PREVENTING AND / OR TREATING REWARD DYSREGULATION DISORDERS

Abstract

The present invention relates to compositions comprising one or more bacteria of the genus Parabacteroides and / or extracts thereof for use in the prevention and / or treatment of reward dysregulation disorders.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to the field of disorders related to reward system dysregulation.In particular, the present invention relates to a composition comprising one or more bacteria of the genus Parabacteroides and / or their extracts and / or their metabolites for use in preventing and / or treating reward system dysregulation. [Background technology]

[0002] 2. Background of the Invention The reward system is often defined as involving a collection of neural circuits that process appetitive stimuli within the limbic system, basal ganglia, prefrontal cortex, ventral tegmental area, and substantia nigra.

[0003] When the reward system is functioning properly, the anticipation or attainment of a reward catalyzes a cascade of events involving neurotransmitters such as dopamine, GABA, glutamate, serotonin, and norepinephrine.

[0004] Dysfunction in reward mechanisms can occur naturally (e.g., when dopamine levels fall during social isolation or when serotonin levels fall with age) or artificially (e.g., when dopamine antagonists are taken). Reward dysfunction can also occur during disease or genetic disorders. Dysfunction in these mechanisms is characterized by reward learning and motivation deficits and emotional abnormalities, such as, for example, lack of pleasure or satisfaction, reduced motivation, and emotional numbness.

[0005] For example, in the context of obesity, where overeating and the consumption of high-calorie foods are the main modes contributing to a positive energy balance (energy input is greater than energy output) and fat accumulation, the reward system, which drives the eating behavior associated with pleasure, becomes the main driver of food intake. Palatable foods rich in fat and sugar can stimulate dopaminergic neurons to induce the release of dopamine, mainly in corticolimbic regions 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 reduced dopamine concentrations in response to the intake of palatable foods and downregulation of dopaminergic markers. The expression of dopamine receptors 1 (D1R) and 2 (D2R), as well as the rate-limiting synthesis enzyme (tyrosine hydroxylase, TH), is decreased, whereas the dopamine transporter (DAT) is increased. It has been suggested that this alteration in the function of the dopamine pathway promotes a vicious cycle of weight gain, as people increase the amount of fat and sweet foods they eat in an attempt to feel the same rewarding effect as before the onset of obesity.

[0006] Reward system dysregulation mechanisms can also occur in many diseases, including addiction-related disorders, affective disorders, obsessive-compulsive disorders, schizophrenia, attention-deficit hyperactivity disorder (ADHD), autism spectrum disorders, major depressive disorder (MDD), anxiety disorders and Parkinson's disease.

[0007] So far, treatments for reward system dysregulation can be based on neuropharmacological compounds and / or psychotherapy.

[0008] Therefore, there is a need in the state of the art to provide alternative therapies for treating reward system dysregulation, and in particular to provide effective treatments for reward system dysregulation. Summary of the Invention [Problem to be solved by the invention]

[0009] overview The present invention relates to a composition comprising one or more bacteria of the genus Parabacteroides and / or extracts thereof and / or metabolites thereof for use in the prevention and / or treatment of reward system dysregulation. [Means for solving the problem]

[0010] In one embodiment, the bacteria of the genus Parabacteroides is selected from the group including or consisting of P. distasonis, P. goldsteinii, P. merdae, P. acidifaciens, P. bouchesdurhonensis, P. chartae, P. chinchilla, P. chongii, P. faecis, P. gordonii, P. johnsonii, P. massiliensis, P. pacaensis, P. provencensis, P. timonensis, Parabacteroides spp., and combinations thereof.

[0011] In one embodiment, the reward system dysregulation comprises or is selected from the group consisting of psychiatric disorders, neurological disorders, and combinations thereof. In one embodiment, the psychiatric disorders comprises or is selected from the group consisting of addiction-related disorders, eating-related disorders, emotional disorders, obsessive-compulsive disorders, schizophrenia, attention-deficit hyperactivity disorder (ADHD), autism spectrum disorders, major depression (MDD), anxiety disorders, and the like. In one embodiment, the eating-related disorders comprises or is selected from the group consisting of anorexia nervosa, bulimia, overweight-related disorders, obesity-related disorders, and the like. In one embodiment, the addiction-related disorders comprises or is selected from the group consisting of alcohol-related addictions, drug-related addictions, gaming-related addictions, and the like. In one embodiment, the neurological disorders comprises or is selected from the group consisting of Parkinson's disease, Tourette's syndrome, and the like.

[0012] In one embodiment, the composition is administered to an animal individual, preferably a mammalian individual, more preferably a human individual.

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

[0014] In one embodiment, the bacteria is about 1×10 2 CFU / g composition ~ approx. 1×10 12 The dose is administered in a volume containing CFU / g of composition.

[0015] In one embodiment, the composition further comprises one or more beneficial microorganism(s). In one embodiment, the one or more beneficial microorganism(s) are selected from the group comprising or consisting of bacteria of the family Clostridiaceae, Peptostreptococcusceae, Prevotellaceae, Methylobacteriumceae, Turicibacter, Coprococcus, Noelia, Prevotella, Staphylococcus, Ackermansia, and the like.

[0016] In one embodiment, the composition is in the form of a pharmaceutical composition further comprising a pharma- ceutically acceptable carrier, hi 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 included in a kit further comprising a means for administering said composition.

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

[0019] The term "about" preceding a value includes up to plus or minus 10% of the value of said number. It is to be understood that the value to which the term "about" refers is itself specifically and preferably disclosed.

[0020] "Comprise" is intended to mean "contain," "include," and "include." In some embodiments, the term "comprise" also encompasses the term "consisting of."

[0021] "Bacteria of the genus Parabacteroides" refers to Gram-negative, obligately anaerobic, non-spore-forming, non-motile bacteria capable of growing in culture medium containing 20% ​​(w / v) bile. Bacteria belonging to the genus Parabacteroides can be easily identified by routine procedures, including physiological and biochemical approaches, evaluation of their intracellular fatty acid profile, evaluation of the menaquinone profile, and their phylogenetic position based on 16S rRNA gene sequence analysis.

[0022] "Isolated bacteria" refers to bacteria that are no longer present in their natural and / or physiological ecological environment or habitat. For example, the bacteria of interest from a microbiome may be collected, separated from other bacteria, and further formulated into a composition. Isolation of bacteria may be performed according to standard protocols in the field of microbiology, such as gram staining, 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 of the genus Parabacteroides is enhanced within the total microbial population of the composition.

[0024] "Extract" refers to any fraction obtained from the bacterium of interest or from the culture medium in which the bacterium of interest has been cultured. In practice, the extract includes cellular and extracellular extracts. In one embodiment, the extract according to the invention includes metabolic products of the bacterium.

[0025] "Reward system" refers to a group of neurobiological mechanisms induced by rewarding stimuli, such as food, drugs, or alcohol. The reward system involves multiple structures in the brain, including the limbic system, basal ganglia, prefrontal cortex, ventral tegmental area, striatum, nucleus accumbens, and substantia nigra. Activation of the reward system by the expectation or acquisition of reward induces a positive sensation or pleasure in an individual that originates from the release of the neurotransmitter dopamine, or other neurotransmitters such as GABA, glutamate, serotonin, and norepinephrine, as well as opioids and / or endocannabinoids. Certain drugs are capable of directly activating the reward system without the use of rewarding stimuli. Importantly, the reward system includes three components: a "liking" component, a "wanting" component, and a "learning" component. The liking component corresponds to hedonic effects and is related to the pleasure provided by rewarding stimuli. The wanting component corresponds to incentive salience and is related to the motivation or incentive an individual obtains to obtain a reward. The learning component corresponds to the ability of an individual to make a predictive association between a reward and a situation (e.g., a place, a time of day, an action or sequence of actions, and the like) and to persistently remember this association for future reward acquisition.

[0026] "Reward system dysregulation" refers to a disorder in which an individual strives to pursue or realize pleasurable stimuli and anticipated pleasure and / or experiences strong responses or positive emotional reactivity to positive or rewarding cues (see Gruber et al., J Abnorm Child Psychol. 2013; 41(7):1053-1065), or in which an individual requires high levels of exposure to rewards to obtain the same pleasure. In some embodiments, any one of the three components of the reward system (i.e., the liking, the appetitive, and the learning components) can be dysregulated. In some embodiments, one, two, or all three components are dysregulated. "Dysregulated" can mean that a component is either abnormally "overstimulated" (i.e., activated, overactivated, increased, upregulated) or "understimulated" (i.e., inhibited, decreased, downregulated). In one embodiment, one or more components are overstimulated or understimulated. In another embodiment, one or more components are overstimulated, and one or more different components are understimulated.In practice, reward system dysregulation encompasses psychiatric and neurological disorders as defined below.The diagnosis of individuals with reward system dysregulation can be performed by qualified personnel, such as physicians, according to standard protocols in the field, in particular by monitoring clinical signs, often with the assistance of a questionnaire.

[0027] As used herein, "mental disorder" refers to a specific subset of reward system dysregulation disorder, and refers to a disorder characterized by a combination of abnormal thinking, perception, emotion, behavior and relationship with others, as defined by the World Health Organization (WHO).In practice, mental disorders include addiction-related disorders, eating-related disorders, affective disorders, obsessive-compulsive disorders, schizophrenia, attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, major depressive disorder (MDD), anxiety disorders and Parkinson's disease.In some embodiments, mental disorders include eating-related disorders and addiction-related disorders.

[0028] "Eating disorders" refers to a specific subset of mental disorders, including anorexia nervosa, bulimia nervosa, overweight-related disorders, obesity-related disorders, and the like. In some embodiments, "overweight-related disorders" and "obesity-related disorders" are used interchangeably and refer to disorders associated with a body mass index (BMI) of 25 or greater (if overweight) or a BMI of 30 or greater (if obese), as defined by the WHO. Within the scope of the present invention, "overweight-related disorders" and "obesity-related disorders" are associated with abnormal food intake that induces and / or maintains a BMI of 25 or 30 or greater.

[0029] "Addiction-related disorders" refers to a special subset of mental disorders, including alcohol-related addictions, drug-related addictions, tobacco or nicotine addictions, gaming-related addictions, and the like.

[0030] "Neurological disorder" as used herein refers to a specific subset of reward system dysregulation and refers to disorders that affect the brain, nerves and spinal cord.In fact, individuals with neurological disorder may experience symptoms such as paralysis, muscle weakness, poor coordination, sensory impairment, epileptic seizures, confusion, pain and changes in consciousness level.Neurological disorders include, but are not limited to, neuromuscular disorders, autism spectrum disorders, neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease), Tourette's syndrome, epilepsy, and amyotrophic lateral sclerosis.

[0031] "Beneficial microorganisms" refer to microorganisms that may provide health benefits to the host, including improving the host's gut microbial balance, maintaining intestinal barrier homeostasis, preventing pathogen survival, and preventing bacterial and viral infections.

[0032] "Prevention" refers to preventing or avoiding the appearance of symptoms of reward system dysregulation. In the present invention, the term "prevention" may refer to secondary prevention, i.e., preventing the recurrence or relapse of symptoms of reward system dysregulation.

[0033] "Treating", "treatment" or "alleviation" refers to both therapeutic treatment and prophylactic or preventative measures in which a subject is prevented or slowed (reduced) from the targeted reward system dysregulation. Subjects in need of treatment include those who already have reward system dysregulation, and those who are prone to have dysregulation, or those in whom reward system dysregulation is prevented. If, after receiving a therapeutic amount of the composition, pharmaceutical composition according to the present invention, alone or in combination with another treatment, the patient shows an observable and / or measurable reduction or disappearance of one or more symptoms associated with reward system dysregulation, and / or a degree of alleviation of one or more symptoms associated with reward system dysregulation or condition, a reduction in morbidity and mortality, and an improvement in quality of life issues, an individual or mammal is successfully "treated" with reward system dysregulation or condition. The above parameters for evaluating the success of treatment and improvement in disease can be easily measured by routine procedures well known to physicians.

[0034] "Therapeutically effective amount" refers to an amount sufficient to effect beneficial or desired results, including clinical results. A therapeutically effective amount may be administered in one or more administrations. In one embodiment, the therapeutically effective amount may depend on the individual being treated.

[0035] A "pharmaceutically acceptable carrier" refers to a carrier that does not produce any adverse, allergic or other untoward reactions when administered to an animal individual, preferably a human individual. It includes any solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. For human administration, preparations must meet sterility, pyrogenicity, general safety, quality and purity standards required by regulatory authorities, such as the Food and Drug Administration (FDA) of the United States or the European Medicines Agency (EMA) of the European Union.

