WO2023001368A1 - Prévention et/ou traitement de troubles de dérégulation liés à la récompense - Google Patents

Prévention et/ou traitement de troubles de dérégulation liés à la récompense Download PDF

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Publication number
WO2023001368A1
WO2023001368A1 PCT/EP2021/070303 EP2021070303W WO2023001368A1 WO 2023001368 A1 WO2023001368 A1 WO 2023001368A1 EP 2021070303 W EP2021070303 W EP 2021070303W WO 2023001368 A1 WO2023001368 A1 WO 2023001368A1
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composition
lxlo
use according
disorders
bacteria
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PCT/EP2021/070303
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English (en)
Inventor
Amandine EVERARD
Alice DE WOUTERS D'OPLINTER
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Université Catholique de Louvain
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Priority to PCT/EP2021/070303 priority Critical patent/WO2023001368A1/fr
Priority to JP2024503373A priority patent/JP2024525879A/ja
Priority to CA3226267A priority patent/CA3226267A1/fr
Priority to EP22753689.3A priority patent/EP4373502A1/fr
Priority to KR1020247005452A priority patent/KR20240040089A/ko
Priority to AU2022315538A priority patent/AU2022315538A1/en
Priority to PCT/EP2022/070430 priority patent/WO2023001934A1/fr
Publication of WO2023001368A1 publication Critical patent/WO2023001368A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • 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

Definitions

  • the present invention relates to the field of disorders related to reward dysregulation.
  • the invention relates to compositions comprising one or more bacteria from the genus Parabacteroides and/or extracts and/or metabolites thereof for use in preventing and/or treating reward dysregulation disorders.
  • the reward system is often defined as being related to the aggregate of neural circuits that process appetitive stimuli, within the limbic system, the basal ganglia, the prefrontal cortex, the ventral tegmental area, and substantia nigra.
  • the anticipation or acquisition of a reward will catalyze a cascade of events involving neurotransmitters such as, e.g., dopamine, GABA, glutamate, serotonin, and norepinephrine.
  • neurotransmitters such as, e.g., dopamine, GABA, glutamate, serotonin, and norepinephrine.
  • Dysfunction in reward mechanisms can occur naturally (e.g., when dopamine levels decline upon social isolation, or when serotonin levels decline because of aging), or artificially (e.g., upon consumption of dopamine antagonist). Reward dysfunction may also occur upon illness or genetic disorders. Dysfunction in these mechanisms is characterized by reward learning and motivation deficits and emotional abnormalities, such as, e.g., a lack of pleasure or satisfaction, reduction in motivation, and emotional numbing.
  • DIR dopamine receptors 1
  • D2R dopamine receptors 2
  • DAT dopamine transporter
  • a reward dysregulation mechanism may also occur in many diseases including addiction-related disorder, affective disorders, obsessive compulsive disorders, schizophrenia, attention deficit hyperactivity disorders (ADHD), autism spectrum disorder, anxiety disorder and Parkinson’s disease.
  • ADHD attention deficit hyperactivity disorders
  • autism spectrum disorder anxiety disorder and Parkinson’s disease.
  • therapy for reward dysregulation disorders may account for neuropharmacological compounds and/or psychotherapy.
  • the present invention relates to a composition comprising one or more bacteria from the genus Parabacteroides and/or an extract thereof, for use in preventing and/or treating reward dysregulation disorders.
  • the bacteria from the genus Parabacteroides are selected in the group comprising or consisting of P. distasonis, P. acidifaciens, P. abroadsdurhonensis, P. chartae, P. chinchilla, P. chongii, P. faecis, P. goldsteinii, P. gordonii, P. johnsonii, P. massiliensis, P. merdae, P. pacaensis, P. provencensis, P. timonensis, Parabacteroides spp. and combinations thereof.
  • the reward dysregulation disorder is selected in a group comprising or consisting of mental disorders, neurological disorders, and combinations thereof.
  • the mental disorder is selected in a group comprising or consisting of addiction-related disorder, eating-related disorder, affective disorders, obsessive compulsive disorders, schizophrenia, attention deficit hyperactivity disorders (ADHD), autism spectrum disorder, anxiety disorder, and the like.
  • the eating disorder is selected in a group comprising or consisting of anorexia, bulimia, overweight-related disorders, obesity-related disorders, and the like.
  • the addiction-related disorder is selected in a group comprising or consisting of alcohol- related addiction, drug-related addiction, game-related addiction, and the like.
  • the neurological disorder is selected in a group comprising or consisting of Parkinson’s disease, Tourette Syndrome, and the like.
  • the composition is to be administered to an animal individual, preferably a mammalian individual, more preferably a human individual.
  • the composition is to be administered orally or rectally.
  • the bacteria are to be administered at a dose comprised from about lxlO 2 CFU/g to about lxlO 12 CFU/g of the composition.
  • the composition further comprises one or more beneficial microbe(s).
  • the one or more beneficial microbe(s) is/are selected in a group comprising or consisting of bacteria from the family Clostridiaceae, from the family Peptostreptococcaceae, from the family Prevotellaceae, from the family Methylobacteriaceae, from the genus Turicibacter, from the genus Coprococcus, from the genus Knoellia, from the genus Prevotella, from the genus Staphylococcus, and the like.
  • the composition is in the form of a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.
