situation to the human of interest, such as those suffering from similar or the same condition(s) and/or of the same ethnic group.
  • suitable other subjects e.g., other subjects who are in a similar situation to the human of interest, such as those suffering from similar or the same condition(s) and/or of the same ethnic group.
  • prevent refers reducing the probability of developing a disease (e.g., obesity or overweight), disorder, or condition (e.g., bariatric surgery) in a subject, who does not have, but is at risk of or susceptible to developing a disease, disorder, or condition.
  • prognosis includes a prediction of the probable course and outcome of obesity or the likelihood of recovery from the disease.
  • use of statistical algorithms provides a prognosis of obesity or outcome of bariatric surgery in an individual.
  • sample used for detecting or determining the presence or level of at least one biomarker is typically brain tissue, cerebrospinal fluid, whole blood, plasma, serum, saliva, urine, stool (e.g., feces), tears, and any other bodily fluid (e.g., as described above under the definition of "body fluids"), or a tissue sample (e.g., biopsy) such as a small intestine, colon sample, or surgical resection tissue.
  • the method of the present invention further comprises obtaining the sample from the individual prior to detecting or determining the presence or level of at least one marker in the sample.
  • subject refers to any healthy animal, mammal or human, or any animal, mammal or human afflicted with obesity or undergone bariatric surgery.
  • subject is interchangeable with “patient.”
  • survival includes all of the following: survival until mortality, also known as overall survival (wherein said mortality may be either irrespective of cause or obesity related); "recurrence-free survival” (wherein the weigh loss fails and obesity re-occurs); obesity-free survival.
  • the length of said survival may be calculated by reference to a defined start point (e.g. time of diagnosis or start of treatment) and end point (e.g. death or recurrence).
  • criteria for efficacy of treatment can be expanded to include response to other therapies within a given time period, and probability of obesity recurrence.
  • therapeutic effect refers to a local or systemic effect in animals, particularly mammals, and more particularly humans, caused by a pharmacologically active substance.
  • the term thus means any substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease or in the enhancement of desirable physical or mental development and conditions in an animal or human.
  • therapeutically-effective amount means that amount of such a substance that produces some desired local or systemic effect at a reasonable benefit/risk ratio applicable to any treatment.
  • a therapeutically effective amount of a compound will depend on its therapeutic index, solubility, and the like.
  • certain compounds discovered by the methods of the present invention may be administered in a sufficient amount to produce a reasonable benefit/risk ratio applicable to such treatment.
  • the subject suitable for the compositions and methods disclosed herein is a mammal (e.g., mouse, rat, primate, non-human mammal, domestic animal, such as a dog, cat, cow, horse, and the like), and is preferably a human.
  • the subject is an animal model of obesity or bariatric surgery.
  • the subject has not undergone treatment for obesity or bariatric surgery. In still other embodiments, the subject has undergone treatment for obesity or bariatric surgery.
  • the methods of the present invention can be used to treat and/or determine the responsiveness to a composition described herein, alone or in combination with other therapies to achieve weight loss, in subjects such as those described herein.
  • compositions of the compositions disclosed herein may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; or (5) aerosol, for example, as an aqueous aerosol, liposomal preparation or solid particles.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes
  • parenteral administration for example, by subcutaneous, intramuscular or intravenous injection as
  • compositions described herein may be used for oral administration to the gastrointestinal tract, directed at the objective of introducing the probiotic bacteria to tissues of the gastrointestinal tract.
  • the formulation for a therapeutic composition of the present invention may also include other probiotic agents or nutrients which promote spore germination and/or bacterial growth.
  • An exemplary material is a bifidogenic oligosaccharide, which promotes the growth of beneficial probiotic bacteria.
  • the probiotic bacterial strain is combined with a therapeutically-effective dose of an (preferably, broad spectrum) antibiotic, or an antifungal agent.
  • the compositions described herein are encapsulated into an enterically-coated, time-released capsule or tablet.
  • the enteric coating allows the capsule/tablet to remain intact (i.e., undisolved) as it passes through the gastrointestinal tract, until after a certain time and/or until it reaches a certain part of the GI tract (e.g., the small intestine).
  • the time-released component prevents the "release" of the probiotic bacterial strain in the compositions described herein for a pre-determined time period.
  • the therapeutic compositions of the present invention may also include known antioxidants, buffering agents, and other agents such as coloring agents, flavorings, vitamins or minerals.