[0036] "Individual" refers to an animal individual, preferably a mammalian individual, more preferably a human individual. In some embodiments, the individual may be a mammalian individual. Mammals include, but are not limited to, all primates (human and non-human), cows (including dairy cows), horses, pigs, sheep, goats, dogs, cats, and any other mammals that are waiting to receive medical care, or are receiving medical care, or have been / are / will be the subject of medical treatment, or are being monitored for progress, for a reward system dysregulation. In some embodiments, the individual may be a "patient", i.e., a warm-blooded animal, more preferably a human, that is waiting to receive medical care, or are receiving medical care, or have been / are / will be the subject of medical treatment, or are being monitored for progress, for a reward system dysregulation. In some embodiments, the individual is an adult (e.g., an individual over 18 years of age). In some embodiments, the individual is a child (e.g., an individual under 18 years of age). In some embodiments, the individual is male. In some embodiments, the individual is female.

[0037] Other definitions may appear throughout the context of this disclosure.

[0038] Detailed Description The present invention relates to a composition comprising one or more bacteria of the genus Parabacteroides and / or an extract thereof for use in the prevention and / or treatment of reward system dysregulation.

[0039] In some embodiments, the present invention also relates to the use of a composition comprising one or more bacteria of the genus Parabacteroides and / or an extract thereof for preventing and / or treating reward system dysregulation.

[0040] The present invention further relates to the use of a composition comprising one or more bacteria of the genus Parabacteroides and / or an extract thereof for the preparation or manufacture of a medicament for preventing and / or treating a reward system dysregulation.

[0041] In another aspect, the present invention relates to a method for preventing and / or treating reward system dysregulation in an individual in need thereof comprising administration of a therapeutically effective amount of a composition comprising one or more bacteria of the genus Parabacteroides and / or an extract thereof.

[0042] According to some embodiments, the bacteria of the genus Parabacteroides is selected from the group including or consisting of P. distasonis, P. gordosteinii, P. meldae, P. acidifaciens, P. boches-dahonensis, P. chaltae, P. chinchilla, P. conghi, P. faesis, P. gordonii, P. johnsonii, P. massiliensis, P. pacensis, P. provencensis, P. timonensis, Parabacteroides spp., and combinations thereof.

[0043] In some embodiments, the Parabacteroides bacteria is selected from the group consisting of or including P. distasonis, P. gordosteinii, and P. merdae. In some embodiments, the Parabacteroides bacteria is P. distasonis or P. gordosteinii. In some embodiments, the Parabacteroides bacteria is P. gordosteinii. In some embodiments, the Parabacteroides bacteria is P. distasonis. In some embodiments, the Parabacteroides bacteria is P. merdae.

[0044] In fact, bacteria belonging to the genus Parabacteroides can be identified by any suitable procedure or a procedure adapted therefrom. Particularly suitable procedures may include physiological and biochemical methods, such as evaluation of the ability to ferment selected nutrients, such as mannose, raffinose; evaluation of resistance to some antibiotics; evaluation of specific enzyme activities, such as alpha-galactosidase, beta-galactosidase, alpha-glucuronidase, alkaline phosphatase, L-arginine arylamidase, leucine lysine arylamidase, phenylalanine arylamidase; evaluation of intracellular fatty acid profile, menaquinone profile; evaluation of their profiles by matrix-assisted laser desorption / ionization-time of flight mass spectrometry (MALDI-TOF MS); evaluation of their phylogenetic position based on 16S rRNA gene sequence analysis.

[0045] In some embodiments, Parabacteroides bacteria is isolated.In some embodiments, Parabacteroides bacteria is isolated from its natural habitat, such as intestinal microflora.In practice, Parabacteroides bacteria can be isolated from fresh or frozen feces or cecal contents, diluted or undiluted in specific media (including cryoprotectant and / or antioxidant), according to standard and ethical procedures in the field.

[0046] Indeed, bacteria of the genus Parabacteroides may be cultured in any suitable culture medium, such as, for example, Yeast Casitone Fatty Acid (YCFA) (available from Fisher Scientific®), Columbia Blood Medium (Sigma Aldrich®, available from DSMZ®), Strictly Anaerobic Broth (DSMZ®, available from Neogen®), Chopped Meat Medium with Carbohydrates (available from DSMZ®), or a modified YCFA medium in which myo-inositol is replaced by glucose.

[0047] In practice, Parabacteroides bacteria can be cultured at a temperature within the range of about 30° C. to about 42° C., preferably about 35° C. to about 40° C., and more preferably 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.

[0048] Indeed, the cultivation of bacteria of the genus Parabacteroides can be carried out under anaerobic conditions, i.e. in the absence of O2.

[0049] In some embodiments, the compositions of the present invention comprise or consist essentially of a microbiota having Parabacteroides bacteria 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 for Parabacteroides bacteria compared to the microbiota of the individual being treated.

[0050] In some embodiments, the compositions of the invention are enriched for bacteria of the genus Parabacteroides. In one embodiment, the compositions of the invention comprise or consist essentially of a microbiome enriched for bacteria of the genus Parabacteroides.

[0051] In fact, Parabacteroides bacteria can be enriched by preferentially stimulating the growth of Parabacteroides bacteria.For example, enrichment can be performed by modifying the physiological conditions of culture.Examples include, but are not limited to, modifying the composition of culture medium, such as nutrient composition, and modifying culture conditions, such as environmental pH value, temperature and oxygen conditions, and the like.

[0052] In some embodiments, the bacteria of the Parabacteroides genus are isolated and enriched. In some embodiments, the compositions of the invention comprise isolated and enriched bacteria from the Parabacteroides genus.

[0053] In one embodiment, the Parabacteroides bacteria is viable. As used herein, the term "viable" refers to bacteria that can maintain active metabolism and / or grow in a suitable culture medium under suitable culture conditions, including suitable pH, temperature, salinity, nutrient content, and O2 content. In some embodiments, the Parabacteroides bacteria is in a long-lasting exponential growth phase and / or stationary growth phase.

[0054] In one embodiment, the bacteria of the genus Parabacteroides are non-viable.The term "non-viable" as used herein refers to bacteria that cannot maintain active metabolism and / or grow in suitable culture medium under suitable culture conditions, including suitable pH, temperature, salt, nutrient content, O2 content.Examples of non-viable bacteria are dormant bacteria, dead bacteria, and inactive bacteria.

[0055] In fact, cell viability (active metabolism) may be evaluated by measuring the consumption of one nutrient in culture medium over time.Cell viability (growth) may be evaluated by spreading a solution containing at least one bacterium of the present invention on a petri dish and counting the number of colonies after a given incubation time under suitable culture conditions, or bacteria may be grown in liquid medium and growth may be measured by measuring the optical density of bacterial culture after a given incubation time under suitable culture conditions.

[0056] In one embodiment, the Parabacteroides bacteria is pasteurized. In one embodiment, the pasteurized Parabacteroides and / or an extract thereof is heated at a temperature within the range of about 50°C to about 100°C, preferably about 60°C to about 95°C, and more preferably about 70°C to about 90°C.

[0057] In some embodiments, the Parabacteroides bacterium is pasteurized Parabacteroides distasonis, pasteurized Parabacteroides gordosteinii, or pasteurized Parabacteroides merdae. In some embodiments, the Parabacteroides bacterium is pasteurized Parabacteroides gordosteinii. In some embodiments, the Parabacteroides bacterium is pasteurized Parabacteroides distasonis. In some embodiments, the Parabacteroides bacterium is pasteurized Parabacteroides merdae.

[0058] As used herein, the term "extract" encompasses both cellular and extracellular extracts.

[0059] In practice, cell extracts include cytoplasmic extracts, membrane extracts, and combinations thereof, in particular extracts obtained from fractionation methods. Cell extracts can be obtained by any standard chemical (implementation of SDS, proteinase K, lysozyme, combinations thereof, and the like) and / or mechanical (sonication, pressure) fractionation approaches, or approaches adapted therefrom.

[0060] In fact, extracellular extract may include secretory fraction, particularly soluble compounds or exosomes. The term "exosomes" as used herein is intended to refer to endocytosis-derived nanovesicles that contain proteins, nucleic acids, and lipids. In fact, secretory fraction may be isolated and / or purified from culture medium according to any suitable method known in the state of the art, or a method adapted therefrom. By way of example, extracellular extract may be isolated from culture medium by differential centrifugation; by polymer precipitation; by high performance liquid chromatography (HPLC), combinations thereof, and the like.

[0061] A non-limiting example of a method for differential centrifugation from culture medium may include the following steps: - centrifugation at a speed of about 300 x g to about 500 x g for 10 to 20 minutes to remove cells; - centrifugation at a speed of about 1,500 x g to about 3,000 x g for 10 to 20 minutes to remove dead cells; - centrifugation at a speed of about 7,500 x g to about 15,000 x g for 20 to 45 minutes to remove cell debris; - One or more ultracentrifugations at speeds of approximately 100,000 x g to approximately 200,000 x g for 30 to 120 minutes to pellet the exosomes.

[0062] Alternative methods for isolating exosomes may utilize commercially available kits, such as, for example, the exoEasy Maxi Kit (Qiagen®) or the Total Exosome Isolation Kit (Thermo Fisher Scientific®).

[0063] Indeed, cellular and / or extracellular extracts may contain nucleic acids, proteins, carbohydrates, lipids and combinations thereof, such as lipoproteins, glycolipids and glycoproteins, bacterial metabolic products, organic acids, inorganic acids, bases, peptides, enzymes and coenzymes, amino acids, carbohydrates, lipids, glycoproteins, lipoproteins, glycolipids, vitamins, biologically active compounds, metabolic products such as metabolic products containing inorganic components, and the like.

[0064] In some embodiments, cellular and / or extracellular extracts are produced during extended periods of exponential and / or stationary growth.

[0065] In some embodiments, the cell extract comprises succinate. In some embodiments, the metabolite is succinate. Thus, the object of the present invention is a composition comprising succinate for use in preventing and / or treating reward system dysregulation.

[0066] It should be understood that reward system dysregulation according to the present invention can be diagnosed and / or monitored through the assessment of clinical signs with or without the aid of a dedicated questionnaire. In practice, the diagnosis and / or monitoring of reward system dysregulation can be carried out by certified personnel.

[0067] The reward system includes at least three components: an "appetitive" component, an "appetitive" component, and a "learning" component. It should be understood that any one of the three components of the reward system can be dysregulated. In some embodiments, one, two, or all three components are dysregulated.

[0068] As used herein, "dysregulated" means that a component is abnormally "overstimulated" (i.e., activated, hyperactivated, increased, upregulated) or abnormally "understimulated" (i.e., inhibited, weakly activated, decreased, downregulated).

[0069] In one embodiment, one or more components are overstimulated or understimulated. In a particular embodiment, one component is overstimulated or understimulated. In a particular embodiment, two components are overstimulated or understimulated. In a particular embodiment, three components are overstimulated or understimulated.

[0070] In certain embodiments, the wanting component is overstimulated. In certain embodiments, the liking component is overstimulated. In certain embodiments, the wanting component is understimulated. In certain embodiments, the learning component is overstimulated. In certain embodiments, the learning component is understimulated. In certain embodiments, the wanting and wanting components are overstimulated. In certain embodiments, the wanting and wanting components are understimulated. In certain embodiments, the wanting and learning components are overstimulated. In certain embodiments, the wanting and learning components are overstimulated. In certain embodiments, the wanting and learning components are understimulated. In certain embodiments, all three components are overstimulated. In certain embodiments, all three components are understimulated.

[0071] In another embodiment, one or more components are overstimulated and one or more different components are understimulated. In a particular embodiment, one component is overexpressed and two components are understimulated. In a particular embodiment, one component is understimulated and two components are overstimulated. In a particular embodiment, one component is overstimulated and one component is understimulated.

[0072] In certain embodiments, the preference component is understimulated and the wanting component is overstimulated. In certain embodiments, the preference component is overstimulated and the wanting component is understimulated. In certain embodiments, the preference component is understimulated and the learning component is overstimulated. In certain embodiments, the preference component is overstimulated and the learning component is understimulated. In certain embodiments, the wanting component is understimulated and the learning component is overstimulated. In certain embodiments, the wanting component is overstimulated and the learning component is understimulated.

