WO2023001368A1 - Prevention and/or treatment of reward dysregulation disorders - Google Patents

Abstract

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.

Description

PREVENTION AND/OR TREATMENT OF REWARD DYSREGULATION

DISORDERS

FIELD OF INVENTION [0001] The present invention relates to the field of disorders related to reward dysregulation. In particular, 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. BACKGROUND OF INVENTION

[0002] 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.

[0003] When the reward system is functioning properly, 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.

[0004] 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.

[0005] For example, in the context of obesity, wherein overeating and consumption of calorie-dense food are major aspects contributing to a positive energy balance (energy input is greater than energy output) and the storage of fat, the reward system, that drives eating behaviors associated with pleasure, is over-stimulated and becomes the major driver for food intake. Palatable food, rich in fat and sugar, can stimulate dopaminergic neurons and induce a release of dopamine mainly in the cortico-limbic areas of the brain (including the striatum, nucleus accumbens and prefrontal cortex). However, obesity, which is often the result of long-term overeating, is associated with a reduction of dopamine concentration in response to palatable food intake and a downregulation of dopaminergic markers. The expressions of dopamine receptors 1 (DIR) and 2 (D2R) are decreased, as well as the rate-limiting synthetizing enzyme (tyrosine hydroxylase, TH) whereas the dopamine transporter (DAT) is increased. This hypo-functioning of the dopamine pathway has been suggested to feed the vicious circle of weight gain since it leads to an increase of the meal size of fatty and sweet food in an attempt to feel the same rewarding effect as before the development of obesity.

[0006] 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. [0007] So far, therapy for reward dysregulation disorders may account for neuropharmacological compounds and/or psychotherapy.

[0008] There is therefore a need to provide the state of the art with alternative therapy to treat reward dysregulation disorders. In particular, there is a need to provide efficient therapy for reward dysregulation disorders.

SUMMARY

[0009] 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. [0010] In one embodiment, the bacteria from the genus Parabacteroides are selected in the group comprising or consisting of P. distasonis, P. acidifaciens, P. bouchesdurhonensis, 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.

[0011] In one embodiment, the reward dysregulation disorder is selected in a group comprising or consisting of mental disorders, neurological disorders, and combinations thereof. In one embodiment, 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. In one embodiment, the eating disorder is selected in a group comprising or consisting of anorexia, bulimia, overweight-related disorders, obesity-related disorders, and the like. In one embodiment, 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. In one embodiment, the neurological disorder is selected in a group comprising or consisting of Parkinson’s disease, Tourette Syndrome, and the like. [0012] In one embodiment, the composition is to be administered to an animal individual, preferably a mammalian individual, more preferably a human individual.

[0013] In one embodiment, the composition is to be administered orally or rectally.

[0014] In one embodiment, the bacteria are to be administered at a dose comprised from about lxlO² CFU/g to about lxlO¹² CFU/g of the composition. [0015] In one embodiment, the composition further comprises one or more beneficial microbe(s). In one embodiment, 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.

[0016] In one embodiment, the composition is in the form of a pharmaceutical composition further comprising a pharmaceutically acceptable carrier. In another embodiment, the composition is in the form of a nutritional composition further comprising a nutritionally acceptable carrier.

[0017] In one embodiment, the composition is comprised in a kit, which further comprises means to administer said composition.

DEFINITIONS

[0018] In the present invention, the following terms have the following meanings:

[0019] “About”, when preceding a value, encompasses plus or minus 10%, or less, of the value of said figure. It is to be understood that the value to which the term “about” refers to is itself also specifically, and preferably, disclosed.

[0020] “Comprise” is intended to mean “contain”, “encompass” and “include”. In some embodiments, the term “comprise” also encompasses the term “consist of’.

[0021] “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.

[0022] “Isolated bacteria” refers to bacteria that are no longer in their natural and/or physiological biotope or habitat. For example, 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. [0023] “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.

[0024] “Extract” refers to any fraction obtained from the bacteria of interest, or from culture media in which the bacteria of interest were cultured. In practice, extracts include cellular and extracellular extracts. In one embodiment, extracts according to the present invention include metabolites from the bacteria.

[0025] “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). In practice, 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.

[0026] “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). In practice, 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.

[0027] “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.

[0028] “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.