  • the therapeutic compositions of the present invention are combined with a carrier which is physiologically compatible with the gastrointestinal tissue of the species to which it is administered.
  • Carriers can be comprised of solid-based, dry materials for formulation into tablet, capsule or powdered form; or the carrier can be comprised of liquid or gel-based materials for formulations into liquid or gel forms.
  • the specific type of carrier, as well as the final formulation depends, in part, upon the selected route(s) of administration.
  • the therapeutic composition of the present invention may also include a variety of carriers and/or binders.
  • a preferred carrier is micro-crystalline cellulose (MCC) added in an amount sufficient to complete the one gram dosage total weight.
  • Carriers can be solid-based dry materials for formulations in tablet, capsule or powdered form, and can be liquid or gel-based materials for formulations in liquid or gel forms, which forms depend, in part, upon the routes of
  • Typical carriers for dry formulations include, but are not limited to: trehalose, malto- dextrin, rice flour, microcrystalline cellulose (MCC) magnesium sterate, inositol, FOS, GOS, dextrose, sucrose, and like carriers.
  • Suitable liquid or gel-based carriers include but are not limited to: water and physiological salt solutions; urea; alcohols and derivatives (e.g., methanol, ethanol, propanol, butanol); glycols (e.g., ethylene glycol, propylene glycol, and the like).
  • water-based carriers possess a neutral pH value (i.e., pH 7.0).
  • Other carriers or agents for administering the compositions described herein are known in the art, e.g., in
  • phrases "pharmaceutically acceptable” is employed herein to refer to those agents, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, 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.
  • phrases "pharmaceutically-acceptable carrier” as used herein means a
  • composition or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ, or portion of the body, to another organ, or portion of the body.
  • a liquid or solid filler such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject.
  • materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of one or more bacterial strains as disclosed herein.
  • lozenges using a flavored basis, usually sucrose and acacia or tragacanth
  • kits for detecting and/or modulating biomarkers described herein may also include instructional materials disclosing or describing the use of the kit or an antibody of the disclosed invention in a method of the disclosed invention as provided herein.
  • a kit may also include additional components to facilitate the particular application for which the kit is designed.
  • a kit may additionally contain means of detecting the label (e.g., enzyme substrates for enzymatic labels, filter sets to detect fluorescent labels, appropriate secondary labels such as a sheep anti- mouse-HRP, etc.) and reagents necessary for controls (e.g., control biological samples or standards).
  • a kit may additionally include buffers and other reagents recognized for use in a method of the disclosed invention. Non-limiting examples include agents to reduce non-specific binding, such as a carrier protein or a detergent.
  • compositions described herein can be used in a variety of diagnostic, prognostic, and therapeutic applications.
  • any method described herein such as a diagnostic method, prognostic method, therapeutic method, or combination thereof, all steps of the method can be performed by a single actor or, alternatively, by more than one actor.
  • diagnosis can be performed directly by the actor providing therapeutic treatment.
  • a person providing a therapeutic agent can request that a diagnostic assay be performed.
  • diagnostician and/or the therapeutic interventionist can interpret the diagnostic assay results to determine a therapeutic strategy.
  • diagnostician and/or the therapeutic interventionist can interpret the diagnostic assay results to determine a therapeutic strategy.
  • alternative processes can apply to other assays, such as prognostic assays.
  • the present invention can pertain to the field of predictive medicine in which diagnostic assays, prognostic assays, and monitoring clinical trials are used for prognostic (predictive) purposes to thereby treat an individual prophylactically. Accordingly, one aspect of the present invention relates to diagnostic assays for determining the amount and/or activity level of a biomarker described herein in the context of a biological sample (e.g., blood, serum, cells, or tissue) to thereby determine whether an individual afflicted with obesity or having undergone bariatric surgery is likely to respond to a composition as disclosed herein.
  • a biological sample e.g., blood, serum, cells, or tissue
  • Such assays can be used for prognostic or predictive purpose alone, or can be coupled with a therapeutic intervention to thereby prophylactically treat an individual prior to the onset or after recurrence of a disorder characterized by or associated with biomarker polypeptide, nucleic acid expression or activity.
  • biomarker polypeptide nucleic acid expression or activity.
  • any method can use one or more (e.g., combinations) of biomarkers described herein, such as those in the tables, figures, examples, and otherwise described in the specification.