[0073] In certain embodiments, the preference and learning components are understimulated and the wanting component is overstimulated. In certain embodiments, the preference and learning components are overstimulated and the wanting component is understimulated. In certain embodiments, the preference and wanting components are understimulated and the learning component is overstimulated. In certain embodiments, the preference and wanting components are overstimulated and the learning component is understimulated. In certain embodiments, the wanting and learning components are understimulated and the preference component is overstimulated. In certain embodiments, the wanting and learning components are overstimulated and the preference component is understimulated.

[0074] In some embodiments, compositions for use according to the invention restore over-stimulated or under-stimulated components to normal levels. In some embodiments, compositions for use according to the invention reduce at least one over-stimulated component. In some embodiments, compositions for use according to the invention increase at least one under-stimulated component.

[0075] According to certain embodiments, the reward system dysregulation is selected in the group including or consisting of psychiatric disorders, neurological disorders, and combinations thereof.

[0076] In some embodiments, the reward system regulation disorder is a mental disorder.Mental disorder or mental illness, also called mental health disorder, refers to a wide range of mental health conditions, that is, disorders that affect mood, thought and behavior.Examples of mental illness include depression, anxiety disorder, schizophrenia, eating-related disorder, compulsive behavior and addictive behavior.

[0077] According to some embodiments, the psychiatric disorder is selected from the group consisting of or includes addiction-related disorders, eating-related disorders, affective disorders, obsessive-compulsive disorders, schizophrenia, attention-deficit hyperactivity disorder (ADHD), autism spectrum disorders, major depressive disorder (MDD), anxiety disorders, and the like. According to some embodiments, the psychiatric disorder is selected from the group consisting of or includes addiction-related disorders, eating-related disorders, and obsessive-compulsive disorders. According to one embodiment, the psychiatric disorder is selected from the group consisting of or includes addiction-related disorders and eating-related disorders.

[0078] In some embodiments, the psychiatric disorder is an eating-related disorder.

[0079] According to certain embodiments, the eating disorder is selected in the group including or consisting of anorexia nervosa, bulimia, binge eating, overweight-related disorders, obesity-related disorders, and the like.

[0080] As used herein, an individual with an overweight-related disorder has a body mass index (BMI) of about 25.0 to about 29.9, inclusive. As used herein, an individual with an obesity-related disorder has a body mass index (BMI) of greater than about 30.0.

[0081] 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 binge eating. As used herein, "binge eating", also referred to as binge eating disorder, refers to abnormal behaviors involving compulsive food intake, overeating and / or food addiction, and binge eating may be associated with binge eating. In one embodiment, the eating-related disorder is an overweight-related disorder or an obesity-related disorder. In one embodiment, the eating-related disorder is an overweight-related disorder. In one embodiment, the eating-related disorder is an obesity-related disorder.

[0082] It should be understood that subjects suffering from eating-related disorders may experience reduced pleasure when eating due to insufficient stimulation of the appetitive component of reward system and dysregulation of the appetitive component of reward system.Dysregulation of appetitive component may be excessive stimulation or insufficient stimulation, which may result in excessive or insufficient food intake.Dysregulation of appetitive component may be partially involved in disorders such as binge eating and anorexia.

[0083] In some embodiments, the eating-related disorder is associated with dysregulation of the appetitive component of the reward system. In some embodiments, the eating-related disorder is associated with excessive stimulation of the appetitive component of the reward system, preferably the eating-related disorder is associated with excessive stimulation of the appetitive component and insufficient stimulation of the appetitive component of the reward system. In some embodiments, the eating-related disorder is induced by excessive stimulation of the appetitive component of the reward system, preferably the eating-related disorder is induced by excessive stimulation of the appetitive component of the reward system and insufficient stimulation of the appetitive component of the reward system.

[0084] In one embodiment, binge eating is associated with excessive stimulation of the appetitive component of the reward system.

[0085] In some embodiments, the psychiatric disorder is an addiction-related disorder.

[0086] According to some embodiments, the addiction-related disorder is selected from the group including or consisting of alcohol-related addiction, drug-related addiction, tobacco or nicotine addiction, gaming-related addiction, and the like.

[0087] According to some embodiments, the obsessive-compulsive disorder (OCD) is selected in the group including or consisting of checking OCD, contamination OCD, counting OCD, harm OCD, hoarding OCD, perinatal OCD, postpartum OCD, and the like.

[0088] In some embodiments, OCD and an eating-related disorder co-occur. In some embodiments, OCD increases or decreases an individual's appetite for certain types of food or nutrients, where "appetite" reflects the desire and / or appetite components of the individual's reward system.

[0089] In some embodiments, the reward system dysregulation is a neurological disorder.

[0090] According to certain embodiments, the neurological disorder is selected in the group including or consisting of Parkinson's disease, Tourette's syndrome, and the like.

[0091] In some embodiments, the neurological disorder comprises dysregulation of the neurotransmitter dopamine, where "dysregulation" refers to altered signal transduction, altered expression of a dopamine marker, altered levels, altered recycling, or a combination thereof.

[0092] According to some embodiments, the composition is administered to an animal individual, preferably a mammalian individual, more preferably a human individual.

[0093] In one embodiment, the individual is a mammalian individual. In one embodiment, the individual is a human individual. In one embodiment, the individual is male. In one embodiment, the individual is female.

[0094] According to certain embodiments, the compositions are administered orally or rectally.

[0095] In one embodiment, the composition is administered to the gastrointestinal tract. It should be understood that the gastrointestinal 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 microflora of an individual.

[0096] In one embodiment, the composition is a solid composition.Indeed, solid forms adapted for oral administration include, but are not limited to, pills, tablets, capsules, soft gelatin capsules, hard gelatin capsules, dragees, granules, gums, chewing gums, caplets, compressed tablets, cachets, wafers, dragees, dragees, or dispersible / disintegrating tablets, powders, solid forms suitable for solution or suspension in liquid before oral administration, and effervescent tablets.

[0097] In one embodiment, the composition is a liquid composition. Indeed, liquid forms adapted for oral administration include, but are not limited to, solutions, suspensions, drinkable solutions, elixirs, vials, drenches, syrups, liquors, and sprays.

[0098] According to some embodiments, the bacteria is about 1×10 2 CFU / g composition ~ approx. 1×10 12 CFU / g composition, preferably about 1×10 3 CFU / g composition ~ approx. 1×10 11 CFU / g composition, more preferably about 1×10 4 CFU / g composition ~ approx. 1×10 10 In one embodiment, the bacteria is administered in a dose comprising about 1×10 4 CFU / g composition ~ approx. 1×10 11 CFU / g composition, approximately 1×10 5 CFU / g composition ~ approx. 1×10 11 CFU / g composition, approximately 1×10 6 CFU / g composition ~ approx. 1×10 11 CFU / g composition, approximately 1×10 7 CFU / g composition ~ approx. 1×10 11 CFU / g composition, or approximately 1 x 10 8 CFU / g composition ~ approx. 1×10 11 The dose is administered in a volume containing CFU / g of composition.

[0099] As used herein, "CFU" stands for "colony forming unit." As used herein, the term "approximately 1 x 10 2 CFU / g ~ approx. 1 x 1012 CFU / g is 1 x 10 2 , 5×10 2 , 1×10 3 , 5×10 3 , 1×10 4 , 5×10 4 , 1×10 5 , 5×10 5 , 1×10 6 , 5×10 6 , 1×10 7 , 5×10 7 , 1×10 8 , 5×10 8 , 1×10 9 , 5×10 9 , 1×10 10 , 5×10 10 , 1×10 11 , 5×10 11 and 1 × 10 12 Contains CFU / g.

[0100] According to some embodiments, the bacteria is about 1×10 2 cells / g composition ~ approx. 1 x 10 12 The term "about 1 x 10 2 cells / g ~ approx. 1×10 12 Cells / g is 1 x 10 2 , 5×10 2 , 1×10 3 , 5×10 3 , 1×10 4 , 5×10 4 , 1×10 5 , 5×10 5 , 1×10 6 , 5×10 6 , 1×10 7 , 5×10 7 , 1×10 8 , 5×10 8 , 1×10 9 , 5×10 9 , 1×10 10 , 5×10 10 , 1×10 11 , 5×10 11 and 1 × 10 12 Contains cells / g.

[0101] According to some embodiments, when the composition is a solid composition, the bacteria is present in an amount of about 1×10 2 CFU / g composition ~ approx. 1×10 12 CFU / g composition. As used herein, the term "about 1 x 10 2 CFU / g ~ approx. 1 x 10 12 CFU / g is 1 x 10 2 , 5×10 2 , 1×10 3 , 5×10 3 , 1×10 4 , 5×10 4 , 1×10 5 , 5×10 5 , 1×10 6 , 5×10 6 , 1×10 7 , 5×10 7 , 1×10 8 , 5×10 8 , 1×10 9 , 5×10 9 , 1×10 10 , 5×10 10 , 1×10 11 , 5×10 11 and 1 × 10 12 Contains CFU / g.

[0102] According to some embodiments, when the composition is a solid composition, the bacteria is present in an amount of about 1×10 2 cells / g composition ~ approx. 1 x 10 12 The term "about 1 x 10 2 cells / g ~ approx. 1×10 12 Cells / g is 1 x 10 2 , 5×10 2 , 1×10 3 , 5×10 3 , 1×10 4 , 5×10 4 , 1×10 5 , 5×10 5 , 1×10 6 , 5×10 6 , 1×10 7 , 5×10 7 , 1×10 8 , 5×108 , 1×10 9 , 5×10 9 , 1×10 10 , 5×10 10 , 1×10 11 , 5×10 11 and 1 × 10 12 Contains cells / g.

[0103] According to some embodiments, when the composition is a liquid composition, the bacteria is present in a concentration of about 1×10 2 CFU / ml composition ~ approx. 1×10 12 CFU / ml of the composition. 2 CFU / ml ~ approx. 1 x 10 12 CFU / ml is 1 x 10 2 , 5×10 2 , 1×10 3 , 5×10 3 , 1×10 4 , 5×10 4 , 1×10 5 , 5×10 5 , 1×10 6 , 5×10 6 , 1×10 7 , 5×10 7 , 1×10 8 , 5×10 8 , 1×10 9 , 5×10 9 , 1×10 10 , 5×10 10 , 1×10 11 , 5×10 11 and 1 × 10 12 Contains CFU / ml.

[0104] According to some embodiments, when the composition is a liquid composition, the bacteria is present in a concentration of about 1×10 2 cells / ml composition ~ approx. 1 x 10 12 The term "about 1 x 10 2 cells / ml ~ approx. 1×10 12 "cells / ml" is 1 x 10 2 , 5×10 2 , 1×10 3 , 5×103 , 1×10 4 , 5×10 4 , 1×10 5 , 5×10 5 , 1×10 6 , 5×10 6 , 1×10 7 , 5×10 7 , 1×10 8 , 5×10 8 , 1×10 9 , 5×10 9 , 1×10 10 , 5×10 10 , 1×10 11 , 5×10 11 and 1 × 10 12 Contains cells / ml.

[0105] The present invention further relates to a composition comprising the succinate salt for use in the prevention and / or treatment of reward system dysregulation, which has been described herein above.

[0106] In some embodiments, the succinate is produced by a bacterium of the genus Parabacteroides. In some embodiments, the succinate is produced by Parabacteroides distasonis, Parabacteroides gordosteinii, or Parabacteroides meldae.

[0107] In some embodiments, the succinate salt is administered to the subject in a therapeutically effective amount.

[0108] "Therapeutically effective amount" refers to a level or amount that is necessary and sufficient to prevent, slow or stop the progression, worsening or aggravation of one or more symptoms of at least one reward system dysregulation defined herein, or to alleviate at least one symptom of at least one reward system dysregulation, or to cure at least one reward system dysregulation, without causing significant negative or harmful side effects to an individual. In certain embodiments, the effective amount of succinate may be within the range of about 0.001 mg to about 3,000 mg per dosage unit.

[0109] Within the scope of the present invention, about 0.001 mg to about 3,000 mg is about 0.001 mg, 0.002 mg, 0.003 mg, 0.004 mg, 0.005 mg, 0.006 mg, 0.007 mg, 0.008 mg, 0.009 mg, 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.4 mg, 0.6 mg, 0.8 mg, 0.9 mg, 0.1 mg, 0.2 mg, 0.6 mg, 0.8 mg, 0.9 mg, 0.1 mg, 0.2 mg, 0.4 ... g, 0.3mg, 0.4mg, 0.5mg, 0.6mg, 0.7mg, 0.8mg, 0.9mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 20mg, 3 0mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 150mg, 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg, 550m g, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1,000mg, 1,100mg, 1,150mg, 1,200mg, 1,250mg, 1 ,300mg, 1,350mg, 1,400mg, 1,450mg, 1,500mg, 1,550mg, 1,600mg, 1,650mg, 1,700mg, 1,750mg, 1,800mg, 1,850 mg, 1,900mg, 1,950mg, 2,000mg, 2,100mg, 2,150mg, 2,200mg, 2,250mg, 2,300mg, 2,350mg, 2,400mg, 2,450mg, 2,500mg, 2,550mg, 2,600mg, 2,650mg, 2,700mg, 2,750mg, 2,800mg, 2,850mg, 2,900mg, 2,950mg and 3,000mg.