  • the composition is in the form of a nutritional composition further comprising a nutritionally acceptable carrier.
  • the composition is comprised in a kit, which further comprises means to administer said composition.
  • Comprise is intended to mean “contain”, “encompass” and “include”. In some embodiments, the term “comprise” also encompasses the term “consist of’.
  • Bacteria from the genus Parabacteroides refers to Gram-negative, obligatory anaerobic, non-spore forming, non-motile bacteria, which are able to grow on a culture medium containing 20% (w/v) bile. Bacteria belonging to the genus Parabacteroides may be easily identified by routine procedures, including physiological and biochemical approaches, assessment of their cellular fatty acid profiles, menaquinone profiles and their phylogenetic position, based on 16S rRNA gene sequence analysis.
  • isolated bacteria refers to bacteria that are no longer in their natural and/or physiological biotope or habitat.
  • bacteria of interest from a microbiota may be collected and separated from other bacteria and further formulated within a composition. Bacterial separation may be performed according to standard protocols in the field of microbiology, such as, e.g., Gram coloration, antibiotic resistance, ability to grow on specific substrates/culture media, and protocols adapted therefrom.
  • Enriched composition refers to a composition in which the population density of bacteria from the genus Parabacteroides is enhanced within the total microbial population of the composition.
  • Extract refers to any fraction obtained from the bacteria of interest, or from culture media in which the bacteria of interest were cultured.
  • extracts include cellular and extracellular extracts.
  • extracts according to the present invention include metabolites from the bacteria.
  • Reward dysregulation disorders refers to disorders wherein the individual is striving to pursue or attain pleasurable stimuli, and anticipatory pleasure; and/or experiences heightened response to positive or reward-laden cues, or positive emotion reactivity (see Gruber et ah, J Abnorm Child Psychol. 2013; 41(7): 1053-1065).
  • reward dysregulation disorders encompass mental disorders and neurological disorders, which are defined below. Diagnosis of individuals with reward dysregulation disorders may be performed by authorized personnel, such as a physician, accordingly to the standards protocols in the field, in particular by monitoring clinical signs, and often with the assistance of a questionnaire.
  • “Mental disorders” refers to disorders that are characterized by a combination of abnormal thoughts, perceptions, emotions, behavior and relationships with others, as defined by the World Health Organization (WHO).
  • mental disorders include addiction-related disorder, eating-related disorder, affective disorders, obsessive compulsive disorders, schizophrenia, attention deficit hyperactivity disorders (ADHD), autism spectrum disorder, anxiety disorder, and the like.
  • Neurological disorders refers to disorders that affect the brain, the nerves and the spinal cord. In practice, individuals with neurological disorders may experience symptoms such as, e.g., paralysis, muscle weakness, poor coordination, loss of sensation, seizures, confusion, pain and altered levels of consciousness.
  • “Beneficial microbes” refers to microorganisms that may provide health benefits to the hosts, including improvement of the host intestinal microbial balance, maintaining the intestinal gut barrier homeostasis, preventing pathogen colonization, preventing bacterial and viral infections.
  • prevention refers to preventing or avoiding the occurrence of symptom of a reward dysregulation disorder.
  • the term “prevention” may refer to a secondary prevention, i.e., to the prevention of the re-occurrence of a symptom or a relapse of a reward dysregulation disorder.
  • Treating” or “treatment” or “alleviation” refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) the targeted reward dysregulation disorder.
  • Those in need of treatment include those already with the reward dysregulation disorder as well as those prone to have the reward dysregulation disorder or those in whom the reward dysregulation disorder is to be prevented.
  • An individual or mammal is successfully “treated” for a reward dysregulation disorder or condition, if, after receiving a therapeutic amount of a composition, pharmaceutical composition, according to the present invention, alone or in combination with another treatment, the patient shows observable and/or measurable reduction in, or absence of, one or more of the symptoms associated with the reward dysregulation disorder; and/or relief to some extent, one or more of the symptoms associated with the reward dysregulation disorder or condition; reduced morbidity and mortality, and improvement in quality of life issues.
  • the above parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician.
  • “Therapeutically effective amount” refers to an amount sufficient to effect beneficial or desired results including clinical results.
  • a therapeutically effective amount can be administered in one or more administrations. In one embodiment, the therapeutically effective amount may depend on the individual to be treated.
  • “Pharmaceutically acceptable carrier” refers to a carrier that does not produce any adverse, allergic or other unwanted reactions when administered to an animal individual, preferably a human individual. It includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • preparations should meet sterility, pyrogenicity, general safety, quality and purity standards as required by regulatory Offices, such as, e.g., the Food and Drug Administration (FDA) in the United States or the European Medicines Agency (EMA) in the European Union.
  • FDA Food and Drug Administration
  • EMA European Medicines Agency
  • “Individual” refers to an animal individual, preferably a mammalian individual, more preferably a human individual. In some embodiments, an individual may be a mammalian individual. Mammalians include, but are not limited to, all primates (human and non-human), cattle (including cows), horses, pigs, sheep, goats, dogs, cats, and any other mammal which is awaiting the receipt of, or is receiving medical care or was/is/will be the object of a medical procedure, or is monitored for the development of a reward dysregulation disorder.