  • the present invention provides, in part, methods, systems, and code for accurately classifying whether a biological sample is associated with obesity or weight loss that is likely to respond to a composition as disclosed herein.
  • the present invention is useful for classifying a sample (e.g., from a subject) as associated with or at risk for responding to or not responding to a composition as disclosed herein using a statistical algorithm and/or empirical data (e.g., the amount or activity of a biomarker described herein, such as in the tables, figures, examples, and otherwise described in the specification).
  • An exemplary method for detecting the amount or activity of a biomarker described herein, and thus useful for classifying whether a sample is likely or unlikely to respond to a composition as disclosed herein involves obtaining a biological sample from a test subject and contacting the biological sample with an agent, such as a protein-binding agent like an antibody or antigen-binding fragment thereof, or a nucleic acid-binding agent like an oligonucleotide, capable of detecting the amount or activity of the biomarker in the biological sample.
  • an agent such as a protein-binding agent like an antibody or antigen-binding fragment thereof, or a nucleic acid-binding agent like an oligonucleotide, capable of detecting the amount or activity of the biomarker in the biological sample.
  • the statistical algorithm is a single learning statistical classifier system.
  • a single learning statistical classifier system can be used to classify a sample as a based upon a prediction or probability value and the presence or level of the biomarker.
  • a single learning statistical classifier system typically classifies the sample as, for example, a likely therapy responder or progressor sample with a sensitivity, specificity, positive predictive value, negative predictive value, and/or overall accuracy of at least about 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.
  • Other suitable statistical algorithms are well-known to those of skill in the art.
  • learning statistical classifier systems include a machine learning algorithmic technique capable of adapting to complex data sets (e.g., panel of markers of interest) and making decisions based upon such data sets.
  • a single learning statistical classifier system such as a classification tree (e.g., random forest) is used.
  • a combination of 2, 3, 4, 5, 6, 7, 8, 9, 10, or more learning statistical classifier systems are used, preferably in tandem.
  • Examples of learning statistical classifier systems include, but are not limited to, those using inductive learning (e.g., decision/classification trees such as random forests, classification and regression trees (C&RT), boosted trees, etc.), Probably Approximately Correct (PAC) learning, connectionist learning (e.g., neural networks (NN), artificial neural networks (ANN), neuro fuzzy networks (NFN), network structures, perceptrons such as multi-layer perceptrons, multi-layer feed-forward networks, applications of neural networks, Bayesian learning in belief networks, etc.), reinforcement learning (e.g., passive learning in a known environment such as naive learning, adaptive dynamic learning, and temporal difference learning, passive learning in an unknown environment, active learning in an unknown environment, learning action- value functions, applications of reinforcement learning, etc.), and genetic algorithms and evolutionary programming.
  • inductive learning e.g., decision/classification trees such as random forests, classification and regression trees (C&RT), boosted trees, etc.
  • PAC Probably Approximately Correct
  • connectionist learning e.g., neural networks
  • the method of the present invention further comprises sending the sample classification results to a clinician, e.g., an oncologist.
  • a clinician e.g., an oncologist.
  • the diagnosis of a subject is followed by administering to the individual a therapeutically effective amount of a defined treatment based upon the diagnosis.
  • the methods further involve obtaining a control biological sample
  • the diagnostic methods described herein can furthermore be utilized to identify subjects having or at risk of developing obesity or weight gain that is likely or unlikely to be responsive to a composition as disclosed herein.
  • the assays described herein such as the preceding diagnostic assays or the following assays, can be utilized to identify a subject having or at risk of developing a disorder associated with a misregulation of the amount or activity of at least one biomarker described herein.
  • the prognostic assays can be utilized to identify a subject having or at risk for developing a disorder associated with a misregulation of the at least one biomarker described herein.
  • the prognostic assays described herein can be used to determine whether a subject can be administered a composition as disclosed herein and/or an additional therapeutic regimen to treat a disease or disorder associated with the aberrant biomarker expression or activity.
  • an “isolated” or “purified” biomarker e.g., bacteria or metabolic products
  • the language “substantially free of cellular material” includes preparations of protein in which the protein is separated from cellular components of the cells from which it is isolated or recombinantly produced.
  • protein that is substantially free of cellular material includes preparations of protein having less than about 30%, 20%, 10%, or 5% (by dry weight) of heterologous protein (also referred to herein as a "contaminating protein").
  • the protein or biologically active portion thereof is recombinantly produced, it is also preferably substantially free of culture medium, i.e., culture medium represents less than about 20%, 10%, or 5% of the volume of the protein preparation.