[0110] In certain embodiments, the succinate salt is administered at a dosage level sufficient to deliver from about 0.001 mg / kg to about 100 mg / kg of the subject's body weight per day.

[0111] The present invention further relates to a method for preventing and / or treating a reward system dysregulation, comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising a succinate salt, in certain embodiments, the effective amount of the succinate salt may be in the range of about 0.001 mg to about 3,000 mg per dosage unit.

[0112] The present invention further relates to a composition comprising the succinate salt for use in the manufacture of a medicament for the treatment and / or prevention of reward system dysregulation.

[0113] According to certain embodiments, the compositions of the present invention further comprise one or more additional active agent(s).

[0114] According to certain embodiments, the one or more additional active agent(s) is(are) one or more beneficial microorganism(s). In other words, in one embodiment, the composition further comprises one or more beneficial microorganism(s).

[0115] According to some embodiments, the one or more beneficial microorganism(s) are selected in the group including or consisting of bacteria of the family Clostridiaceae, Peptostreptococcaceae, Prevotellaceae, Methylobacteriaceae, Turicibacter, Coprococcus, Knoellia, Prevotella, Staphylococcus, Akkermansiaceae, and the like.

[0116] According to some embodiments, the one or more beneficial microorganism(s) are selected in the group including or consisting of bacteria of the family Clostridium, Peptostreptococcus, Prevotellaceae, Methylobacterium, Turicibacter, Coprococcus, Noelia, Prevotella, Staphylococcus, and the like.

[0117] According to certain embodiments, the composition is in the form of a pharmaceutical composition further comprising a pharma- ceutically acceptable carrier.

[0118] According to certain embodiments, pharma- ceutically acceptable carriers that may be used in the pharmaceutical compositions according to the present 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, polyvinylpyrrolidone; cellulosic materials (e.g., sodium carboxymethylcellulose), polyethylene glycol; polyacrylates; waxes; polyethylene-polyoxypropylene block polymers; polyethylene glycol; wool fat; and the like; and any combination thereof.

[0119] According to certain embodiments, the composition is in the form of a nutritional composition further comprising a nutritionally acceptable carrier.

[0120] The term "nutritional composition" as used herein is intended to refer to any food product, additive food, supplement food, or fortified food, including liquid 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, dairy drinks, and the like. In practice, solid food products include, but are not limited to, candy bars, cereal bars, energy bars, and the like.

[0121] In some embodiments, the nutritional compositions of the present invention are for non-therapeutic uses or for use in non-therapeutic methods.

[0122] In some embodiments, the present invention relates to a medicament comprising a therapeutically effective amount of one or more isolated bacteria of the genus Parabacteroides and / or an extract thereof for use in preventing and / or treating reward system dysregulation.

[0123] In some embodiments, the compositions, pharmaceutical compositions, nutritional compositions, pharmaceutical devices or medicaments according to the present invention are sterile. In fact, methods for obtaining sterile pharmaceutical compositions include, but are not limited to, GMP synthesis (GMP stands for "Good Manufacturing Practice").

[0124] The present invention also relates to a medical device comprising, consisting of, or consisting essentially of one or more isolated bacteria of the genus Parabacteroides and / or extracts thereof for use in preventing and / or treating reward system dysregulation. In one embodiment, the medical device according to the present invention comprises a therapeutically effective amount of one or more isolated bacteria of the genus Parabacteroides and / or extracts thereof.

[0125] According to certain embodiments, the composition is included in a kit that further comprises a means for administering said composition.

[0126] The present invention also relates to a composition comprising one or more active ingredients or substances that increase the level of Parabacteroides bacteria in the microbiome of an individual in need thereof. As used herein, "increasing the level of Parabacteroides bacteria in the microbiome" refers to increasing the relative abundance of Parabacteroides bacteria in the microbiome of an individual after administration of the composition of the present invention, compared to the relative abundance of Parabacteroides bacteria in the microbiome of the individual before administration of the composition of the present invention.

[0127] The present invention further relates to a method for restoring reward system function in an individual in need thereof. In one embodiment, the method comprises administering a composition comprising one or more active ingredients or substances that increase the level of Parabacteroides bacteria in microbiota. In a particular embodiment, the method comprises administering a composition comprising one or more bacteria of Parabacteroides and / or its extract. In another embodiment, the method comprises administering a composition comprising succinate. In one embodiment, the method is non-therapeutic.

[0128] The present invention further relates to a method for restoring the microbiota of an individual in need thereof.In one embodiment, the method comprises administering a composition comprising one or more active ingredients or substances that increase the level of Parabacteroides bacteria in the microbiota.In a particular embodiment, the method comprises administering a composition comprising one or more bacteria of Parabacteroides and / or its extract.In one embodiment, the method is non-therapeutic.

[0129] The present invention further relates to a method for increasing the level of Parabacteroides in the microbiome of an individual in need thereof.In one embodiment, the method comprises administering a composition comprising one or more active ingredients or substances that increase the level of Parabacteroides bacteria in the microbiome.In a particular embodiment, the method comprises administering a composition comprising one or more bacteria of the Parabacteroides genus and / or an extract thereof.In one embodiment, the method is non-therapeutic.

[0130] The present invention also relates to a method for reducing reward feeding in an individual in need thereof. In one embodiment, the method comprises administering a composition comprising one or more active ingredients or substances that increase the level of Parabacteroides bacteria in the microbiota. In a particular embodiment, the method comprises administering a composition comprising one or more bacteria of the Parabacteroides genus and / or an extract thereof. In another embodiment, the method comprises administering a composition comprising succinate. In one embodiment, the method is non-therapeutic. In some embodiments, the method reduces the intake of palatable food. In some embodiments, the method does not reduce the intake of palatable food.

[0131] The present invention further relates to a method for reducing the intake of palatable food in an individual in need thereof. In one embodiment, the method comprises administering 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 administering a composition comprising one or more bacteria of the genus Parabacteroides and / or an extract thereof. In another embodiment, the method comprises administering a composition comprising succinate. In one embodiment, the method is non-therapeutic.

[0132] The present invention further relates to a method of modulating reward system function in an individual in need thereof, comprising administering to the individual a composition comprising one or more bacteria of the genus Parabacteroides and / or an extract thereof.

[0133] As used herein, "modulating reward system function" means increasing or decreasing the activity of at least one of the three components of the reward system (i.e., preference, desire, and learning), thereby restoring at least one component to normal levels. In some embodiments, one component is modulated. In some embodiments, two components are modulated. In some embodiments, three components are modulated.

[0134] In some embodiments, the method is for modulating a desire component. In some embodiments, the method is for increasing or decreasing a desire component. In a preferred embodiment, the method is for decreasing a desire component. In another embodiment, the method is for increasing a desire component.

[0135] In some embodiments, the method is for modulating the palatable component. In some embodiments, the method is for increasing or decreasing the palatable component. In a preferred embodiment, the method is for increasing the palatable component. In another embodiment, the method is for decreasing the palatable component.

[0136] In some embodiments, the method is for modulating the learning component. In some embodiments, the method is for increasing or decreasing the learning component. In one embodiment, the method is for decreasing the learning component. In another embodiment, the method is for increasing the learning component.

[0137] Another object of the present invention is a method as described hereinbefore, comprising administering to an individual a composition comprising the succinate salt. [Brief description of the drawings]