  • an individual may be a “patient”, i.e., a warm-blooded animal, more preferably a human, who/which is awaiting the receipt of, or is receiving medical care or was/is/will be the object of a medical procedure, or is monitored for the development of a reward dysregulation disorder.
  • the individual is an adult (e.g ., an individual above the age of 18).
  • the individual is a child (e.g., an individual below the age of 18).
  • the individual is a male.
  • the individual is a female.
  • This invention relates to a composition comprising one or more bacteria from the genus Parabacteroides and/or extracts thereof, for use in preventing and/or treating reward dysregulation disorders.
  • the invention also relates to the use of a composition comprising one or more bacteria from the genus Parabacteroides and/or extracts thereof, for preventing and/or treating reward dysregulation disorders.
  • the invention further pertains to the use of a composition comprising one or more bacteria from the genus Parabacteroides and/or extracts thereof, for the preparation or the manufacture of a medicament for preventing and/or treating reward dysregulation disorders.
  • the invention relates to a method for preventing and/or treating reward dysregulation disorders in an individual in need thereof, comprising the administration of a therapeutically effective amount of a composition comprising one or more bacteria from the genus Parabacteroides and/or extracts thereof.
  • the bacteria from the genus Parabacteroides are selected in the group comprising or consisting of P. distasonis, P. acidifaciens, P. abroadsdurhonensis, P. chartae, P. chinchilla, P. chongii, P. faecis, P. goldsteinii, P. gordonii, P. johnsonii, P. massiliensis, P. merdae, P. pacaensis, P. provencensis, P. timonensis, Parabacteroides spp. and combinations thereof.
  • bacteria belonging to the genus Parabacteroides may be identified by any suitable procedures, or a procedure adapted therefrom.
  • suitable procedures may include physiological and biochemical methods, such as the assessment of the capacity to ferment on selected nutrients, e.g., mannose, raffinose; the assessment of the resistance to some antibiotics; the assessment of specific enzymatic activities, such as, e.g., alpha-galactosidase, beta-galactosidase, alpha-glucuronidase, alkaline phosphatase, L-arginine arylamidase, Leucine glycine arylamidase, Phenylalanine arylamidase; the assessment of their cellular fatty acid profiles, menaquinone profiles; the assessment of their profile by matrix-assisted laser-desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS); the assessment of their phylogenetic position,
  • the bacteria from the genus Parabacteroides are isolated from a natural habitat, such as, e.g., the gut microbiota.
  • the bacteria from the genus Parabacteroides may be isolated from feces or ceacal content, fresh or frozen, diluted or not in a specific medium (including cryoprotectants and/or antioxidants), accordingly to the standard and ethical procedures in the field.
  • bacteria from the genus Parabacteroides may be cultured in any suitable culture medium, such as, e.g., the Columbia blood medium (commercially available from Sigma Aldrich®, DSMZ®), the fastidious anaerobe broth (commercially available from DSMZ®, Neogen®), the chopped meat medium with carbohydrates (commercially available from DSMZ®).
  • any suitable culture medium such as, e.g., the Columbia blood medium (commercially available from Sigma Aldrich®, DSMZ®), the fastidious anaerobe broth (commercially available from DSMZ®, Neogen®), the chopped meat medium with carbohydrates (commercially available from DSMZ®).
  • cultures of bacteria from the genus Parabacteroides may be performed at a temperature ranging from about 30°C to about 42°C, preferably from about 35°C to about 40°C, more preferably at about 37°C.
  • the term “about 30°C to about 42°C” includes about 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C and 42°C.
  • cultures of bacteria from the genus Parabacteroides may be performed in anaerobic conditions, i.e., in the absence of O2.
  • the composition of the invention comprises or substantially consist of a microbiota with bacteria from the genus Parabacteroides obtained from an individual.
  • the microbiota is a gut microbiota obtained from the feces of an individual.
  • the microbiota is enriched with bacteria from the genus Parabacteroides compared to the microbiota of the individual to be treated.
  • the composition of the invention is enriched with bacteria from the genus Parabacteroides .
  • the composition of the invention comprises or substantially consist of a microbiota enriched with bacteria from the genus Parabacteroides .
  • bacteria from the genus Parabacteroides may be enriched by preferentially stimulating the growth of the bacteria from the genus Parabacteroides .
  • enrichment may be performed by modifying physiological conditions of the culture. Examples include, but are not limited to, modification of the composition of the culture media, such as the nutrient composition; and modification of the culture conditions, such as environmental pH value, temperature and oxygen conditions, and the like.
  • the bacteria from the genus Parabacteroides are isolated and enriched.
  • the composition of the invention comprises isolated, enriched bacteria from the genus Parabacteroides .
  • the bacteria from the genus Parabacteroides are viable.
  • the term “viable” refers to bacteria that are able to maintain an active metabolism and/or proliferate in a suitable culture medium, under suitable culture conditions, including suitable pH, temperature, salinity, nutrients content, O2 content.
  • the bacteria from the genus Parabacteroides are non- viable.
  • the term “non-viable” refers to bacteria that are not able to maintain an active metabolism and/or proliferate in a suitable culture medium, under suitable culture conditions, including suitable pH, temperature, salinity, nutrients content, O2 content.
  • Example of non-viable bacteria are dormant bacteria, dead bacteria and inactive bacteria.