  • culture medium represents less than about 20%, 10%, or 5% of the volume of the protein preparation.
  • the protein is produced by chemical synthesis, it is preferably substantially free of chemical precursors or other chemicals, i.e., it is separated from chemical precursors or other chemicals which are involved in the synthesis of the protein. Accordingly such preparations of the protein have less than about 30%, 20%, 10%, 5% (by dry weight) of chemical precursors or compounds other than the polypeptide of interest.
  • agents that specifically bind to a biomarker protein other than antibodies are used, such as peptides.
  • Peptides that specifically bind to a biomarker protein can be identified by any means known in the art. For example, specific peptide binders of a biomarker protein can be screened for using peptide phage display libraries.
  • biomarker amount and/or activity measurement(s) in a sample from a subject is compared to a predetermined control (standard) sample.
  • the control sample can be from the same subject or from a different subject.
  • the control sample is typically a normal, non-diseased sample.
  • the control sample can be from a diseased tissue.
  • the control sample can be a combination of samples from several different subjects.
  • the biomarker amount and/or activity measurement(s) from a subject is compared to a pre-determined level. This pre-determined level is typically obtained from normal samples.
  • a "pre-determined" biomarker amount and/or activity measurement(s) may be a biomarker amount and/or activity measurement(s) used to, by way of example only, evaluate a subject that may be selected for treatment (e.g., based on the number of genomic mutations and/or the number of genomic mutations causing non- functional proteins for DNA repair genes), evaluate a response to a composition as disclosed herein, alone or in combination with other NK immunotherapies and with one or more additional anti-obesity or weight loss therapies.
  • a pre-determined biomarker amount and/or activity measurement(s) may be determined in populations of patients with or without obesity.
  • the pre-determined biomarker amount and/or activity measurement(s) can be a single number, equally applicable to every patient, or the pre-determined biomarker amount and/or activity measurement(s) can vary according to specific subpopulations of patients. Age, weight, height, and other factors of a subject may affect the pre-determined biomarker amount and/or activity measurement(s) of the individual. Furthermore, the pre-determined biomarker amount and/or activity can be determined for each subject individually. In some embodiments, the amounts determined and/or compared in a method described herein are based on absolute measurements.
  • disease includes a metabolic disorder and/or a status of a subject when weight loss will be generally beneficial to at least the health (e.g., both physical and psychological health) of the subject.
  • health e.g., both physical and psychological health
  • obesity or overweight is included in the scope of "diseases” described herein, whether or not it fits in the medical definition of a disease according to a medical professional.
  • a metabolic disorder includes any disease, disorder, or symptom when normal metabolic process in body is disturbed, due to either inherited or acquired causes. Some of the possible symptoms that can occur with metabolic disorders are: lethargy, weight loss, jaundice, seizures, etc.
  • Metabolic syndrome includes, at least, abdominal (central) obesity (cf.
  • the at least one bacterial strain is administered to a subject has raised triglycerides, reduced HDL
  • BP rasised blood pressure
  • FPG raised fasting plasma glucose
  • the amounts determined and/or compared in a method described herein are based on relative measurements, such as ratios (e.g., biomarker copy numbers, level, and/or activity before a treatment vs. after a treatment, such biomarker measurements relative to a spiked or man-made control, such biomarker measurements relative to the expression of a housekeeping gene, and the like).
  • the relative analysis can be based on the ratio of pre-treatment biomarker measurement as compared to post-treatment biomarker measurement.
  • Pre-treatment biomarker measurement can be made at any time prior to initiation of anti-obesity or weight loss therapy.
  • Post-treatment biomarker measurement can be made at any time after initiation of therapy.
  • post-treatment biomarker measurements are made 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20 weeks or more after initiation of therapy, and even longer toward indefinitely for continued monitoring.
  • Treatment can comprise weight loss therapy, such as a therapeutic regimen comprising a composition as disclosed herein, or further in combination with other agents.
  • the pre-determined biomarker amount and/or activity measurement(s) can be any suitable standard.
  • the pre-determined biomarker amount and/or activity can be any suitable standard.
  • the pre-determined biomarker amount and/or activity can be any suitable standard.
  • the pre-determined biomarker amount and/or activity measurement(s) can be obtained from a previous assessment of the same patient. In such a manner, the progress of the selection of the patient can be monitored over time.