[0138] [Figure 1A-F]Figure 1A-C are a series of graphs showing that obese mice exhibit reduced food preference for high fat, high sucrose (HFHS) compared to lean mice. (Figure 1A) Weight change (grams) and (Figure 1B) Final weight (grams) after 5 weeks for lean donor mice (Lean_do; squares) and DIO donor mice (DIO_do; triangles). (Figure 1C) Fat mass gain change (grams) and (Figure 1D) Final fat mass gain (grams) for lean donor mice (Lean_do; squares) and DIO donor mice (DIO_do; triangles). (Figure 1E) Food preference test showing HFHS and CT intake during the 180 min test by lean donor mice (Lean_do; squares) and DIO donor mice (DIO_do; triangles). (Figure 1F) Food preference test showing total HFHS and CT intake from Figure 1E. 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) and unpaired Student's t-test (Fig. 1B,D). *: p-value ≤ 0.05; **: p-value ≤ 0.01; ***: p-value ≤ 0.001; ****: p-value ≤ 0.0001. $$$$: p-value ≤ 0.0001 CT intake vs. HFHS intake. Different superscripts represent significant p-values ​​between groups and diet types (CT or HFHS) at each time point (Fig. 1F). [Figure 2A-G]Figures 2A-G are a series of graphs showing that recipient mice exhibit similar hedonic eating behavior to donor mice after fecal transplantation. (Figure 2A) Experimental design of the FMT protocol. (Figure 2B) Body weight variation (grams) and (Figure 2C) Final body weight (grams) of lean recipient mice (Lean_rec; squares) and DIO recipient mice (DIO_rec; triangles). (Figure 2D) Body fat mass gain variation (grams) and (Figure 2E) Final body fat mass gain (grams) of lean recipient mice (Lean_rec; squares) and DIO recipient mice (DIO_rec; triangles). (Figure 2F) Food preference test showing total HFHS and CT intake after 180 min of the test by lean recipient mice (Lean_rec) and DIO recipient mice (DIO_rec). Data are presented as mean ± SEM (n=7-8 / group). (Fig. 2G) Food preference test showing HFHS (curves 3 and 4) and CT (curves 1 and 2) intakes for 180 min by lean recipient mice (Lean_rec; curves 1 and 3) and DIO recipient mice (DIO_rec; curves 2 and 4). p values ​​were obtained after two-way ANOVA followed by Bonferroni post-hoc test (Fig. 2B,D,F,G) or unpaired Student's t-test (Fig. 2C,E). *: p value ≤ 0.05; **: p value ≤ 0.01; $$: p value < 0.01; $$$$: p value ≤ 0.0001 CT intake vs. HFHS intake (Fig. 2F). [Figure 3A-D] Figure 3A-D are a series of graphs showing changes in dopaminergic signaling in recipient mice by obese gut microbiota. Striatal mRNA expression of dopamine receptor 1 (D1R) (Figure 3A), dopamine receptor 2 (D2R) (Figure 3B), tyrosine hydroxylase (TH) (Figure 3C) and dopamine transporter (DAT) (Figure 3D) measured by real-time qPCR in lean recipient mice (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 (Figure 3C) or nonparametric Mann-Whitney test (Figure 3A,B,D). [Figure 4A-F]Figure 4A-F are a series of graphs showing that the gut microbiota of recipient mice is similar to that from donor mice. (Figure 4A-D) Venn diagram based on OUT similarity between donor mice (Lean_do and DIO_do) and recipient mice (Lean_rec and DIO_rec). (Figure 4E-F) Principal coordinate analysis (PCoA) based on unweighted UniFrac analysis on operational taxonomic units (OTUs); (Figure 4E) PCoA PC1 vs. PC2; (Figure 4F) PCoA PC3 vs. PC2; ▽ (right-facing triangle): Lean_do; ■: Lean_rec; ●: DIO_do; △: DIO_rec. [Diagram 5] Figure 5 is a graph showing the correlation between gut microbes and dopaminergic markers. Spearman correlation after FDR correction. p-values ​​were obtained after Spearman correlation test. *: p≦0.05. [Figure 6A-B] Figure 6A-6B are a series of histograms showing that the dopaminergic and opioid systems of gut microbiota recipient mice from obese donors are insufficiently stimulated. Nucleus accumbens mRNA expression of (Figure 6A) dopamine receptor 2 (Drd2), dopamine receptor 1 (Drd1), tyrosine hydroxylase (Th), dopamine transporter (Dat), (Figure 6B) μ-opioid receptor (Oprm), κ-opioid receptor (Oprk), δ-opioid receptor (Oprd) and preprodynorphin (Pdyn) measured by qPCR in gut microbiota recipient mice from lean donor mice (Lean_rec) and in gut microbiota recipient mice from diet-induced obese donor mice (DIO_rec). Data are shown as mean ± SEM (n=6 / group). p-values ​​were obtained after unpaired Student's t-samples or nonparametric Mann-Whitney test. *: p-value ≤ 0.05. [Figure 7A-B]7A-7B are a series of histograms showing that obese mice exhibit altered learning components of the food reward system that are in part shifted by the gut microbiota. FIG. 7A shows the conditioned place preference preference score based on the difference in time spent (seconds) on the palatable food-associated side of the cage versus the neutral-associated side during pre-testing and testing by lean donor mice (Lean_do) or diet-induced obese donor mice (DIO_do). FIG. 7B shows the conditioned place preference preference score based on the difference in time spent (seconds) on the palatable food-associated side of the cage versus the neutral-associated side during pre-testing and testing by gut microbiota recipient mice from lean donor mice (Lean_rec) and gut microbiota recipient mice from diet-induced obese donor mice (DIO_rec). Data are shown as mean ± SEM (n=6 / group). p values ​​were obtained after paired Student's t-test. *: p-value ≦ 0.05 Preference scores during the test versus the pre-test. [Figure 8A-D] Figures 8A-8D are a series of graphs showing that gut microbes from obese donors lead to excessive motivation for the food reward system. Operant conditioning test showing (Figure 8A) active lever presses and (Figure 8B) pellets obtained during a progressive ratio session (PR) by lean donor mice (Lean_do) and diet-induced obese donor mice (DIO_do). Operant conditioning test showing (Figure 8C) active lever presses and (Figure 8D) pellets obtained during a progressive ratio session (PR) by gut microbiota recipient mice from lean donors (Lean_rec) and gut microbiota recipient mice from obese donors (DIO_rec). Data are shown as mean ± SEM (n=6 / group). p values ​​were obtained after unpaired Student's t-test. *: p value ≤ 0.05; **: p value ≤ 0.01; ***: p value ≤ 0.001; ****: p value ≤ 0.0001. [Figure 9A-E]Figures 9A-9E are a series of histograms showing that homeostatic regulators of food intake are similar between recipient mice. Plasma concentrations of (Figure 9A) ghrelin, (Figure 9B) insulin, (Figure 9C) leptin, (Figure 9D) glucagon-like peptide 1 (GLP-1), and (Figure 9E) peptide YY (PYY) in gut microbiota recipient mice from lean donors (Lean_rec) and gut microbiota recipient mice from obese donors (DIO_rec). Data are shown as mean ± SEM (n = 7-8 / group). p values ​​were obtained after unpaired Student's t-test or nonparametric Mann-Whitney test, separately between lean and obese (DIO) donor mice and between lean and obese (DIO) recipient mice. **: p value ≤ 0.01; ***: p value ≤ 0.001. [Figure 10] Figure 10 is a histogram showing that Parabacteroides distasonis reduces fat mass gain under HFD. Fat mass in ND PBS, ND PD, HFD PBS, and HFD PD after 8 weeks. Data are shown as mean ± SEM (n=9-10 / group). P values ​​were obtained after one-way ANOVA followed by Tukey post-hoc test. **: P<0.01; ****: P<0.0001. [Figure 11] Figure 11 is a histogram showing the effect of Parabacteroides distasonis on the palatable component of the food reward system during the food preference test. Food preference test showing total HFHS and CT intake after 3 h of testing by ND PBS, ND PD, HFD PBS, HFD PD mice. Data are presented as mean ± SEM (n = 5–6 / group). P values ​​were obtained after Mann-Whitney test. **: P < 0.01 CT vs. HFHS in the ND PBS group, and *: P < 0.05 CT vs. HFHS in the ND PD group. [Figure 12]Figure 12 is a graph showing that Parabacteroides distasonis reduces motivation to obtain food reward in normal chow-fed mice. Operant wall test showing active lever presses to obtain sucrose pellets in ND PBS, ND PD, HFD PBS, and HFD PD. Data are presented as mean ± SEM (n=6 / group). P values ​​were obtained after two-way repeated measures ANOVA followed by Bonferroni post-hoc test. ****: P<0.001 ND PBS vs. HFD PBS; +P<0.05; ++++P<0.001 ND PBS vs. ND PD. [Figure 13A-B] Figures 13A-13B are a series of histograms showing the effect of Parabacteroides gordosteinii on body weight gain and fat mass under HFD. Body weight gain (Figure 13A) and fat mass (Figure 13B) after 5 weeks in ND PBS, ND PG, HFD PBS, and HFD PG. Data are presented as mean ± SEM (n=20 / group. These data correspond to the results of two independent experiments). P values ​​were obtained after one-way ANOVA followed by Tukey post-hoc test. *: P<0.05; **: P<0.01; ***: P<0.001; ****: P<0.0001. [Figure 14] Figure 14: Histograms showing the effect of Parabacteroides gordosteinii on the palatable component of the food reward system during the food preference test. Food preference test showing total HFHS and CT intake after a 3-h session by ND PBS, ND PG, HFD PBS and HFD PG mice. Data are presented as mean ± SEM (n = 10–12 / group. These data correspond to the results of two independent experiments). P values ​​were obtained after two-way ANOVA followed by Bonferroni post-hoc test. *: P<0.05; **: P<0.01; ***: P<0.001. [Figure 15]Figure 15 is a graph showing that Parabacteroides gordosteinii reduces motivation to obtain food reward in normal chow-fed mice. Operant wall test showing the number of active lever presses to obtain sucrose pellets in ND PBS, ND PG, HFD PBS, and HFD PG mice. Data are presented as mean ± SEM (n = 11–12 per group. These data correspond to the results of two independent experiments). P values ​​were obtained after two-way repeated measures ANOVA followed by Bonferroni post-hoc test. **: P<0.01; ***: P<0.001 ND PBS vs. HFD PBS; + P<0.05; +++ P<0.001 ND PBS vs. ND PG; £ P<0.05; ££ P<0.01; £££ P<0.001 ND PBS vs. HFD PG. [Figure 16] Figure 16 is a histogram showing that Parabacteroides gordosteinii induces strong positive reinforcement in the learning component of the food reward system. Conditioned place preference test showing CPP scores in ND PBS, ND PG, HFD PBS, and HFD PG mice. Data are presented as mean ± SEM (n = 11-12 / group. These data correspond to the results of two independent experiments). P values ​​were obtained after two-tailed paired t-test. * P < 0.05; ** P < 0.01; *** P < 0.001; **** P < 0.0001 pretest vs test; P values ​​were obtained after one-way ANOVA followed by Tukey's coincidence test. $ P < 0.05 HFD PG test vs HFD PBS test. [Figure 17A-B] Figures 17A-17B are a series of graphs showing that succinate has a beneficial effect on the obese phenotype. Body weight (Figure 17A) and fat mass (Figure 17B) for ND PBS, ND PD, HFD PBS, and HFD PD after 5 weeks. Data are presented as mean ± SEM (n=10 / group). P values ​​were obtained after two-way repeated measures ANOVA followed by Bonferroni post-hoc test. £P<0.05; £££P<0.001 ND vs. HFD; *P<0.05; **P<0.01; ****P<0.0001 HFD vs. HFD SUC; $P<0.05 ND vs. ND SUC. [Figure 18] Figure 18 is a histogram showing that succinate improves the palatable component of the food reward system altered during HFD-induced obesity. Food preference test showing total HFHS and CT intake after a 3-h session in ND, HFD, ND SUCC and HFD SUCC mice. Data are presented as mean ± SEM (n = 5-6 per group). P values ​​were obtained after two-way ANOVA followed by Bonferroni post-hoc test. *: P<0.05; **: P<0.01; ***: P<0.001; ***: P<0.0001 CT vs. HFHS, +P<0.05 HFD SUC HFHS vs. ND SUC HFHS; ++ P<0.01 HFD SUC HFHS vs. ND HFHS; ++++ P<0.0001 HFD SUC HFHS vs. HFD HFHS. [Figure 19] Figure 19 is a graph showing that succinate reverses the reward system component «wanting» in obese mice and reduces motivation to obtain food reward in normal-fed mice. Operant wall test showing the number of active lever presses to obtain sucrose pellets in ND, HFD, ND SUC, HFD SUC mice. Data are shown as mean ± SEM (n = 6 / group). P values ​​were obtained after two-way repeated measures ANOVA followed by Bonferroni post-hoc test (£P<0.05; ££P<0.01; £££P<0.001 ND vs. HFD) and unpaired t-test for PR individual analysis (*P<0.05 HFD SUC vs. HFD; $P<0.05 ND SUC vs. ND). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0139] Working Example The invention is further illustrated by the following examples.

[0140] Example 1: material and method 1. Mice and Experimental Design 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 were carried out according to the guidelines of the local ethical committee and in accordance with the Belgian law of 29 May 2013 for the protection of laboratory animals (agreement number LA1230314).

[0141] 2. Donor Mice A cohort of 8-week-old specific opportunistic pathogen and specific pathogen-free (SOPF) male C57BL / 6J mice (10 mice, n=5 / group) (Janvier laboratories®, France) was housed in a controlled environment (room temperature of 22±2°C, 12-h light / dark cycle) in groups of 2 mice per cage with free access to sterile food (irradiated) and sterile water. Upon delivery, the mice were subjected to a 1-week acclimation period during which they were fed a control diet (CT, AIN93Mi, Research Diet, New Brunswick, NJ, USA). They were then randomized into 2 groups and fed a control low-fat diet (CT, AIN93Mi) or a high-fat diet (HFD, 60% fat and 20% carbohydrate (kcal / 100g) D12492i, Research diet, New Brunswick, NJ, USA) for 5 weeks. Body weight, food intake, and water intake were recorded once a week. Body composition was assessed by utilizing a 7.5MHz time-domain nuclear magnetic resonance (TD-NMR, LF50 Minispec, Bruker®, Rheinstetten, Germany). After 4 weeks of observation, the mice were placed in a metabolic chamber and a food preference test was performed.

[0142] 3. Recipient Mice A cohort of 3-week-old specific opportunistic pathogen and specific pathogen-free (SOPF) male C57BL / 6J mice (15 mice, n=7-8 / group) (Janvier laboratories®, France) was housed in a controlled environment (room temperature of 22±2°C, 12-h light / dark cycle) in groups of 2 mice per cage with ad libitum access to sterile food (irradiated) and sterile water. Mice were fed a low-fat control diet (CT, AIN93Mi) during the entire transplantation protocol and after gut microbiota transplantation. Body weight, food intake, and water intake were recorded weekly. Body composition was assessed by utilizing a 7.5 MHz, time-domain nuclear magnetic resonance (TD-NMR, LF50 Minispec, Bruker®, Rheinstetten, Germany). After 12 weeks of follow-up, mice were placed in a metabolic chamber for a detailed assessment of food intake and metabolism, followed by a food preference test.

[0143] 4. Fecal microbiota transplantation At the end of the donor experiment, the cecal contents were collected in a sterile container and immediately diluted (1:50 w / vol) with sterile Ringer's buffer (4.5 g NaCl, 200 mg KCl, 125 mg CaCl2). The suspension was diluted (1:1 v / v) with 20% (w / v) skim milk (Nonfat dry milk, Biorad®, 2005668A) and then stored at -80°C. Two CT-fed and two HFD-fed mice from the donor cohort were selected as fecal microbiota donors for 7 or 8 recipient mice per group, with one donor per 3 or 4 recipient mice, respectively. Prior to intestinal microbiota inoculation, the intestinal microbiota of 3-week-old SOPF recipient mice was depleted by daily oral gavage for 5 days of a broad-spectrum poorly absorbed antibiotic mix (100 mg / kg ampicillin, neomycin and metronidazole, and 50 mg / kg vancomycin, diluted in sterile water) supplemented with an antifungal drug (amphotericin B 1 mg / kg). Antibiotic treatment was then followed by intestinal lavage by administration of 600 μl of PEG solution (PEG / Macrogol 4000, Colofort®, Ipsen, France) by oral gavage twice at 30 min intervals after a 2-h fast. Engraftment was then obtained by intragastric gavage of 300 μl inoculum three times a week for 1 week. During antibiotic treatment and inoculation, mice were transferred to clean cages four times a week. All recipient mice were fed a CT diet (CT, AIN93Mi).

[0144] 5. Metabolic Chamber After 11 weeks of observation, the recipient mice were housed separately for 1 week and then placed in metabolic chambers (Labmaster, TSE systems GmbH, Bad Homburg, Germany). The mice were then subjected to a 4-day metabolic evaluation followed by a food preference test. The mice were analyzed for oxygen consumption and carbon dioxide production by indirect calorimetry (Labmaster, TSE systems GmbH). These parameters were expressed as a function of total body weight. Locomotor activity was recorded (expressed as beam break counts per hour) using an infrared beam-based locomotor monitoring system. Sensors recorded the precise intake of each meal every 15 min. Measurements were performed inside the chamber every 15 min. The final data presentation (total, day or night) corresponds to all the measured and summed values ​​(light or dark phase). Mean values ​​(n=7) were finally compared between groups.