  • cell viability active metabolism
  • cell viability proliferation
  • proliferation may be measured by measuring optical density of the bacterial culture after a determined time of incubation in suitable culture conditions.
  • the bacteria from the genus Parabacteroides are pasteurized.
  • the pasteurized Parabacteroides and/or extracts thereof were heated at a temperature ranging from about 50°C to about 100°C, preferably from about 60°C to about 95 °C, more preferably from about 70°C to about 90°C.
  • extracts encompasses both cellular and extracellular extracts.
  • cellular extracts include cytoplasmic extracts, membrane extracts, and combination thereof, in particular, extracts obtained from fractionation methods.
  • Cellular extracts may be obtained by any standard chemical (implementing SDS, proteinase K, lysozyme, combinations thereof, and the like) and/or mechanical (sonication, pressure) fractionation approaches, or approaches adapted therefrom.
  • extracellular extracts may include the secreted fraction, in particular soluble compounds or exosomes.
  • exosomes is intended to refer to endocytic-derived nanovesicles that comprise proteins, nucleic acids, and lipids.
  • the secreted fraction may be isolated and/or purified from the culture medium, according to any suitable method known in the state of the art, or a method adapted therefrom.
  • the extracellular extracts may be isolated by differential centrifugation from culture medium; by polymer precipitation; by high-performance liquid chromatography (HPLC), combination thereof, and the like.
  • Non-limitative example of differential centrifugation method from culture medium may include the following steps: centrifugation for 10-20 min at a speed of about 300xg to about 500xg, so as to remove cells; centrifugation for 10-20 min at a speed of about l,500xg to about 3,000xg, so as to remove dead cells; centrifugation for 20-45 min at a speed of about 7,500xg to about 15,000xg, so as to remove cell debris; one or more ultracentrifugation for 30-120 min at a speed of about 100,000xg to about 200,000xg, so as to pellet the exosomes.
  • exoEasy Maxi Kit Qiagen®
  • Total Exosome Isolation Kit Thermo Fisher Scientific®
  • cellular and/or extracellular extracts may comprise nucleic acids, proteins, carbohydrates, lipids and combinations of these such as lipoproteins, glycolipids and glycoproteins, bacterial metabolites, organic acids, inorganic acids, bases, peptides, enzymes and co-enzymes, amino acids, carbohydrates, lipids, glycoproteins, lipoproteins, glycolipids, vitamins, bioactive compounds, metabolites such as metabolites containing an inorganic component, and the like.
  • the reward dysregulation disorders according to the invention may be diagnosed and/or monitored through the evaluation of clinical signs, with or without the assistance of a dedicated questionnaire.
  • diagnosis and/or monitoring of reward dysregulation disorders may be performed by authorized personnel.
  • the reward dysregulation disorder is selected in a group comprising or consisting of mental disorders, neurological disorders, and combinations thereof.
  • the mental disorder is selected in a group comprising or consisting of addiction-related disorder, eating-disorder, affective disorders, obsessive compulsive disorders, schizophrenia, attention deficit hyperactivity disorders (ADHD), autism spectrum disorder, anxiety disorder, and the like.
  • the eating-related disorder is selected in a group comprising or consisting of anorexia, bulimia, overweight-related disorders, obesity-related disorders, and the like.
  • an individual with overweight-related disorder has a body mass index (BMI) comprised from about 25.0 to about 29.9.
  • BMI body mass index
  • an individual with obesity-related disorder has a body mass index (BMI) above about 30.0.
  • the eating-related disorder is anorexia. In one embodiment, the eating-related disorder is bulimia. In one embodiment, the eating-related disorder is overweight-related disorder or obesity-related disorder. In one embodiment, the eating- related disorder is overweight-related disorder. In one embodiment, the eating-related disorder is obesity -related disorder.
  • the addiction-related disorder is selected in a group comprising or consisting of alcohol-related addiction, drug-related addiction, tobacco or nicotine addiction, game-related addiction, and the like.
  • the neurological-related disorder is selected in a group comprising or consisting of Parkinson’s disease, Tourette Syndrome, and the like.
  • the composition is to be administered to an animal individual, preferably a mammalian individual, more preferably a human individual.
  • the individual is a mammalian individual.
  • the individual is a human individual.
  • the individual is a male.
  • the individual is a female.
  • the composition is to be administered orally or rectally.
  • the composition is administered into the digestive tract. It is to be understood that the digestive tract is the final location of the bacteria according to the invention. In other words, the bacteria according to the invention are intended to be incorporated into the microbiota of the individual.
  • the composition is a solid composition.
  • solid forms adapted to oral administration include, but are not limited to, pill, tablet, capsule, soft gelatin capsule, hard gelatin capsule, dragees, granules, gums, chewing gums, caplet, compressed tablet, cachet, wafer, sugar-coated pill, sugar coated tablet, or dispersing/or disintegrating tablet, powder, solid forms suitable for solution in, or suspension in, liquid prior to oral administration and effervescent tablet.
  • the composition is a liquid composition.
  • liquid form adapted to oral administration include, but are not limited to, solutions, suspensions, drinkable solutions, elixirs, sealed phial, potion, drench, syrup, liquor and sprays.
  • the bacteria are to be administered at a dose comprised from about lxlO 2 CFU/g to about lxlO 12 CFU/g of the composition, preferably from about lxlO 3 CFU/g to about lxlO 11 CFU/g of the composition, more preferably from about lxlO 4 CFU/g to about lxlO 10 CFU/g of the composition.