  • the control can be obtained from an assessment of another human or multiple humans, e.g., selected groups of humans, if the subject is a human. In such a manner, the extent of the selection of the human for whom selection is being assessed can be compared to suitable other humans, e.g., other humans who are in a similar situation to the human of interest, such as those suffering from similar or the same condition(s) and/or of the same ethnic group.
  • the change of biomarker amount and/or activity measurement s) from the pre-determined level was about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 fold or greater, or any range in between, inclusive.
  • cutoff values apply equally when the measurement is based on relative changes, such as based on the ratio of pre-treatment biomarker measurement as compared to post- treatment biomarker measurement.
  • Body fluids refer to fluids that are excreted or secreted from the body as well as fluids that are normally not (e.g., amniotic fluid, aqueous humor, bile, blood and blood plasma, cerebrospinal fluid, cerumen and earwax, cowper's fluid or pre-ejaculatory fluid, chyle, chyme, stool, female ejaculate, interstitial fluid, intracellular fluid, lymph, menses, breast milk, mucus, pleural fluid, pus, saliva, sebum, semen, serum, sweat, synovial fluid, tears, urine, vaginal lubrication, vitreous humor, vomit).
  • the subject and/or control sample is selected from the group consisting of cells, cell lines, histological slides, paraffin embedded tissues, biopsies, whole blood, nipple aspirate, serum, plasma, buccal scrape, saliva, cerebrospinal fluid, urine, stool, and bone marrow.
  • the sample is serum, plasma, or urine. In other embodiments, the sample is serum.
  • the samples can be collected from individuals repeatedly over a longitudinal period of time (e.g., once or more on the order of days, weeks, months, annually, biannually, etc.).
  • Obtaining numerous samples from an individual over a period of time can be used to verify results from earlier detections and/or to identify an alteration in biological pattern as a result of, for example, disease progression, drug treatment, etc.
  • subject samples can be taken and monitored every month, every two months, or combinations of one, two, or three month intervals according to the present invention.
  • biomarker amount and/or activity measurements of the subject obtained over time can be conveniently compared with each other, as well as with those of normal controls during the monitoring period, thereby providing the subject's own values, as an internal, or personal, control for long-term monitoring.
  • Sample preparation and separation can involve any of the procedures, depending on the type of sample collected and/or analysis of biomarker measurement(s).
  • Such procedures include, by way of example only, concentration, dilution, adjustment of pH, removal of high abundance polypeptides (e.g., albumin, gamma globulin, and transferrin, etc.), addition of preservatives and calibrants, addition of protease inhibitors, addition of denaturants, desalting of samples, concentration of sample proteins, extraction and purification of lipids.
  • concentration dilution, adjustment of pH
  • removal of high abundance polypeptides e.g., albumin, gamma globulin, and transferrin, etc.
  • preservatives and calibrants e.g., albumin, gamma globulin, and transferrin, etc.
  • the sample preparation can also isolate molecules that are bound in non-covalent complexes to other protein (e.g., carrier proteins).
  • carrier proteins e.g., albumin
  • This process may isolate those molecules bound to a specific carrier protein (e.g., albumin), or use a more general process, such as the release of bound molecules from all carrier proteins via protein denaturation, for example using an acid, followed by removal of the carrier proteins.
  • Removal of undesired proteins (e.g., high abundance, uninformative, or undetectable proteins) from a sample can be achieved using high affinity reagents, high molecular weight filters, ultracentrifugation and/or electrodialysis.
  • High affinity reagents include antibodies or other reagents (e.g., aptamers) that selectively bind to high abundance proteins.
  • Sample preparation could also include ion exchange chromatography, metal ion affinity chromatography, gel filtration, hydrophobic chromatography, chromatofocusing, adsorption chromatography, isoelectric focusing and related techniques.
  • Molecular weight filters include membranes that separate molecules on the basis of size and molecular weight. Such filters may further employ reverse osmosis, nanofiltration, ultrafiltration and microfiltration.
  • Ultracentrifugation is a method for removing undesired polypeptides from a sample. Ultracentrifugation is the centrifugation of a sample at about 15,000-60,000 rpm while monitoring with an optical system the sedimentation (or lack thereof) of particles.