[0029] “Prevention” refers to preventing or avoiding the occurrence of symptom of a reward dysregulation disorder. In the present invention, 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. [0030] “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.

[0031] “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. [0032] “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. For human administration, 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.

[0033] “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. In some embodiments, 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. In some embodiments, the individual is an adult ( e.g ., an individual above the age of 18). In some embodiments, the individual is a child (e.g., an individual below the age of 18). In some embodiments, the individual is a male. In some embodiments, the individual is a female. [0034] Other definitions may appear in context throughout this disclosure.

DETAILED DESCRIPTION

[0035] 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.

[0036] In some aspects, 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.

[0037] 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.

[0038] In another aspect, 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.

[0039] According to some embodiments, the bacteria from the genus Parabacteroides are selected in the group comprising or consisting of P. distasonis, P. acidifaciens, P. bouchesdurhonensis, 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.

[0040] In practice, bacteria belonging to the genus Parabacteroides may be identified by any suitable procedures, or a procedure adapted therefrom. In particular, 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, based on 16S rRNA gene sequence analysis. [0041] In some embodiments, the bacteria from the genus Parabacteroides are isolated.

In some embodiments, the bacteria from the genus Parabacteroides are isolated from a natural habitat, such as, e.g., the gut microbiota. In practice, 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.

[0042] In practice, 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®).

[0043] In practice, 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. As used herein, 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.

[0044] In practice, cultures of bacteria from the genus Parabacteroides may be performed in anaerobic conditions, i.e., in the absence of O2.

[0045] In some embodiments, the composition of the invention comprises or substantially consist of a microbiota with bacteria from the genus Parabacteroides obtained from an individual. In one embodiment, the microbiota is a gut microbiota obtained from the feces of an individual. In one embodiment, the microbiota is enriched with bacteria from the genus Parabacteroides compared to the microbiota of the individual to be treated.

[0046] In some embodiments, the composition of the invention is enriched with bacteria from the genus Parabacteroides . In one embodiment, the composition of the invention comprises or substantially consist of a microbiota enriched with bacteria from the genus Parabacteroides .

[0047] In practice, bacteria from the genus Parabacteroides may be enriched by preferentially stimulating the growth of the bacteria from the genus Parabacteroides . For example, 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.

[0048] In some embodiments, the bacteria from the genus Parabacteroides are isolated and enriched. In some embodiments, the composition of the invention comprises isolated, enriched bacteria from the genus Parabacteroides .

[0049] In one embodiment, the bacteria from the genus Parabacteroides are viable. As used herein, 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. [0050] In one embodiment, the bacteria from the genus Parabacteroides are non- viable. As used herein, 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.

[0051] In practice, cell viability (active metabolism) may be assessed by measuring the consumption of one nutrient in the culture medium over time. Cell viability (proliferation) may be assessed by spreading a solution containing at least one bacterium of the invention across a petri dish and counting the number of colonies after a determined time of incubation in suitable culture conditions; alternatively, bacteria may be grown in liquid medium, and proliferation may be measured by measuring optical density of the bacterial culture after a determined time of incubation in suitable culture conditions.

[0052] In one embodiment, the bacteria from the genus Parabacteroides are pasteurized. In one embodiment, 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.

[0053] As used herein, the term “extracts” encompasses both cellular and extracellular extracts.

[0054] In practice, 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.

[0055] In practice, extracellular extracts may include the secreted fraction, in particular soluble compounds or exosomes. As used herein, the term “exosomes” is intended to refer to endocytic-derived nanovesicles that comprise proteins, nucleic acids, and lipids. In practice, 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. Illustratively, 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.

[0056] 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.

[0057] Alternative methods to isolate exosomes may take advantage of commercial kits, such as, e.g., the exoEasy Maxi Kit (Qiagen®) or the Total Exosome Isolation Kit (Thermo Fisher Scientific®).

[0058] In practice, 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.

[0059] It is to be understood that 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. In practice, the diagnosis and/or monitoring of reward dysregulation disorders may be performed by authorized personnel.

[0060] According to certain embodiments, the reward dysregulation disorder is selected in a group comprising or consisting of mental disorders, neurological disorders, and combinations thereof. [0061] According to some embodiments, 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. [0062] According to certain embodiments, the eating-related disorder is selected in a group comprising or consisting of anorexia, bulimia, overweight-related disorders, obesity-related disorders, and the like.