[0145] 6. Food Preference Test During a 3-h daytime period, mice were exposed to two diets in metabolic chambers (Labmaster / Phenomaster, TSE systems, Germany): a low-fat, control normal diet (CT, AIN93Mi, Research Diet, New Brunswick, NJ, USA) or a high-fat, high-sucrose sample (HFHS, 45% fat and 27.8% sucrose (kcal / 100g) D17110301i, Research diet, New Brunswick, NJ, USA). Sensors recorded precise food intake for each meal every 15 min.

[0146] 7. Tissue collection At the end of each experiment, mice were fed and exposed to HFHS for 1 h before anesthetization with isoflurane (Forene®, Abbott, UK). This aims to mimic the conditions of food preference testing and mimic the dopaminergic food reward system. Mice were then euthanized by exsanguination and cervical dislocation. The striatum, nucleus accumbens, prefrontal cortex and caudate-putamen were precisely dissected and the cecal contents were collected and immediately immersed in liquid nitrogen, then stored at -80°C for further analysis.

[0147] 8. RNA Preparation and Real-time qPCR Analysis Total RNA was prepared from striatum using TriPure reagent (Roche®). Total RNA quantification and integrity analysis was performed by running 2 μl of each sample on an Agilent® 2100 Bioanalyzer (Agilent® RNA 6000 Nano Kit, Agilent). Samples were excluded from further analysis if the resulting RNA integrity number (RIN) was less than 6. cDNA was prepared by reverse transcription of 1 μg of total RNA using the GoScript® Reverse Transcriptase kit (Promega®, Madison, WI, USA). Real-time PCR was performed on a QuantStudio 3 Real-Time PCR System (Thermo Fisher Scientific®, Waltham, MA, USA). Rpl19 RNA was selected as a housekeeping gene. All samples were performed in duplicate and data were analyzed according to the 2-ΔΔCT method. The identity and purity of the amplified products were assessed by melting curve analysis at the end of the amplification. The sequences of the primers used for real-time qPCR are available in Table 1. [Table 1]

[0148] 9. DNA Isolation and Sequencing from Mouse Cecal Samples Cecal contents were collected and stored frozen at -80°C until use. Metagenomic DNA was extracted from cecal contents using the QIAamp® DNA Stool Mini Kit (Qiagen®, Hilden, Germany) according to modified manufacturer's instructions (see Everard et al., ISME J 2014; 8:2116-30). The V1-V3 regions of the 16S rRNA gene were amplified from mouse cecal microbiota 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 using MiSeq® according to 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 (v1.9 with 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 OUTs 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 average number of sequences per sample was 63,7392 ± 10,798 (standard deviation). The Q25 sequence data obtained from the sequencing process was analyzed with the QIIME 1.9 pipeline. Briefly, the barcodes and primers of the sequences were removed. We then removed 1000bp of sequences, and also removed sequences with ambiguous base calls and homoprimer runs >6bp. Sequences were denoised to create operational taxonomic units (OTUs). Chimeras were also removed. OTUs were defined by clustering at 3% diversity (97% similarity). Final OTUs were taxonomically classified using BLASTn against a curated Greengenes database.Using the unweighted UniFrac distance matrix between samples, PCoA was generated in QIIME as previously described. Data are available upon request.

[0149] 10.Statistical analysis Statistical analysis was performed using GraphPad Prism® version 8.1.2 for Windows (GraphPad® Software, San Diego, CA, USA), except for the microbiota analysis described previously. Data are expressed as mean ± SEM. Differences between two groups were evaluated using unpaired Student's t-test. If there were differences that were significantly different between groups according to Fisher's test, a nonparametric (Mann-Whitney) test was performed. Differences between more than two groups were evaluated using one-way ANOVA or two-way ANOVA if repeated measures, followed by Tukey or Bonferroni post-hoc tests, respectively. If there were differences where the variances were significantly different between groups, a nonparametric Kruskal-Wallis test followed by Dunnett's post-hoc test was performed.

[0150] 11. Conditioned place preference test The learning component of the food reward system was evaluated in donor and recipient mice by the conditioned place preference (CPP) test, which was performed at the end of the light phase in a biased apparatus (Phenotyper chambers, Noldus, The Netherlands) as previously described. The behavioral observation cage is separated into two compartments, characterized by a smooth or rough floor and black or striped walls. All compartments were thoroughly cleaned before and after each session. Each session (pre-test, training, test) lasted exactly 30 min. Locomotor activity was recorded with an infrared camera monitoring system and analyzed with the provided software (EthoVision XT 14). On day 1, a pre-test was utilized to determine the baseline less preferred compartment (the compartment in which the mouse spent less time spontaneously), which was defined as the reward-associated compartment (biased CPP method). On days 2-9, donor and recipient mice received 8 training sessions (4 sessions in each compartment) with or without reward stimuli (Reese's®) in the least and most preferred compartments, respectively. During testing, mice were allowed to run freely (no reward stimuli) in each compartment of the cage, and the time spent in each compartment was recorded (EthoVision XT14). Preference scores were based on the difference between the time(s) spent in the palatable food-associated side versus the time spent in the neutral-associated side of the cage during pre-testing and testing.

[0151] 12. Operant Wall Test The appetitive component translates into motivation to obtain the reward system, which is assessed by the operant wall test in donor and recipient mice as previously described. Each test session was performed at the end of the light phase in operant conditioning chambers (Phenotyper chambers, Noldus, The Netherlands) and analyzed with the provided software (Ethovision XT 14). Briefly, mice intermittently approached the operant wall in their home cage. The operant wall system consists of two levers, two lights, and a pellet dispenser. One lever was arbitrarily designated as active, meaning that pressing this lever initiates the delivery of sucrose pellets (5-TUT peanut butter flavored sucrose pellets, TestDiet, St. Louis, MO) and is associated with the light on. Meanwhile, the other lever, associated with the light off, was arbitrarily designated as inactive and never delivers a reward. Mice were trained twice overnight on the system with a FR schedule (one lever press corresponds to one reward) followed by two 1 h 30 min sessions. Mice were then transferred to a PR session (2 h) in which the number of lever presses to obtain a reward was gradually increased with each pellet (n+3). Mice that did not press the active lever during different sessions were excluded.

[0152] 13. Other Stimuli For example, food and different rewarding stimuli such as alcohol or drugs may be used.

[0153] result 1. DIO donor mice show alterations in hedonic feeding Initially, 10 donor mice were exposed to a low-fat diet (control, CT) or a high-fat diet (HFD) for 5 weeks to induce a lean or obese phenotype (diet-induced obesity, DIO), respectively. As expected, HFD-fed mice showed a 12% increase in body weight (Figure 1A-B) and a 230% increase in fat mass gain (Figure 1C-D) compared to CT-fed mice. We then analyzed the hedonic sensations associated with palatable food consumption in these mice to test the hedonic component of feeding.

[0154] To assess natural hedonic food intake, donor mice were subjected to a food preference test in which they were exposed to a palatable diet (high-fat high-sucrose, HFHS) for the first time. During this food preference test, donor mice were exposed to a HFHS diet and a low-fat control diet (CT) for 3 h during the light phase, and the consumption of each diet was recorded (Figure 1E and Figure 1F). Both lean and obese mice consumed more HFHS than CT during the food preference test, and therefore preferred the HFHS diet to CT. However, lean mice consumed significantly more HFHS than CT from the start of the test, whereas DIO mice significantly preferred the palatable diet to the control diet after only 90 min, and thus lean mice showed a more rapid tropism to HFHS (Figure 1E). Overall, DIO found the palatable diet less attractive, consuming 58% less (p<0.0001) HFHS than lean mice in the entire food preference test (Figure 1F).

[0155] 2. Gut microbiota transplantation in obese mice reverses obesity-related hedonic eating disorders To test the causal role of gut microbes in obesity-associated hedonic eating disorder, gut microbiota from two lean and two obese mice were transplanted into seven and eight recipient mice, respectively. All recipient mice received the same low-fat control diet during the entire experiment (Figure 2A).

[0156] Lean and obese gut microbiota recipient mice (Lean_rec and DIO_rec, respectively) did not show any differences in terms of body weight (Figure 2B-C) and fat mass gain (Figure 2D-E). However, DIO gut microbiota recipient mice tended to gain more fat mass over time, with statistical significance on day 64 (Figure 2D). To investigate the energy metabolism of lean and obese gut microbiota recipient mice, we also performed precise measurements of O2 consumption and CO2 production in metabolic chambers. We did not observe any differences between mice that received obese or lean gut microbiota. These results suggest that donor mice do not transfer their obese phenotype to recipient mice in terms of fat mass and body weight after fecal transplantation.

[0157] Interestingly, during the entire follow-up, the recipient mice of lean and obese gut microbiota had similar control diet intake. However, differences in HFHS intake became evident during the first exposure to palatable food (i.e., food preference test) (Figure 2F and Figure 2G). The recipient mice of lean gut microbiota exhibited a more rapid HFHS preference than the recipient mice of DIO gut microbiota. Indeed, the recipient mice of lean gut microbiota ingested significantly more HFHS than the CT samples 90 min after the test, whereas the difference between HFHS intake and CT intake in the recipient mice of DIO gut microbiota was significant only after 150 and 180 min (Figure 2G). Similar to the donor mice, the two recipient mice groups showed a preference for the palatable diet over the CT samples. Strikingly, total HFHS intake was 40% lower 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 showed similar patterns of hedonic feeding behavior to their respective microbiota donors, and this effect is independent of obesity development or non-hedonic feeding behavior. Of note, ambulatory activity during testing was comparable between recipient mice, suggesting similar exploratory behavior toward this novel food high in sugar and fat content. In summary, the causal role of the gut microbiota in obesity-associated alterations in hedonic feeding behavior was not elucidated.

[0158] 3. Dopaminergic markers in the striatum suggest impaired function of the food reward system in DIO recipient mice The pleasant sensations associated with palatable food intake are driven primarily by mesocortical dopaminergic pathways. In fact, it has been shown that the intake of a diet rich in fat and sugar is associated with a dopamine release in the dorsal striatum that is proportional to the self-reported level of pleasant sensations derived from ingesting the food. Dopamine receptors 1 and 2 (D1R and D2R) are the most highly 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 is associated accordingly with a reduction in the pleasant sensations associated with palatable food intake. Since transplantation of obese gut microbiota reproduces the food preference changes associated with obesity (Figure 2F), the question arose as to whether this is associated with the modification of dopaminergic markers. Therefore, the expression of dopaminergic markers in the striatum of recipient mice was investigated by qPCR.

[0159] Results show that after microbiota transplantation, DIO recipient mice express at least 60% lower Drd1 and drd2 in the striatum compared to lean recipient mice, which failed to meet the statistical threshold due to high variation in the Lean_rec group (p<0.05, Figure 3A-B). Expression of tyrosine hydroxylase (TH), the rate-limiting enzyme synthesizing dopamine, was also reduced (50%) in mice receiving obese microbiota compared to mice receiving lean microbiota (p<0.05, Figure 3C). Consistent with these results, dopamine transporter (DAT), responsible for the recapture of around 80% of released dopamine, was expressed twice as much in DIO_rec compared to Lean_rec (p>0.05, Figure 3D), suggesting a lower function of the dopaminergic system in mice transplanted with obese gut microbiota. Of note, altered expression of dopaminergic markers was not associated with changes in locomotor activity, suggesting that the qPCR results observed in the striatum are specific to the reward system rather than motor functions.

[0160] Besides the dopaminergic system in the striatum, other brain regions such as the caudate-putamen, nucleus accumbens and prefrontal cortex are involved in the food reward system. Therefore, we further investigated and analyzed the mRNA levels of dopaminergic markers in these regions (Table 2). [Table 2]

[0161] No differences were observed between mice receiving lean and obese gut microbiota in the prefrontal cortex and caudate-putamen, but results tend to indicate a slight modulation of dopaminergic marker expression in the nucleus accumbens.