  • Electrodialysis is a procedure which uses an electromembrane or semipermable membrane in a process in which ions are transported through semi-permeable membranes from one solution to another under the influence of a potential gradient. Since the membranes used in electrodialysis may have the ability to selectively transport ions having positive or negative charge, reject ions of the opposite charge, or to allow species to migrate through a semipermable membrane based on size and charge, it renders electrodialysis useful for concentration, removal, or separation of electrolytes.
  • Separation and purification in the present invention may include any procedure known in the art, such as capillary electrophoresis (e.g., in capillary or on-chip) or chromatography (e.g., in capillary, column or on a chip).
  • Electrophoresis is a method which can be used to separate ionic molecules under the influence of an electric field. Electrophoresis can be conducted in a gel, capillary, or in a microchannel on a chip. Examples of gels used for electrophoresis include starch, acrylamide, polyethylene oxides, agarose, or combinations thereof.
  • a gel can be modified by its cross-linking, addition of detergents, or denaturants, immobilization of enzymes or antibodies (affinity electrophoresis) or substrates (zymography) and incorporation of a pH gradient.
  • capillaries used for electrophoresis include capillaries that interface with an electrospray.
  • CE Capillary electrophoresis
  • CE technology can also be implemented on microfluidic chips.
  • CE can be further segmented into separation techniques such as capillary zone electrophoresis (CZE), capillary isoelectric focusing (CIEF), capillary isotachophoresis (cITP) and capillary electrochromatography (CEC).
  • CZE capillary zone electrophoresis
  • CIEF capillary isoelectric focusing
  • cITP capillary isotachophoresis
  • CEC capillary electrochromatography
  • CE techniques can be coupled to electrospray ionization through the use of volatile solutions, for example, aqueous mixtures containing a volatile acid and/or base and an organic such as an alcohol or acetonitrile.
  • Capillary isotachophoresis is a technique in which the analytes move through the capillary at a constant speed but are nevertheless separated by their respective mobilities.
  • Capillary zone electrophoresis also known as free-solution CE (FSCE)
  • FSCE free-solution CE
  • CIEF Capillary isoelectric focusing
  • HPLC high performance liquid chromatography
  • Chromatography can be based on the differential adsorption and elution of certain analytes or partitioning of analytes between mobile and stationary phases.
  • Different examples of chromatography include, but not limited to, liquid chromatography (LC), gas chromatography (GC), high performance liquid chromatography (HPLC), etc.
  • Example 1 Gut Microbiome Is Associated with Changes in Obesity and Eating Behaviors after Bariatric Therapy
  • microbiota such as those in Figures 3 and 4, including, at least, Firmicutes, Fusobacteria, Tenericutes, and Proteobacteria, improved outcomes of bariatric surgery of patients.
  • the presence of such bacteria prior to bariatric surgery was associated with better outcomes of weight loss, measured by, e.g., BMI at six months after bariatric surgery.
  • Gut microbiota was also associated with changes in hunger (fasting), fullness after a meal, food addiction scores (YFAS), and desire for high calorie or low calorie food ( Figures 1-4).
  • Gut bacteria were capable of metabolizing amino acids, such as tyrosine ( Figure 5) and tryptophan (Figure 6), into metabolites that may improve patient health (such as weight loss, appetite change, etc.).
  • Metabolic products of gut bacteria such as phenol sulfate, indole propionate and 3-indoxyl sulfate, were capable of increasing satiety after meals, changes of appetite and weight loss as well as of modifying brain function at regions related with feeding behaviors (Figure 5- Figure 7). Changes in (4hydroxyiphenyl) lactate, indolelactate, kynurenate and kynurenine were also associated with BMI. Interventions that increase levels of fermentation of dietary protein or amino acid (such as bacterial consortiums, symbiotic products) or dietary supplements that include these compounds could be orally administered to improve weight loss outcomes with bariatric surgery or other interventions for obesity and metabolic syndrome.
  • any polynucleotide and polypeptide sequences which reference an accession number correlating to an entry in a public database, such as those maintained by The Institute for Genomic Research (TIGR) on the world wide web at tigr.org and/or the National Center for Biotechnology Information (NCBI) on the World Wide Web at ncbi.nlm.nih.gov.
  • TIGR The Institute for Genomic Research
  • NCBI National Center for Biotechnology Information

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Abstract

La présente invention concerne des compositions thérapeutiques pour favoriser la perte de poids chez un sujet, comprenant au moins une souche bactérienne et/ou un métabolite d'acide aminé, et des procédés pour favoriser la perte de poids par l'administration de telles compositions.