[0063] As used herein, an individual with overweight-related disorder has a body mass index (BMI) comprised from about 25.0 to about 29.9. As used herein, an individual with obesity-related disorder has a body mass index (BMI) above about 30.0.

[0064] In one embodiment, 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.

[0065] According to some embodiments, 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.

[0066] According to certain embodiments, the neurological-related disorder is selected in a group comprising or consisting of Parkinson’s disease, Tourette Syndrome, and the like.

[0067] According to some embodiments, the composition is to be administered to an animal individual, preferably a mammalian individual, more preferably a human individual. [0068] In one embodiment, the individual is a mammalian individual. In one embodiment, the individual is a human individual. In one embodiment the individual is a male. In one embodiment, the individual is a female. [0069] According to certain embodiments, the composition is to be administered orally or rectally.

[0070] In one embodiment, 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.

[0071] In one embodiment, the composition is a solid composition. In practice, 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.

[0072] In one embodiment, the composition is a liquid composition. In practice, 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.

[0073] According to some embodiments, the bacteria are to be administered at a dose comprised from about lxlO² CFU/g to about lxlO¹² CFU/g of the composition, preferably from about lxlO³ CFU/g to about lxlO¹¹ CFU/g of the composition, more preferably from about lxlO⁴ CFU/g to about lxlO¹⁰ CFU/g of the composition. In one embodiment, the bacteria are to be administered at a dose comprised from about lxlO⁴ CFU/g to about lxlO¹¹ CFU/g of the composition, from about lxlO⁵ CFU/g to about lxlO¹¹ CFU/g of the composition, from about lxlO⁶ CFU/g to about lxlO¹¹ CFU/g of the composition, from about lxlO⁷ CFU/g to about lxlO¹¹ CFU/g of the composition or from about 1x10^s CFU/g to about lxlO¹¹ CFU/g of the composition. [0074] As used herein, “CFU” stands for “Colony Forming Unit”. As used herein the term “about lxlO² CFU/g to about lxlO¹² CFU/g” includes lxlO², 5xl0², lxlO³, 5xl0³, lxlO⁴, 5xl0⁴, lxlO⁵, 5xl0⁵, lxlO⁶, 5xl0⁶, lxlO⁷, 5xl0⁷, 1x10^s, 5x10^s, lxlO⁹, 5xl0⁹, lxlO¹⁰, 5xl0¹⁰, lxlO¹¹, 5xl0^u and lxlO¹² CFU/g. [0075] According to some embodiments, the bacteria are to be administered at a dose comprised from about lxlO² cells/g to about lxlO¹² cells/g of the composition. As used herein the term “about lxlO² cells/g to about lxlO¹² cells/g” includes lxlO², 5xl0², lxlO³, 5xl0³, lxlO⁴, 5xl0⁴, lxlO⁵, 5x10^s, lxlO⁶, 5xl0⁶, lxlO⁷, 5xl0⁷, 1x10^s, 5x10^s, lxlO⁹, 5xl0⁹, lxlO¹⁰, 5xl0¹⁰, lxlO¹¹, 5xl0ⁿ and lxlO¹² cells/g.

[0076] According to some embodiments, when the composition is a solid composition, the bacteria are to be administered at a dose comprised from about lxlO² CFU/g to about lxlO¹² CFU/g of the composition. As used herein the term “about lxlO² CFU/g to about lxlO¹² CFU/g” includes lxlO², 5xl0², lxlO³, 5xl0³, lxlO⁴, 5xl0⁴, lxlO⁵, 5x10^s, lxlO⁶, 5xl0⁶, lxlO⁷, 5xl0⁷, 1x10^s, 5x10^s, lxlO⁹, 5xl0⁹, lxlO¹⁰, 5xl0¹⁰, lxlO¹¹, 5xl0^u and lxlO¹² CFU/g.

[0077] According to some embodiments, when the composition is a solid composition, the bacteria are to be administered at a dose comprised from about lxlO² cells/g to about lxlO¹² cells/g of the composition. As used herein the term “about lxlO² cells/g to about lxlO¹² cells/g” includes lxlO², 5xl0², lxlO³, 5xl0³, lxlO⁴, 5xl0⁴, lxlO⁵, 5x10^s, lxlO⁶, 5xl0⁶, lxlO⁷, 5xl0⁷, 1x10^s, 5x10^s, lxlO⁹, 5xl0⁹, lxlO¹⁰, 5xl0¹⁰, lxlO¹¹, 5xl0^u and lxlO¹² cells/g.