[0162] To confirm these results, another series of experiments was performed, this time using mice that were maintained under calorie-restricted conditions during the study. The expression of dopaminergic and opioid markers in the nucleus accumbens (NAc) of gut microbe recipient mice from lean and obese donors was examined (Figure 6A-B). A significant decrease in the expression of dopamine receptor 2 (Drd2), as well as tyrosine hydroxylase (Th), a dopamine synthesis enzyme, was found in the NAc of mouse recipients of gut microbes from obese donors compared to mouse recipients of gut microbes from lean donors. Dopamine receptor 1 (Drd1) and dopamine transporter (Dat) tended to be reduced in mice transplanted with prepared microbiota from obese mice compared to mice transplanted with gut microbiota from lean mice (Figure 6A).

[0163] As the opioid system is also involved in the food reward system and has been shown to be blunted in obese states, we measured the expression of several key markers and found that DIO_rec had a significant reduction in NAc expression of μ-opioid receptors (Oprm) with a similar trend for reduction of κ-opioid receptors (Oprk, p=0.05) and the precursor of dynorphin (Pdyn, preprodynorphin, p=0.06, Figure 6B). Expression of δ-opioid receptors (Oprd) did not differ between Lean_rec and DIO_rec (Figure 6B).

[0164] 4. Fecal material transplantation from obese donors to lean recipient mice is efficient To verify the efficiency of gut microbiota transplantation, the bacterial composition of cecal contents from donor and recipient mice was analyzed utilizing 16S rRNA sequencing. The common OTUs (operational taxonomic units) of donors and recipients were compared at the end of each experiment immediately after the food preference test (Figure 4A-D). Two mice from each donor group (CT-fed or HFD-fed) were donors for seven Lean_rec recipient mice and eight DIO_rec recipient mice, respectively, resulting in one donor mouse for every three or four recipient mice. Venn diagrams showed high similarity of OTUs (>50%) between donors and recipients, confirming that gut microbiota from donors engrafted in antibiotic-treated recipients (Figure 4A-D).

[0165] Furthermore, as represented by PCoA, obese donor and obese gut recipient mice have gut microbiota profiles that differ from lean donor and lean gut microbiota recipient mice according to the basal component PC2 (Figure 4E-F).

[0166] 5. Parabacteroides represents a potential link in the gut-brain axis regulating hedonic food intake As a preliminary approach to highlight the potential link between the gut microbiota and the food reward system in the context of obesity, the association between multiple parameters of the food reward system and multiple parameters of the gut microbiota was established using Spearman's correlation coefficient. Data from donor and recipient mice were combined to create a correlation matrix. The table showed that 18 OUTs correlated with the total HFHS intake measured during the food preference test (Table 3). In addition, a positive correlation was found between an unidentified genus of the Peptococcus family and the mRNA expression of D1R, D2R and TH (Table 3). [Table 3] TIFF2024525879000004.tif161159TIFF2024525879000005.tif142159

[0167] However, after correction for multiple comparisons using the FDR (false discovery rate) method, only Parabacteroides remained highly positively correlated with HFHS intake (Figure 5), suggesting that the more Parabacteroides a mouse had, the more HFHS it consumed during the food preference test, a behavior that is indicative of a functional reward system.

[0168] 6. Fecal material transplantation from obese donors alters learning components To examine the role of gut microbes in learning, the learning component of the food reward system was assessed in donor and recipient mice by the CPP test (Figure 7A-B). The purpose of this test is to evaluate the extent to which mice can be conditioned to prefer the compartment that contained a food stimulus even after that stimulus was removed. Thus, the goal was to increase the time the mice spent on one side of the cage after restraining them on that side during a training session with palatable food pellets (Reese's®) that stimulate the reward system. A preliminary test was used to determine whether the mice had a pre-existing preference for any of the compartments at baseline.

[0169] Both lean and obese donor mice spent more time in the compartment associated with the palatable food during testing than during pre-testing, suggesting that both mice were able to reverse their initial preference for one side of the cage after the training session (Figure 7A). However, the learning component of the food reward system is more efficient in lean mice than in obese mice. Indeed, the difference in time spent in the compartment associated with the palatable food compared to the neutral compartment tended to be smaller in obese mice compared to lean mice (p=0.1, Figure 7A).

[0170] Recipients of gut microbiota from lean donors reversed the initial preference for one compartment and significantly increased the time spent in the palatable side during testing compared to pre-testing (Figure 7B). Conversely, recipient mice of gut microbiota from obese donors did not show a significant difference in palatable side preference scores during testing compared to pre-testing, even though the mice spent more time in the compartment associated with palatability during testing (Figure 7B). The DIO_rec group was unable to reverse the initial preference for one side of the cage, reflecting their inability to effectively associate that side of the cage with palatable food-induced pleasure. These results suggest that recipient mice of gut microbiota from obese donors have dysregulation of the learning component of the food reward system. Collectively, these data demonstrate that obesity-related changes in learning components are partially transferred through FMT between donor and recipient mice.

[0171] 7. Gut microbiota recipient mice from obese donors show excessive motivation for food reward To evaluate the appetitive component or motivation to obtain a food reward, donor and recipient mice were subjected to an operant wall test in which they had to press a lever to receive a rewarding sucrose pellet (Figure 8A-D). The first three sessions of the test were based on the fixed ratio (FR) principle, where one food reward required one lever press. Then, in the progressive ratio sessions (PR), to evaluate the motivation to obtain a food reward, mice had to press the lever a gradually increasing number of times (n + 3) to obtain each new sucrose pellet.

[0172] Obese mice pressed the lever significantly less times during PR sessions compared to lean mice (Figure 8A). The number of reward pellets obtained was also significantly lower in obese donors than in lean donors during PR sessions (Figure 8B). Because PR sessions are a better reflection of motivation to obtain rewards, our data indicate that obesity is associated with changes in the appetitive component of the food reward system.

[0173] Strikingly, gut microbiota recipient mice from obese donors pressed the lever more during PR sessions 2, 3, and 4 compared to lean gut microbiota recipient mice (p=0.05 during PR2, p<0.05 during PR3, p=0.07 during PR4) (Figure 8C). This trend was reflected by the greater number of rewards obtained by mice inoculated with gut microbes from obese donors during PR sessions 2, 3, and 4 (Figure 8D). These results suggest that gut microbiota recipient mice from obese donors behaved in an opposite manner to obese donors in this test evaluating motivation to obtain rewards, because recipient mice pressed the lever approximately 100 times more than donors to obtain the food reward system. It is noteworthy that the absolute number of lever presses was similar between the Lean_rec and Lean_do groups (Figures 8A, 8C). Gut microbiota recipient mice from obese donors notably displayed higher values ​​of active lever pressing (Figure 8D), suggesting excessive motivation for food reward rather than the normal motivated behavior observed in the lean state.

[0174] 8. Excessive motivation for food reward is not associated with modulation of homeostatic regulators of food intake To understand how gut microbes from obese mice may act on the behavioral neural reward system in the lean state (recipient mice), we analyzed multiple mediators of the gut-brain correlation that are involved in the regulation of homeostatic food intake and may also affect the food reward system. Therefore, ghrelin, insulin, leptin, GLP-1 and PYY were measured in the plasma of recipient and donor mice. None of the homeostatic regulators analyzed in plasma was different between lean donor gut microbiota recipient mice and obese donor gut microbiota recipient mice (Figure 9A-E). In contrast, typical hormonal changes associated with obesity, such as a significant decrease in ghrelin (Figure 9A), a significant increase in insulinemia (Figure 9B) and leptinemia (Figure 9C) compared to lean mice, were observed in the plasma of obese donor mice. Plasma levels of GLP-1 and PYY were not significantly different between lean and obese donor mice (Figure 9D-E).

[0175] Example 2: Materials and Methods 1. Mice and Experimental Design All mouse experiments were approved by the Ethics Committee for Animal Care of the Health Sector of the UCLouvain, Universite catholique de Louvain, under the specific number 2021 / UCL / MD / 061, and were carried out according to the guidelines of the local ethical committee and in accordance with the Belgian law of 29 May 2013 for the protection of laboratory animals (agreement number LA1230314).

[0176] Cohorts of 9-week-old specific opportunistic pathogen and specific pathogen-free (SOPF) male C57BL / 6J mice (Janvier laboratories, Le Genest-Saint-Isle, France) were housed in groups of two per cage in a controlled environment (room temperature 22 ± 2°C, 12-h light / dark cycle) with ad libitum access to sterile food (irradiated) and sterile water. Upon delivery, mice were allowed to acclimate for 1 week, during which they were fed a control diet (CT, AIN93Mi, Research Diet, New Brunswick, NJ, USA). Mice were then randomly assigned into four groups (40 mice, n = 10 / group, designated ND PBS, ND PD, HFD PBS, HFD PD) and fed a control low-fat diet (CT, AIN93Mi) or a high-fat diet (HFD, 60% fat and 20% carbohydrate (kcal / 100 g) D12492i, Research diet, New Brunswick, NJ, USA) for 8 weeks. 2 × 10 mice per mouse in 200 μL of anaerobic PBS containing 1.2% glycerol were cultured at 10°C for 8 h. 8 Daily oral treatment with colony forming units (CFU) of Parabacteroides distasonis (PD) was performed in the ND PD and HFD PD groups. Daily oral treatment with the same volume of sterile PBS containing 1.2% glycerol was performed in the ND and HFD control groups. Body weight was recorded once a week. Body composition was evaluated once a week by utilizing a 7.5 MHz time-domain nuclear magnetic resonance (TD-NMR, LF50 Minispec, Bruker, Reinstetten, Germany). After 4 weeks of observation, mice were placed in behavioral cages (Phenotyper, Noldus, Wageningen, The Netherlands) to perform food preference tests and operant wall tests. During the last test, mice were food restricted and body weight was maintained at 85% of the initial weight (before behavioral tests) as previously described. Caloric restriction allowed for enhanced reward responses to stimuli.

[0177] 2. Cultivation and Preparation of Parabacteroides distasonis Parabacteroides distasonis were cultured in anaerobic liquid YCFA medium and agar YCFA medium. Parabacteroides distasonis were harvested by centrifugation (2x 20 min at 4000 g at 4°C), resuspended in sterile PBS containing 25% glycerol, and immediately frozen in anaerobic vials and stored at -80°C. Prior to administration, cell pellets were resuspended in anaerobic PBS.

[0178] 3. Food preference test During a 3-h daytime period, mice were exposed to two diets in behavioral cages (Phenotyper chambers, Noldus, Wageningen, The Netherlands): a low-fat control diet (CT, AIN93Mi, Research Diet, New Brunswick, NJ, USA) or a high-fat, high-sucrose diet (HFHS, 45% fat and 27.8% sucrose (kcal / 100g) D17110301i, Research diet, New Brunswick, NJ, USA). Food intake was recorded during a 3-h session at the end of the light phase in a satiated state (food was accessible ad libitum before and after testing). Mice showing significant food spilling during testing were excluded.

[0179] 4. Operant Wall Test The appetitive component is linked to the motivation to obtain reward, which is assessed using a modified version of the operant wall test described previously. Each test session was performed at the end of the light phase in operant conditioning chambers (Phenotyper chambers, Noldus, The Netherlands) and analyzed with the provided software (Ethovision XT 14). Mice intermittently approached the operant wall in their home cage. The operant wall system consists of two levers, two lights, and a pellet dispenser. One lever is arbitrarily designated as active, meaning that pressing this lever initiates the delivery of sucrose pellets (5-TUT peanut butter flavored sucrose pellets, TestDiet, St. Louis, MO) and is associated with the light on, whereas the other lever, associated with the light off, is arbitrarily designated as inactive and never delivers reward. Mice were trained in the system twice overnight in a fixed ratio scheme (one lever press in the active lever corresponds to one reward) and then subjected to four sessions of 1 h 30 min each. Mice were then transferred to a progressive ratio session (PR) (2 h). During the PR session, the number of lever presses on the active lever to obtain a reward was increased with each pellet (n+3). Mice that did not press the active lever during different sessions were excluded.

[0180] 5.Statistical analysis Statistical analysis was performed using GraphPad Prism version 9.1.2 for Windows (GraphPad Software, San Diego, CA, USA). Data are expressed as mean ± SEM. Differences between groups were evaluated using one-way ANOVA followed by Tukey post-hoc test. Differences between groups and different time points were evaluated using two-way linear repeated measures ANOVA followed by Bonferroni post-hoc test. Outliers were excluded after Grubbs' test.

[0181] 6. Other Stimuli Rewarding stimuli other than food may be used, such as alcohol or drugs.