  • the bacteria are to be administered at a dose comprised from about lxlO 4 CFU/g to about lxlO 11 CFU/g of the composition, from about lxlO 5 CFU/g to about lxlO 11 CFU/g of the composition, from about lxlO 6 CFU/g to about lxlO 11 CFU/g of the composition, from about lxlO 7 CFU/g to about lxlO 11 CFU/g of the composition or from about 1x10 s CFU/g to about lxlO 11 CFU/g of the composition.
  • CFU stands for “Colony Forming Unit”.
  • the term “about lxlO 2 CFU/g to about lxlO 12 CFU/g” includes lxlO 2 , 5xl0 2 , lxlO 3 , 5xl0 3 , lxlO 4 , 5xl0 4 , lxlO 5 , 5xl0 5 , lxlO 6 , 5xl0 6 , lxlO 7 , 5xl0 7 , 1x10 s , 5x10 s , lxlO 9 , 5xl0 9 , lxlO 10 , 5xl0 10 , lxlO 11 , 5xl0 u and lxlO 12 CFU/g.
  • the bacteria are to be administered at a dose comprised from about lxlO 2 cells/g to about lxlO 12 cells/g of the composition.
  • the term “about lxlO 2 cells/g to about lxlO 12 cells/g” includes lxlO 2 , 5xl0 2 , lxlO 3 , 5xl0 3 , lxlO 4 , 5xl0 4 , lxlO 5 , 5x10 s , lxlO 6 , 5xl0 6 , lxlO 7 , 5xl0 7 , 1x10 s , 5x10 s , lxlO 9 , 5xl0 9 , lxlO 10 , 5xl0 10 , lxlO 11 , 5xl0 n and lxlO 12 cells/g.
  • the bacteria are to be administered at a dose comprised from about lxlO 2 CFU/g to about lxlO 12 CFU/g of the composition.
  • the term “about lxlO 2 CFU/g to about lxlO 12 CFU/g” includes lxlO 2 , 5xl0 2 , lxlO 3 , 5xl0 3 , lxlO 4 , 5xl0 4 , lxlO 5 , 5x10 s , lxlO 6 , 5xl0 6 , lxlO 7 , 5xl0 7 , 1x10 s , 5x10 s , lxlO 9 , 5xl0 9 , lxlO 10 , 5xl0 10 , lxlO 11 , 5xl0 u and lxlO 12 CFU/g.
  • the bacteria are to be administered at a dose comprised from about lxlO 2 cells/g to about lxlO 12 cells/g of the composition.
  • the term “about lxlO 2 cells/g to about lxlO 12 cells/g” includes lxlO 2 , 5xl0 2 , lxlO 3 , 5xl0 3 , lxlO 4 , 5xl0 4 , lxlO 5 , 5x10 s , lxlO 6 , 5xl0 6 , lxlO 7 , 5xl0 7 , 1x10 s , 5x10 s , lxlO 9 , 5xl0 9 , lxlO 10 , 5xl0 10 , lxlO 11 , 5xl0 u and lxlO 12 cells/g.
  • the bacteria when the composition is a liquid composition, the bacteria are to be administered at a dose comprised from about lxlO 2 CFU/ml to about lxlO 12 CFU/ml of the composition.
  • the term “about lxlO 2 CFU/ml to about lxlO 12 CFU/ml” includes lxlO 2 , 5xl0 2 , lxlO 3 , 5xl0 3 , lxlO 4 , 5xl0 4 , lxlO 5 , 5x10 s , lxlO 6 , 5xl0 6 , lxlO 7 , 5xl0 7 , 1x10 s , 5x10 s , lxlO 9 , 5xl0 9 , lxlO 10 , 5xl0 10 , lxlO 11 , 5xl0 n and lxlO 12 CFU/ml
  • the bacteria when the composition is a liquid composition, the bacteria are to be administered at a dose comprised from about lxlO 2 cells/ml to about lxlO 12 cells/ml of the composition.
  • the term “about lxlO 2 cells/ml to about lxlO 12 cells/ml” includes lxlO 2 , 5xl0 2 , lxlO 3 , 5xl0 3 , lxlO 4 , 5xl0 4 , lxlO 5 , 5x10 s , lxlO 6 , 5xl0 6 , lxlO 7 , 5xl0 7 , 1x10 s , 5x10 s , lxlO 9 , 5xl0 9 , lxlO 10 , 5xl0 10 , lxlO 11 , 5xl0 n and lxlO 12 cells/ml. [0080]
  • the one or more additional active agent(s) are one or more beneficial microbe(s).
  • the composition further comprises one or more beneficial microbe(s).
  • the one or more beneficial microbe(s) is/are selected in a group comprising or consisting of bacteria from the family Clostridiaceae, from the family Peptostreptococcaceae, from the family Prevotellaceae, from the family Methylobacteriaceae, from the genus Turicibacter, from the genus Coprococcus, from the genus Knoellia, from the genus Prevotella, from the genus Staphylococcus, and the like.