[0078] According to some embodiments, when the composition is a liquid composition, the bacteria are to be administered at a dose comprised from about lxlO² CFU/ml to about lxlO¹² CFU/ml of the composition. As used herein the term “about lxlO² CFU/ml to about lxlO¹² CFU/ml” includes lxlO², 5xl0², lxlO³, 5xl0³, lxlO⁴, 5xl0⁴, lxlO⁵, 5x10^s, lxlO⁶, 5xl0⁶, lxlO⁷, 5xl0⁷, 1x10^s, 5x10^s, lxlO⁹, 5xl0⁹, lxlO¹⁰, 5xl0¹⁰, lxlO¹¹, 5xl0ⁿ and lxlO¹² CFU/ml.

[0079] According to some embodiments, when the composition is a liquid composition, the bacteria are to be administered at a dose comprised from about lxlO² cells/ml to about lxlO¹² cells/ml of the composition. As used herein the term “about lxlO² cells/ml to about lxlO¹² cells/ml” includes lxlO², 5xl0², lxlO³, 5xl0³, lxlO⁴, 5xl0⁴, lxlO⁵, 5x10^s, lxlO⁶, 5xl0⁶, lxlO⁷, 5xl0⁷, 1x10^s, 5x10^s, lxlO⁹, 5xl0⁹, lxlO¹⁰, 5xl0¹⁰, lxlO¹¹, 5xl0ⁿ and lxlO¹² cells/ml. [0080] According to certain embodiments, the composition further comprises one or more additional active agent(s).

[0081] According to certain embodiments, the one or more additional active agent(s) are one or more beneficial microbe(s). In other words, in one embodiment, the composition further comprises one or more beneficial microbe(s).

[0082] According to some embodiments, 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.

[0083] According to certain embodiments, the composition is in the form of a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

[0084] In certain embodiments, 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.

[0085] According to certain embodiments, the composition is in the form of a nutritional composition further comprising a nutritionally acceptable carrier.

[0086] As used herein, the term “nutritional composition” is intended to refer to any food product, additive food, supplement food, fortified food, including liquid food products and solid food products. In practice, 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. In practice, solid food products include, but are not limited to candy bars, cereal bars, energy bars, and the like.

[0087] In some embodiments, the nutritional composition of the invention is for non- therapeutic use, or for use in a non-therapeutic method.

[0088] In some aspects, 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. [0089] In some embodiments, the composition, the pharmaceutical composition, the nutritional composition, the medical device or the medicament according to the invention is sterile. In practice, methods for obtaining a sterile pharmaceutical composition include, but are not limited to, GMP synthesis (GMP stands for “Good manufacturing practice”).

[0090] 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. In one embodiment, 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. [0091] According to certain embodiments, the composition is comprised in a kit, which further comprises means to administer said composition.

[0092] 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. As used herein, “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.

[0093] The present invention further relates to a method for restoring the reward function in an individual in need thereof. In one embodiment, 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. In a particular embodiment, 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. [0094] The present invention further relates to a method for restoring the microbiota of an individual in need thereof. In one embodiment, 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. In a particular embodiment, 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.

[0095] The present invention further relates to a method for increasing the level of Parabacteroides in the microbiota of an individual in need thereof. In one embodiment, 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. In a particular embodiment, 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. [0096] The present invention also relates to a method for reducing the reward eating in an individual in need thereof. In one embodiment, 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. In a particular embodiment, 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.

[0097] The present invention further relates to a method for reducing the intake of palatable diet in an individual in need. In one embodiment, 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. In a particular embodiment, 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.

BRIEF DESCRIPTION OF THE DRAWINGS

[0098] Figures 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). (Fig. IE) Food preference test showing HFHS and CT intake during 180 minutes of test by lean (Lean_do) and DIO donor mice (DIO_do). (Fig. IF) Food preference test showing total HFHS and CT intake, from Fig. IE. Data are shown as mean ± SEM (n=5/group). P- values were obtained after Two-way ANOVA, followed by Bonferroni post-hoc test (Fig. 1A, C, E, F), unpaired Student’s t-test (Fig. IB, D). *: p-value <0,05; **: p-value < 0,01; ***: p-value < 0,001; ****: p-value < 0,0001. $$$$: p-value < 0.0001 between CT vs HFHS intake. Different superscript letters represent significant p-values between groups and type of diet (CT or HFHS) at each time-point (Fig. IF).