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CN110420228A (zh) * 2019-09-16 2019-11-08 山东大学齐鲁医院 脆弱拟杆菌ych46在制备治疗或辅助治疗高血压的药物中的应用
CN110558516A (zh) * 2019-09-29 2019-12-13 乌林奇 一种通过靶向补充bdnf、fto基因配体治疗肥胖的组合物及其制备方法和应用
WO2020087046A1 (fr) * 2018-10-26 2020-04-30 Sun Genomics Inc. Procédé universel d'extraction de molécules d'acide nucléique en provenance d'une population variée de microbes
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WO2021030198A1 (fr) * 2019-08-09 2021-02-18 Vedanta Biosciences, Inc. Compositions et méthodes pour supprimer des organismes pathogènes
WO2021030091A1 (fr) * 2019-08-09 2021-02-18 The Regents Of The University Of California Compositions et méthodes de traitement d'une maladie métabolique
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KR20210087390A (ko) * 2020-01-02 2021-07-12 삼육대학교산학협력단 부티리시모나스 속 균주를 유효성분으로 포함하는 당뇨병 예방 또는 치료용 조성물
KR20210087391A (ko) * 2020-01-02 2021-07-12 삼육대학교산학협력단 부티리시모나스 속 균주를 유효성분으로 포함하는 비알콜성 지방간 질환의 예방 또는 치료용 약학적 조성물
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CN113854568A (zh) * 2021-08-05 2021-12-31 中南大学湘雅二医院 一种复合益生菌膳食纤维组合物及其应用和保健食品
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WO2020206051A1 (fr) * 2019-04-02 2020-10-08 The Procter & Gamble Company Procédé de production d'acide indole-3-propionique dérivé d'une bactérie et compositions les comprenant
WO2020206050A1 (fr) * 2019-04-02 2020-10-08 The Procter & Gamble Company Composition pour supporter une fonction cérébrale saine
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WO2021030198A1 (fr) * 2019-08-09 2021-02-18 Vedanta Biosciences, Inc. Compositions et méthodes pour supprimer des organismes pathogènes
WO2021030091A1 (fr) * 2019-08-09 2021-02-18 The Regents Of The University Of California Compositions et méthodes de traitement d'une maladie métabolique
CN110420228A (zh) * 2019-09-16 2019-11-08 山东大学齐鲁医院 脆弱拟杆菌ych46在制备治疗或辅助治疗高血压的药物中的应用
CN110558516A (zh) * 2019-09-29 2019-12-13 乌林奇 一种通过靶向补充bdnf、fto基因配体治疗肥胖的组合物及其制备方法和应用
US20230026402A1 (en) * 2019-10-22 2023-01-26 Cornell University Microbiota based therapies to promote mental health
KR102470108B1 (ko) * 2020-01-02 2022-11-23 삼육대학교산학협력단 부티리시모나스 속 균주를 유효성분으로 포함하는 당뇨병 예방 또는 치료용 조성물
KR102470116B1 (ko) * 2020-01-02 2022-11-23 삼육대학교산학협력단 부티리시모나스 속 균주를 유효성분으로 포함하는 비알콜성 지방간 질환의 예방 또는 치료용 약학적 조성물
WO2021137494A1 (fr) * 2020-01-02 2021-07-08 삼육대학교산학협력단 Composition pour la prévention ou le traitement du diabète comprenant une souche de butyricimonas sp. en tant que principe actif
KR20210087390A (ko) * 2020-01-02 2021-07-12 삼육대학교산학협력단 부티리시모나스 속 균주를 유효성분으로 포함하는 당뇨병 예방 또는 치료용 조성물
KR20210087391A (ko) * 2020-01-02 2021-07-12 삼육대학교산학협력단 부티리시모나스 속 균주를 유효성분으로 포함하는 비알콜성 지방간 질환의 예방 또는 치료용 약학적 조성물
US20230113843A1 (en) * 2020-01-24 2023-04-13 Daniel Q. Barkey Compositions and methods for weight loss
EP4125878A4 (fr) * 2020-04-23 2024-04-10 Duke University Compositions et procédés permettant de moduler une activité de canal trp
WO2021222309A1 (fr) * 2020-04-27 2021-11-04 Ixcela, Inc. Détection et modification de la population microbienne intestinale
CN113854568A (zh) * 2021-08-05 2021-12-31 中南大学湘雅二医院 一种复合益生菌膳食纤维组合物及其应用和保健食品

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