  • the composition is in the form of a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions according to the invention include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; serum proteins, such as human serum albumin; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of vegetable oil saturated fatty acids; water; salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate, polyvinyl pyrrolidone; cellulose-based substances (e.g., sodium carboxymethyl cellulose), polyethylene glycol; poly acrylates; waxes; polyethylene- polyoxypropylene- block polymers; polyethylene glycol; wool fat; the like; and any combination thereof.
  • ion exchangers e.g., sodium carboxymethyl cellulose
  • cellulose-based substances e.g
  • the composition is in the form of a nutritional composition further comprising a nutritionally acceptable carrier.
  • liquid food products include, but are not limited to, soups, soft drinks, sports drinks, energy drinks, fruit juices, lemonades, teas, milk-based drinks, and the like.
  • solid food products include, but are not limited to candy bars, cereal bars, energy bars, and the like.
  • the nutritional composition of the invention is for non- therapeutic use, or for use in a non-therapeutic method.
  • the invention relates to a medicament comprising a therapeutically effective amount of one or more isolated bacteria from the genus Parabacteroides and/or extracts thereof, for use in preventing and/or treating reward dysregulation disorders.
  • the composition, the pharmaceutical composition, the nutritional composition, the medical device or the medicament according to the invention is sterile.
  • methods for obtaining a sterile pharmaceutical composition include, but are not limited to, GMP synthesis (GMP stands for “Good manufacturing practice”).
  • the present invention also relates to a medical device comprising, consisting of, or consisting essentially of one or more isolated bacteria from the genus Parabacteroides and/or extracts thereof, for use in preventing and/or treating reward dysregulation disorders.
  • the medical device according to the invention comprises a therapeutically effective amount of one or more isolated bacteria from the genus Parabacteroides and/or extracts thereof.
  • the composition is comprised in a kit, which further comprises means to administer said composition.
  • the present invention also relates to a composition comprising one or more active ingredients or substances that increase the level of bacteria from the genus Parabacteroides in the microbiota of an individual in need thereof.
  • “increasing the level of bacteria from the genus Parabacteroides in the microbiota” means increasing the relative abundance of bacteria from the genus Parabacteroides in the microbiota of the individual after administration of the composition of the invention, compared to the relative abundance of bacteria from the genus Parabacteroides in the microbiota of the individual before administration of the composition of the invention.
  • the present invention further relates to a method for restoring the reward function in an individual in need thereof.
  • the method comprises the administration of a composition comprising one or more active ingredients or substances that increase the level of bacteria from the genus Parabacteroides in the microbiota.
  • the method comprises the administration of a composition comprising one or more bacteria from the genus Parabacteroides and/or extracts thereof. In one embodiment, this method is non-therapeutic.
  • the present invention further relates to a method for restoring the microbiota of an individual in need thereof.
  • the method comprises the administration of a composition comprising one or more active ingredients or substances that increase the level of bacteria from the genus Parabacteroides in the microbiota.
  • the method comprises the administration of a composition comprising one or more bacteria from the genus Parabacteroides and/or extracts thereof. In one embodiment, this method is non-therapeutic.
  • the present invention further relates to a method for increasing the level of Parabacteroides in the microbiota of an individual in need thereof.
  • the method comprises the administration of a composition comprising one or more active ingredients or substances that increase the level of bacteria from the genus Parabacteroides in the microbiota.
  • the method comprises the administration of a composition comprising one or more bacteria from the genus Parabacteroides and/or extracts thereof. In one embodiment, this method is non- therapeutic.
  • the present invention also relates to a method for reducing the reward eating in an individual in need thereof.
  • the method comprises the administration of a composition comprising one or more active ingredients or substances that increase the level of bacteria from the genus Parabacteroides in the microbiota.
  • the method comprises the administration of a composition comprising one or more bacteria from the genus Parabacteroides and/or extracts thereof. In one embodiment, this method is non-therapeutic.
  • the present invention further relates to a method for reducing the intake of palatable diet in an individual in need.
  • the method comprises the administration of a composition comprising one or more active ingredients or substances that increase the level of Parabacteroides in the microbiota.
  • the method comprises the administration of a composition comprising one or more bacteria from the genus Parabacteroides and/or extracts thereof. In one embodiment, this method is non-therapeutic.
  • FIGS 1A-C are a set of graphs showing that obese mice present a reduced food preference for high fat, high sucrose (HFHS) compared to lean mice.
  • Fig. 1A Body weight evolution (in grams) of lean (Lean_do; squares) and DIO donor mice (DIO_do; triangles) and
  • Fig. IB final body weight (in grams), after a 5 weeks period.
  • Fig. 1C Fat mass gain evolution (in grams) of lean (Lean_do; squares) and DIO donor mice (DIO_do; triangles) and
  • Fig. ID final fat mass gain (in grams).
  • Figures 2A-G are a set of graphs showing that recipient mice show hedonic food behaviour similar to donor mice after fecal transplantation.
  • FIG. 2A Experimental plan of the FMT protocol.
  • FIG. 2B Body weight evolution (in grams) and
  • FIG. 2C final body weight (in grams), of lean (Lean_rec; squares) and DIO recipient mice (DIO_rec; triangles).
  • Fig. 2D Fat mass gain evolution (in grams) and
  • Fig. 2E final fat mass gain (in grams), of lean (Lean_rec; squares) and DIO recipient mice (DIO_rec; triangles).
  • Figures 4A-F are a set of graphs showing that the gut microbiota of recipient mice is similar to the gut microbiota from donor mice.