[0099] 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). (Fig. 2F) Food preference test showing total HFHS and CT intake after 180 minutes of test by lean (Lean_rec) and DIO recipient mice (DIO_rec). Data are shown as mean ± SEM (n=7-8/group). (Fig. 2G) Food preference test showing HFHS (curves 3 and 4) and CT (curves 1 and 2) intake during 180 minutes by lean (Lean_rec; curves 1 and 3) and DIO recipient mice (DIO_rec; curves 2 and 4). P-values were obtained after Two- way ANOVA, followed by Bonferroni post-hoc test (Fig. 2B, D, F, G) or unpaired Student t-test (Fig.2C, E). *: p-value <0,05; **: p-value < 0,01. $$: p-value < 0.01; $$$$: p-value < 0.0001 between CT vs HFHS intake (Fig. 2F).

[0100] Figures 3A-D are a set of graphs showing alterations in dopaminergic signaling in recipient mice with obese gut microbiota. Striatal mRNA expression of dopamine receptor 1 (DIR) (Fig. 3A), dopamine receptor 2 (D2R) (Fig. 3B), tyrosine hydroxylase (TH) (Fig. 3C) and dopamine transporter (DAT) (Fig. 3D) measured by real-time qPCR in lean (Lean_rec) and DIO recipient mice (DIO_rec). Data are shown as mean ± SEM (n=7-8/group). P-values were obtained after unpaired Student’s t-test (Fig. 3C) or non- parametric Mann- Whitney test (Fig. 3A, B, D).

[0101] 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; (Fig. 4F) PCoA PC3 vs PC2; ►: Lean_do; ■: Lean rec; ·: DIO do; ▲ : DIO_rec. [0102] 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. EXAMPLES

[0103] The present invention is further illustrated by the following examples.

Example 1:

Materials and Methods 1. Mice and experimental design

[0104] All mouse experiments were approved by the ethical committee for animal care of the Health Sector of the UCLouvain, Universite catholique de Louvain under the specific number 2017/UCL/MD/005 and performed in accordance with the guidelines of the local ethics committee and in accordance with the Belgian Law of May 29, 2013 regarding the protection of laboratory animals (agreement number LA1230314).

2. Donor mice

[0105] A cohort of 8-week-old specific-opportunistic and pathogen-free (SOPL) male C57BL/6J mice (10 mice, n=5 per group) (Janvier laboratories®, Lrance) were housed in a controlled environment (room temperature of 22 ± 2 °C,12h daylight cycle) in groups of two mice per cage, with free access to sterile food (irradiated) and sterile water. Upon delivery, mice underwent an acclimatization period of one week, during which they were fed a control diet (CT, AIN93MΪ, Research Diet, New Brunswick, NJ, USA). Then, mice were randomly divided in two groups, and were fed for 5 weeks with control low-fat diet (CT, AIN93MΪ) 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

[0106] A cohort of 3 -week-old specific-opportunistic and pathogen-free (SOPL) male C57BL/6J mice (15 mice, n=7-8 per group) (Janvier laboratories®, France) were housed in a controlled environment (room temperature of 22 ± 2 °C, 12h daylight cycle) in groups of two mice per cage, with free access to sterile food (irradiated) and sterile water. Mice were fed a low-fat control diet (CT, AIN93MΪ) during the entire transplantation protocol as well as after gut microbiota transplantation. 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, LF50 Minispec, Bruker®, Rheinstetten, Germany). After 12 weeks of follow-up, the mice entered the metabolic chambers to assess precisely their food intake and metabolism then perform the food preference test. 4. Fecal Microbiota Transplantation

[0107] At the end of the donor experiment, caecal content was collected in sterile containers and immediately diluted (1:50 w/vol) in sterile Ringer buffer (4,5 g NaCl, 200 mg KC1, 125 mg CaCF). This suspension was then diluted (1:1 v/v) in 20% (w/v) skim milk (Nonfat dry milk, Biorad®, 2005668 A) before storage at -80°C. Two CT-fed mice and two HFD-fed mice from donor cohort were selected as fecal microbiota donors for seven or eight recipient mice per group respectively with 1 donor for 3 or 4 recipient mice. Prior to gut microbiota inoculation, 3-week old SOPF recipient mice were depleted in intestinal microbiota by daily gavage of a broad- spectrum, poorly absorbed mix of antibiotics during 5 days (100 mg/kg of ampicillin, neomycin and metronidazole and 50 mg/kg of vancomycin diluted in sterile water) added with antifungal (amphotericin B 1 mg/kg). Antibiotic treatment was then followed by a bowel cleansing with the administration of 600 pi of PEG solution (PEG/Macrogol 4000, Colofort®, Ipsen, France) by oral gavage in two times at 30 min intervals after a 2-hour fasting. Colonization was then achieved by intragastric gavage with 300 mΐ 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, AIN93MΪ).

5. Metabolic chambers

[0108] After 11 weeks of follow-up, recipient mice were separated and housed individually one week before entering metabolic chambers (Labmaster, TSE systems GmbH, Bad Homburg, Germany). Then they underwent 4 days of metabolic assessment before the food preference test. The mice were analyzed for oxygen consumption, and carbon dioxide production using indirect calorimetry (Labmaster, TSE systems GmbH). These parameters were expressed as a function of whole-body weight. Locomotor activity was recorded using an infrared light beam-based locomotion monitoring system (expressed as beam breaks count per hour). Sensors recorded the precise food intake of each diet every 15 minutes. Inside the chambers, measurements were taken every 15 minutes. The final data representation (total, day or night) corresponds to all the values measured and summed (light phase or dark phase). The means (n=7) were finally compared between groups.

6. Food preference test

[0109] During 3 hours in the daylight, mice were exposed to two kinds of diets: a low- fat, control normal diet (CT, AIN93MΪ, 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.

7. Tissue sampling [0110] At the end of each experiment, 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.

8. RNA preparation and real-time qPCR analysis

[0111] Total RNA was prepared from the striatum using TriPure reagent (Roche®). Quantification and integrity analysis of total RNA was performed by running 2 mΐ of each sample on an Agilent® 2100 Bioanalyzer (Agilent® RNA 6000 Nano Kit, Agilent). If the RNA integrity number (RIN) obtained less than 6, the sample was excluded from further analyses. cDNA was prepared by reverse transcription of 1 pg total RNA using the GoScript® Reverse Transcriptase kit (Promega®, Madison, WI, USA). Real-time PCR was performed with the QuantStudio 3 real-time PCR system (Thermo Fisher Scientific®, Waltham, MA, USA). Rpll9 RNA was chosen as the housekeeping gene. All samples were performed in duplicate, and data were analyzed according to the 2- AACT method. The identity and purity of the amplified product were assessed by melting curve analysis at the end of amplification. Sequences of the primers used for real- time qPCR are available in Table 1.

[0112] Table 1: primers used for real-time qPCR

9. DNA isolation from mouse caecal samples and sequencing

[0113] Caecal contents were collected and kept frozen at -80 °C until use. Metagenomic DNA was extracted from the caecal content using a QIAamp® DNA Stool Mini Kit (Qiagen®, Hilden, Germany) according to the manufacturer’s instructions with modifications (see Everard el ah, ISME J 2014; 8:2116-30). The 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). Sequences were demultiplexed and processed using the QIIME pipeline (vl.9 using default options: Q25, minimum sequence length = 200 bp, maximum sequence length = 1,000 bp, maximum number of ambiguous bases = 6, maximum number of homopolymers = 6, maximum number of primer mismatches = 0). For the 22 samples analyzed, 102 OTUs have been identified (97% similarity). 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. Briefly, 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.

10. Statistical analysis

[0114] Statistical analyses were performed using GraphPad Prism® version 8.1.2 for Windows (GraphPad® Software, San Diego, CA, USA) except for microbiota analyses as described above. Data are expressed as mean ± SEM. Differences between two groups were assessed using unpaired Student’s t-test. In case variance differed significantly between groups according to the Fisher test, a non-parametric (Mann- Whitney) test was performed. Differences between more than two groups were assessed using one-way ANOVA or two-way ANOVA if repeated measurements, followed by Tuckey or Bonferroni respectively post-hoc test. In case variance differed significantly between groups, a non-parametric Kruskal-Wallis test was performed, followed by the Dunnett post-hoc test. Results

1. DIO donor mice show alteration in hedonic eating

[0115] First, 10 donor 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. As expected, 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. Then, in order to study the hedonic component of food intake, the pleasure associated with palatable food consumption in these mice was analyzed.