  • FIG. 4A-D Venn diagram based on OTUs similarity between donor (Lean_do and DIO_do) and recipient (Lean_rec and DIO_rec) mice.
  • FIG. 4E-F Principal coordinates analysis (PCoA) based on the unweighted UniFrac analysis on operational taxonomic units (OTUs);
  • Fig. 4E PCoA PCI vs PC2;
  • Figures 5A-B are a set of graphs showing the correlations between gut microbes and dopaminergic markers.
  • Fig. 5A Heatmap of bacterial composition and food reward patters. Spearman’s correlations were calculated for each parameter for donor and recipient mice.
  • Fig. 5B Spearman’s correlation after FDR correction. P-values were obtained after Spearman’s correlation test. *: p ⁇ 0,05.
  • CT control diet
  • mice were randomly divided in two groups, and were fed for 5 weeks with control low-fat diet (CT, AIN93M ⁇ ) or a high-fat diet (HLD, 60% fat and 20% carbohydrates (kcal/lOOg) D12492i, Research diet, New Brunswick, NJ, USA). Body weight, food and water intake were recorded once a week. Body composition was assessed by using 7.5 MHz time domain-nuclear magnetic resonance (TD-NMR, LL50 Minispec, Bruker®, Rheinstetten, Germany). After 4 weeks of follow-up, the mice entered the metabolic chambers to perform the food preference test. 3. Recipient mice
  • CTL low-fat control diet
  • Colonization was then achieved by intragastric gavage with 300 m ⁇ of inoculum three times a week for one week. During antibiotics treatment and inoculation, mice were transferred into clean cages 4 times a week. All recipient mice were kept under CT diet (CT, AIN93M ⁇ ).
  • mice were exposed to two kinds of diets: a low- fat, control normal diet (CT, AIN93M ⁇ , Research diet, New Brunswick, NJ, USA) or a high-fat high-sucrose diet (HFHS, 45% fat and 27.8% sucrose (kcal/lOOg) D17110301i, Research diet, New Brunswick, NJ, USA) in metabolic chambers (Labmaster/Phenomaster, TSE systems, Germany). Sensors recorded the precise food intake of each diet every 15 minutes.
  • CT control normal diet
  • HFHS high-fat high-sucrose diet
  • mice were fed and exposed for 1 hour to HFHS before anesthesia with isoflurane (Forene®, Abbott, England). This aims to mimic the conditions of the food preference test and stimulate the dopaminergic food reward system. Then the mice were euthanatized by exsanguination and cervical dislocation. Striatum, nucleus accumbens, prefrontal cortex and caudate putamen were precisely dissected, the caecal content was harvested and immediately immersed into liquid nitrogen, then stored at -80°C for further analysis.
  • isoflurane Forme®, Abbott, England
  • Table 1 primers used for real-time qPCR
  • V1-V3 region of the 16S rRNA gene was amplified from the caecal microbiota of the mice using the following universal eubacterial primers: 27Fmod (5’-agrgtttgatcmtggctcag-3’; SEQ ID NO: 11) and 519Rmodbio (5’-gtnttacngcggckgctg-3’; SEQ ID NO: 12). Purified amplicons were sequenced utilizing a MiSeq® following the manufacturer’s guidelines. Sequencing was performed at MR DNA (www.mrdnalab.com, Shallowater, TX, USA).
  • Q25 minimum sequence length
  • maximum sequence length 1,000 bp
  • maximum number of ambiguous bases 6
  • maximum number of homopolymers 6
  • maximum number of primer mismatches 0.
  • the minimum number of sequences per sample was 48,170 and the maximum number of sequences per sample was 86,360.
  • the median number of sequences per sample was 61,143 and the mean number of sequences per sample was 63,7392 ⁇ 10,798 (standard deviation).
  • the Q25 sequence data derived from the sequencing process were analyzed with the QIIME 1.9 pipeline.
  • sequences were depleted of barcodes and primers. Sequences 1,000 bp were then removed; sequences with ambiguous base calls and with homopolymer runs exceeding 6 bp were also removed. Sequences were denoised, and operational taxonomic units (OTUs) were generated. Chimeras were also removed. OTUs were defined by clustering at 3% divergence (97% similarity). Final OTUs were taxonomically classified using BLASTn against a curated Greengenes database. PCoA was generated with QIIME using the unweighted UniFrac distance matrix between the samples and as previously described 34, 35 36, 37. Data are available upon request.
  • OTUs operational taxonomic units
  • DIO donor mice show alteration in hedonic eating
  • mice were exposed to low-fat (control, CT) or high-fat diet (HFD) for 5 weeks to induce a lean or obese phenotype (diet-induced obesity, DIO), respectively.
  • HFD high-fat diet
  • mice fed with an HFD showed an increase of 12% in body weight (Fig. 1A-B) and 230% in fat mass gain (Fig. 1C-D) compared to CT-fed mice.
  • Fig. 1A-B body weight
  • Fig. 1C-D fat mass gain
  • HFHS High-Fat High-Sucrose
  • CT low-fat control diet
  • lean mice preferred HFHS diet to CT as they ate more HFHS than CT during the food preference test.
  • lean mice showed a faster tropism towards HFHS since they ate significantly more HFHS than CT from the beginning of the test, whereas DIO mice preferred significantly palatable diet over control diet only after 90 min (Fig. IE).