[0116] To assess spontaneous hedonic food intake, the donor mice underwent a food preference test in which they were exposed for the first time to palatable diet (High-Fat High-Sucrose, HFHS). During this food preference test, donor mice were exposed to HFHS and low-fat control diet (CT) for three hours during the light phase and the consumption of each diet was recorded (Fig. IE and Fig. IF). Both lean and obese mice preferred HFHS diet to CT as they ate more HFHS than CT during the food preference test. However, 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). Overall, DIO mice were significantly less attracted to palatable diet, eating 58% less HFHS (p < 0.0001) than lean mice over the whole food preference test (Fig. IF). 2. Obese gut microbiota transplantation transfers alteration in hedonic eating associated with obesity

[0117] To study the causal role of the gut microbiota in obesity-related hedonic eating disorders, the gut microbiota from 2 lean and 2 obese donor mice were transplanted into 7 and 8 recipient mice respectively. All recipient mice were fed with the same low-fat, control diet during the whole experiment (Fig. 2A).

[0118] Lean and obese gut microbiota recipient mice (Lean_rec and DIO_rec, respectively) did not show any difference in terms of body weight (Fig. 2B-C) or fat mass gain (Fig. 2D-E). However, DIO gut microbiota recipient mice tended to gain more fat mass over time, with a statistical significance at day 64 (Fig. 2D). In order to investigate energy metabolism of lean and obese gut microbiota recipient mice, precise measurements of O2 consumption and CO2 production in metabolic chambers were also performed. It was not observed any differences between mice receiving an obese or lean gut microbiota. These results suggest that donor mice did not transfer their obese phenotype to recipient mice in terms of fat mass and body weight after fecal transplantation.

[0119] Interestingly, during the entire follow up, lean and obese gut microbiota recipient mice had similar intake of control diet. However, during their first exposure to palatable food (i.e. food preference test), differences in HFHS intake were revealed (Fig. 2F and Fig. 2G). Lean gut microbiota recipient mice displayed a faster preference for HFHS than DIO gut microbiota recipient mice. In fact, lean gut microbiota recipient mice ate significantly more HFHS than CT diet after 90 minutes of test, whereas the difference between HFHS and CT intake in DIO gut microbiota recipient mice was only significant after 150 and 180 min (Fig. 2G). Like the donor mice, the two recipient groups showed a preference for palatable diet over CT diet. Strikingly, the total HFHS intake was 40% less important in DIO gut microbiota recipient mice compared to lean gut microbiota recipient mice (p < 0.01, Fig. 2F). These results demonstrate that lean and DIO gut microbiota recipient mice show similar patterns in terms of hedonic eating behavior as their respective microbiota donors and this effect was independent from obesity development or non-hedonic feeding behavior. Of note, ambulatory activity during the test was comparable between recipient mice, suggesting a similar exploratory behavior towards this novel food high in sugar and fat. Taken together, a causal role of the gut microbiota in the hedonic food behavior alterations associated with obesity was uncovered.

3. Dopaminergic markers in the striatum suggest a hypofunctional food reward system in DIO recipient mice

[0120] 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 (DIR and D2R) 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. 2F), it was wondered if this was associated with modifications in dopaminergic markers. Therefore, we investigated the expression of dopaminergic markers in the striatum of recipient mice by qPCR. [0121] The results show that after microbiota transplantation, DIO recipient mice express at least 60% less DIR and D2R in the striatum compared to lean recipient mice, although this failed to pass the statistical threshold due to high variability in the Lean_rec group (p>0.05, Fig. 3A-B). The expression of tyrosine hydroxylase (TH), the rate- limiting enzyme synthetizing dopamine, was also decreased (50%) in mice receiving obese microbiota compared to mice receiving lean microbiota (p > 0.05, Fig. 3C). In line with these results, the dopamine transporter (DAT), responsible for the recapture of around 80% of the dopamine released, was two-fold more expressed in DIO_rec compared to Lean_rec (p > 0.05, Fig. 3D), suggesting low function of the dopaminergic system in obese gut microbiota transplanted mice. Of note, the modifications of expression of dopaminergic markers are not associated with changes in the ambulatory activity, suggesting that the qPCR results observed in the striatum are specific to the reward system rather than the motor function.

[0122] Besides the dopaminergic system in the striatum, other brain areas are involved in food reward as caudate putamen, nucleus accumbens and prefrontal cortex. Therefore, it was further investigated and analyzed mRNA levels of the dopaminergic markers in these regions (Table 2).

[0123] 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

[0124] It was not observed any differences between lean and obese gut microbiota recipient mice in these brain areas, suggesting that modulations of the expression of dopaminergic markers between lean and obese gut microbiota recipient mice seem to be specific to the striatum. 4. Fecal material transplantation from obese donors into lean recipient mice is efficient

[0125] To validate the efficiency of the gut microbiota transplantation, bacterial composition of caecum contents from donor and recipient mice were analyzed using 16S rRNA sequencing. Common OTUs (Operational Taxonomic Units) between donors and recipients were compared at the end of each experiment, just after food preference tests (Fig. 4A-D). Two mice from each donor group (CT-fed or HFD-fed) were donors for 7 Lean_rec and 8 DIO_rec recipient mice respectively with one donor mouse for 3 or 4 recipient mice. Venn diagram showed a high similarity of OTUs (more than 50%) between donors and recipients, confirming the colonization of antibiotic-treated recipients with gut microbiota from donors (Fig. 4A-D).

[0126] Furthermore, as represented on the PCoA, 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).

5. Parabacteroides represents a potential link in the gut-to-brain axis controlling hedonic food intake

[0127] As a preliminary approach to highlight a potential link between the gut microbiota and the food reward system in the context of obesity, Spearman’s correlations was used to establish associations between several parameters of the food reward system and the gut microbiota. Data from donor and recipient mice were combined to create the correlation matrix. The heatmap showed that 18 OTUs correlated with the total HFHS intake measured during the food preference test (Fig. 5A). In addition, positive correlations were found between an unidentified genus of the Peptococcaceae family and mRNA expression of D 1R, D2R and TH (Fig.5A). However, after correcting for multiple comparisons using the FDR (false discovery rate) method, only Parabacteroides remained highly positively correlated with the HFHS intake (Fig. 5B). This suggested that the more Parabacteroides the mice had, the more HFHS they ate during the food preference test and this behavior implies a functional reward system.

Claims

1. 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.

2. Composition for use according to claim 1, wherein the bacteria from the genus Parabacteroides are selected in the group comprising or consisting of P. distasonis, P. acidifaciens , P. bouchesdurhonensis, 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.

3. Composition for use according to claim 1 or 2, wherein the reward dysregulation disorder is selected in a group comprising or consisting of mental disorders, neurological disorders, and combinations thereof.

4. Composition for use according to claim 3, wherein 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.

5. Composition for use according to claim 4, wherein the eating disorder is selected in a group comprising or consisting of anorexia, bulimia, overweight-related disorders, obesity-related disorders, and the like.

6. Composition for use according to claim 4, wherein 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.

7. Composition for use according to claim 3, wherein the neurological disorder is selected in a group comprising or consisting of Parkinson’s disease, Tourette Syndrome, and the like.

8. Composition for use according to any one of claims 1 to 6, wherein the composition is to be administered to an animal individual, preferably a mammalian individual, more preferably a human individual.

9. Composition for use according to any one of claims 1 to 7, wherein the composition is to be administered orally or rectally.

10. Composition for use according to any one of claims 1 to 8, wherein the bacteria are to be administered at a dose comprised from about lxlO² CFU/g to about lxlO¹² CFU/g of the composition.

11. Composition for use according to any one of claims 1 to 9, wherein the composition further comprises one or more beneficial microbe(s).

12. Composition for use according to any one of claims 1 to 10, wherein 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.

13. Composition for use according to any one of claims 1 to 11, wherein the composition is in the form of a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

14. Composition for use according to any one of claims 1 to 11, wherein the composition is in the form of a nutritional composition further comprising a nutritionally acceptable carrier.

15. Composition for use according to any one of claims 1 to 12, wherein the composition is comprised in a kit, which further comprises means to administer said composition.