  • Pleasure associated with palatable food intake is mainly driven by dopaminergic pathways in the mesocorticolimbic system. Indeed, ingestion of diet rich in fat and sugar has been shown to be associated with the release of dopamine in the dorsal striatum in proportion to the self-reported level of pleasure derived from eating the food.
  • Dopamine receptors 1 and 2 are the most expressed dopamine receptors of the reward system and the scientific literature describes a downregulation of these receptors in the context of obesity in humans and rodents, which in turn is associated with a reduction of the pleasure related to palatable food ingestion. Since transplantation of obese gut microbiota replicated food preference alterations associated with obesity (Fig.
  • Table 2 mRNA levels of the dopaminergic markers D2R, DIR, TH and DAT in brain areas such as the nucleus accumbens, the caudate putamen, and the prefrontal cortex
  • obese donors and obese gut recipient mice have gut microbiota profiles that differ from lean donors and lean gut microbiota recipient mice according to the principal component PC2 (Fig. 4E-F).
  • Parabacteroides represents a potential link in the gut-to-brain axis controlling hedonic food intake

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Abstract

La présente invention concerne une composition comprenant une ou plusieurs bactéries du genre Parabacteroides et/ou un extrait de celles-ci, destinée à être utilisée dans la prévention et/ou le traitement de troubles de la dérégulation liés à la récompense.
PCT/EP2021/070303 2021-07-20 2021-07-20 Prévention et/ou traitement de troubles de dérégulation liés à la récompense WO2023001368A1 (fr)

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PCT/EP2021/070303 WO2023001368A1 (fr) 2021-07-20 2021-07-20 Prévention et/ou traitement de troubles de dérégulation liés à la récompense
JP2024503373A JP2024525879A (ja) 2021-07-20 2022-07-20 報酬系調節障害（ｒｅｗａｒｄ ｄｙｓｒｅｇｕｌａｔｉｏｎ ｄｉｓｏｒｄｅｒｓ）の防止および／または処置
CA3226267A CA3226267A1 (fr) 2021-07-20 2022-07-20 Prevention et/ou traitement de troubles lies a une dysregulation du systeme de recompense
EP22753689.3A EP4373502A1 (fr) 2021-07-20 2022-07-20 Prévention et/ou traitement de troubles liés à une dysrégulation du système de récompense
KR1020247005452A KR20240040089A (ko) 2021-07-20 2022-07-20 보상 조절 장애의 방지 및/또는 치료
AU2022315538A AU2022315538A1 (en) 2021-07-20 2022-07-20 Prevention and/or treatment of reward dysregulation disorders
PCT/EP2022/070430 WO2023001934A1 (fr) 2021-07-20 2022-07-20 Prévention et/ou traitement de troubles liés à une dysrégulation du système de récompense

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Citations (6)

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WO2017160711A1 (fr) * 2016-03-14 2017-09-21 Holobiome, Inc. Modulation du microbiome intestinal pour traiter les troubles mentaux ou les maladies du système nerveux central
US9956255B1 (en) * 2017-08-18 2018-05-01 Chang Gung Biotechnology Corp. Method to reduce body weight, fat accumulation and adipocyte size using Parabacteroides goldsteinii
WO2018119048A1 (fr) * 2016-12-20 2018-06-28 The Regents Of The University Of California Compositions et procédés pour inhiber les crises d'épilepsie
WO2018229189A1 (fr) * 2017-06-14 2018-12-20 4D Pharma Research Limited Compositions comprenant des souches bactériennes
US20200078414A1 (en) * 2018-09-04 2020-03-12 Multistars Biotechnology Company Limited Method of preventing or treating obesity using a novel strain of parabacteroides goldsteinii
US20210077549A1 (en) * 2019-09-18 2021-03-18 Research Development Foundation Methods and probiotic compositions for the treatment of metabolic diseases and disorders

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WO2017160711A1 (fr) * 2016-03-14 2017-09-21 Holobiome, Inc. Modulation du microbiome intestinal pour traiter les troubles mentaux ou les maladies du système nerveux central
WO2018119048A1 (fr) * 2016-12-20 2018-06-28 The Regents Of The University Of California Compositions et procédés pour inhiber les crises d'épilepsie
WO2018229189A1 (fr) * 2017-06-14 2018-12-20 4D Pharma Research Limited Compositions comprenant des souches bactériennes
US9956255B1 (en) * 2017-08-18 2018-05-01 Chang Gung Biotechnology Corp. Method to reduce body weight, fat accumulation and adipocyte size using Parabacteroides goldsteinii
US20200078414A1 (en) * 2018-09-04 2020-03-12 Multistars Biotechnology Company Limited Method of preventing or treating obesity using a novel strain of parabacteroides goldsteinii
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DE WOUTERS D'OPLINTER ALICE ET AL: "Gut microbes participate in food preference alterations during obesity", GUT MICROBES, vol. 13, no. 1, 1 January 2021 (2021-01-01), United States, XP055901989, ISSN: 1949-0976, Retrieved from the Internet <URL:https://www.tandfonline.com/doi/pdf/10.1080/19490976.2021.1959242?needAccess=true> DOI: 10.1080/19490976.2021.1959242 *
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