[0182] result 1.Effect of Parabacteroides distasonis on fat mass gain To evaluate the effect of Parabacteroides distasonis on fat mass, mice were exposed to ND and HDF for 8 weeks, and daily administration of Parabacteroides distasonis or vehicle (PBS) was performed in the ND PD / HFD PD and ND PBS / HFD PBS groups, respectively (Figure 10). As expected, mice fed an HFD showed a significant increase in fat mass over time compared to ND mice. Furthermore, a significant decrease in fat mass is also observed in HFD PD mice compared to HFD PBS (P<0.05).

[0183] 2. Effect of Parabacteroides distasonis on the palatable components of the food reward system As part of the study of hedonic food intake, a food preference test was performed during the fourth week of exposure to the different diets (ND and HFD). During this test, mice were exposed to a control diet (CT) as well as a palatable novel food (HFHD), allowing the evaluation of the "preference" component of the food reward system (Figure 11). Comparing the amount of control (CT) and palatable food (HFHD) consumed during the test, ND PBS mice consumed significantly more HFHD than CT (p<0.01 according to the Mann-Whitney test), whereas no significant differences were observed in the HFD PBS group.

[0184] These results demonstrate that the palatable component of food intake during HFD-induced obesity was impaired. Palatable food consumption and control food consumption were not significantly different between HFD PBS and HFD PD mice.

[0185] These results suggest that Parabacteroides distasonis does not affect the palatable component of the reward system under either lean or obese conditions.

[0186] 3. Effect of Parabacteroides distasonis on motivation to obtain food reward To further characterize the different components of the food reward system, specifically the motivation of mice to obtain food rewards (i.e., the "appetitive" component of food intake), the operant wall test was performed to assess the motivation of mice during the progressive ratio sessions (Figure 12). This study showed a significant decrease in the number of active lever presses to obtain sucrose pellets in HFD PBS mice compared to ND PBS mice during PR1, PR2, and PR3 sessions, reflecting a lack of behavior related to the appetitive component of the reward system during obesity. No significant differences in the number of active lever presses were observed between the HFD PBS and HFD PD groups.

[0187] Strikingly, mice receiving Parabacteroides distasonis under ND pressed the active lever significantly less frequently compared to ND PBS mice during PR3 (P<0.0001) and PR4 (P<0.05) sessions. Since reduced active lever pressing was associated with reduced binge eating in control conditions under normal diet, these results reveal a potential beneficial effect of Parabacteroides distasonis in controlling food reward craving in the context of leanness.

[0188] These results support the use of Parabacteroides distasonis to treat eating-related disorders and, more generally, to treat dysregulation of the reward system in which the appetitive component is overstimulated, typically in patients with compulsive behavior in response to rewarding stimuli.

[0189] Example 3: Materials and Methods 1. Mice and Experimental Design See Example 2

[0190] 2. Cultivation and Preparation of Parabacteroides gordosteinii Parabacteroides gordosteinii (19448) was purchased from Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ, Germany). Parabacteroides gordosteinii was cultured in anaerobic liquid YCFA medium and agar YCFA medium. Parabacteroides gordosteinii were harvested by centrifugation (2x 20 min at 4000g at 4°C), resuspended in sterile PBS containing 25% glycerol, and immediately frozen in anaerobic vials and stored at -80°C. Before administration, cell pellets were resuspended in anaerobic PBS.

[0191] 3. Food Preference Test and Operant Wall Test See Example 2

[0192] 5. Conditioned Place Preference Test See Example 1

[0193] 6.Statistical analysis Statistical analysis was performed using GraphPad Prism version 9.1.2 for Windows (GraphPad Software, San Diego, CA, USA). Data are presented as mean ± SEM. Differences between CPP scores at pretest and during test were assessed using paired Student's t-test. Differences between groups were assessed using one-way ANOVA followed by Tukey post-hoc test. Differences between groups and different time points were assessed using two-way linear repeated measures ANOVA followed by Bonferroni post-hoc test. Outliers were excluded after Grubbs' test.

[0194] result 1.Effect of Parabacteroides gordosteinii on body weight gain and fat mass To evaluate the effect of Parabacteroides gordosteinii on the obese phenotype, mice were exposed to ND and HFD for 5 weeks and daily administration of Parabacteroides gordosteinii or vehicle (PBS) was performed in the ND PG / HFD PG and ND PBS / HFD PBS groups, respectively (Figures 13A-13B). As expected, HFD-fed mice show a significant increase in weight gain (P<0.0001) and fat mass (P<0.01) compared to ND-fed mice. However, no significant differences were observed in mice receiving daily administration of Parabacteroides gordosteinii compared to placebo. These results suggest that Parabacteroides gordosteinii has no significant effect on the obese phenotype induced by HFD. It should also be noted that no significant differences were observed between the ND PBS and ND PG groups with regard to body weight gain and fat mass, suggesting that Parabacteroides gordosteinii in the ND feeding condition does not affect these parameters.

[0195] 2. Effect of Parabacteroides gordosteinii on the palatable components of the food reward system To evaluate the pleasant sensations associated with food intake, a food preference test was performed after 5 weeks of exposure to the different diets (ND and HFD). During this test, mice were exposed to a control diet (CT) and a palatable novel food (HFHS), thus allowing the evaluation of the "preference" component of the food reward system. The consumption of the different foods was measured (Figure 14). When comparing the amount of CT and HFHS food consumed during this test, mice from the ND PBS and ND PG groups consumed significantly more palatable (HFHS) food than the control diet (CT) (P<0.001; P<0.01). However, no significant differences were observed between ND PBS and ND PG mice in terms of HFHS consumed. In the obese state, HFD PBS and HFD PG mice do not show any significant differences between the palatable food (HFHS) intake and the control food (CT) intake. Moreover, HFD PBS mice consumed significantly less palatable food than ND PBS mice (P<0.05).

[0196] These results suggest that Parabacteroides gordosteinii does not affect the palatable component of the reward system in either lean or obese conditions.

[0197] 3. Effect of Parabacteroides gordosteinii on motivation to obtain food reward To further characterize the different components of the food reward system, specifically the motivation of mice to obtain food rewards (i.e., the "appetitive" component of food intake), the operant wall test was performed to assess the motivation of mice during the progressive ratio sessions (Figure 15). This study showed a significant decrease in the number of active lever presses to obtain sucrose pellets in HFD PBS mice compared to ND PBS mice during PR2 (P<0.01), PR3 (P<0.001) and PR4 sessions (P<0.01), reflecting a deficit in behavior related to the appetitive component of the reward system during obesity. No significant differences in the number of active lever presses were observed between the HFD PBS and HFD PG groups.

[0198] Strikingly, mice receiving Parabacteroides gordosteinii under ND also pressed the active lever significantly less frequently compared to ND PBS mice during PR2 (P<0.05), PR3 (P<0.001) and PR4 (P<0.001) sessions. Because reduced active lever pressing was associated with reduced binge eating in control conditions under normal diet, these results highlight the potential beneficial effect of Parabacteroides gordosteinii in controlling food reward seeking in the context of leanness.

[0199] These results support the use of Parabacteroides gordosteinii to treat eating-related disorders and, more generally, to treat dysregulation of the reward system in which the appetitive component is overstimulated, typically in patients with compulsive behavior in response to rewarding stimuli.

[0200] 4. Effect of Parabacteroides gordosteinii on positive reinforcement in the lean component of the food reward system To explore another component of the food reward system, "learning," a conditioned place preference test was used. The purpose of this test is to evaluate the extent to which mice can be conditioned to prefer a compartment that contained a food stimulus even after that stimulus has been removed. The goal was to increase the time the mice spent on one side of the cage after restraining them on that side during a training session with palatable food pellets (Reese's®) to stimulate the reward system. A preliminary test was used to determine whether the mice had a pre-existing preference for any of the compartments at baseline.

[0201] As shown in FIG. 16, with regard to the time spent in the compartment associated with the palatable food (Reese's®), the conditioning session induced a significant increase in the time spent in this compartment during testing compared to the time spent during pre-testing in ND PBS mice (P<0.01). This effect was also observed in HFD PBS mice, but with a less significant effect (P<0.05). In ND PG mice, positive reinforcement was also observed by a significant increase in the time spent in the compartment during testing compared to the time spent in the compartment during pre-testing (P<0.001).

[0202] Interestingly, administration of Parabacteroides gordosteinii in the HFD PG group induced strong positive reinforcement reflected by a significant increase in the time spent in the compartment during testing compared with the time spent in the compartment during pre-testing (P<0.0001). In addition, during testing, HFD PG mice exhibited significantly higher CPP scores than HFD PBS CPP scores (P<0.05).

[0203] These results support a diet-dependent effect of Parabacteroides gordosteinii on the learning components of the food-related reward system and on any other stimulus-related learning of the reward system.

[0204] Example 4: Materials and Methods 1. Mice and Experimental Design 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 were carried out according to the guidelines of the local ethical committee and in accordance with the Belgian law of 29 May 2013 for the protection of laboratory animals (agreement number LA1230314).

[0205] Cohorts of 9-week-old specific opportunistic pathogen and specific pathogen-free (SOPF) male C57BL / 6J mice (Janvier laboratories, Le Genest-Saint-Isle, France) were housed in groups of two per cage in a controlled environment (room temperature 22 ± 2°C, 12-h light / dark cycle) with ad libitum access to sterile food (irradiated) and sterile water. Upon delivery, mice were allowed to acclimate for 1 week, during which they were fed a control low-fat diet (ctrl, AIN93Mi, Research Diet, New Brunswick, NJ, USA). Mice were then randomly divided into four groups (40 mice, n=10 / group, designated ND, HFD, ND SUCC, HFD SUCC) and fed a control low-fat diet (ND) 10 kcal% fat (D1245Oji, Research Diet, New Brunswick, NJ, USA), a high-fat diet (HFD) 60 kcal% fat (D12492i, Research Diet, New Brunswick, NJ, USA), ND supplemented with 5% w / w sodium succinate (W327700, Sigma), and HFD supplemented with 5% w / w sodium succinate for 8 weeks. Sodium levels were matched for all diets. Body weights were recorded weekly. Body composition was assessed weekly by utilizing a 7.5 MHz time-domain nuclear magnetic resonance (TD-NMR, LF50 Minispec, Bruker, Rheinstetten, Germany). After 4 weeks of observation, mice were placed in behavioral cages (Phenotyper, Noldus, Wageningen, The Netherlands) and subjected to food preference and operant wall tests. During this last test, mice were food restricted and maintained at 85% of their initial weight (before behavioral tests) as previously described. Caloric restriction allowed for enhanced reward responses to stimuli.

[0206] 2. Food preference test See Example 2

[0207] 3. Operant Wall Test See Example 2

[0208] 4.Statistical analysis See Example 2

[0209] 5. Other Stimuli Rewarding stimuli other than food may be used, such as alcohol or drugs.

[0210] result 1. Effect of succinate on the obese phenotype To evaluate the effect of succinate on the obesity phenotype, mice were exposed to ND and HFD supplemented or not with 5% w / w sodium succinate in the ND SUCC / HFD SUCC and ND / HFD groups, respectively, for 8 weeks (Figures 17A-17B). As expected, mice fed an HFD showed a significant increase in body weight and fat mass compared to ND-fed mice. In addition, mice fed an HFD diet combined with succinate also showed a significant decrease in body weight and fat mass compared to HFD mice. The ND diet combined with succinate induced a significant decrease in body weight in ND SUCC mice compared to ND mice, but no significant variation in fat mass was observed.

[0211] These results highlight the potential beneficial effects of succinate supplementation in the setting of diet-induced obesity.

[0212] 2. Effects of succinate on the preference component of the food reward system As part of the study of hedonic food intake, a food preference test was performed during the fourth week of exposure to the different diets (ND and HFD). During this test, mice were exposed to a control diet (CT) and a palatable novel food (HFHS), which allows the evaluation of the "preference" component of the food reward system (Figure 18). When comparing the food intake of the control (CT) and HFHS, mice from the ND and ND SUCC groups ate significantly more HFHS than CT food (P<0.01; P<0.001). However, no significant differences were observed in the amount of HFHS consumed between ND and ND SUCC mice. No significant differences were observed in the intake of CT and HFHS by HFD mice, in contrast to HFD SUCC mice. HFD SUCC mice consumed more HFHS in this study than CT mice, but also consumed more HFHS than mice in the ND, ND SUCC, and HFD groups (P<0.01 ND HFHS vs. HFD SUCC HFHS; P<0.05 ND SUCC HFHS vs. HFD SUCC HFHS; P<0.0001 HFD HFHS vs. HFD SUCC HFHS).

[0213] These results highlight the potential involvement of succinate in restoring the palatable component of the food-associated reward system.

[0214] This result is particularly interesting in the context of the treatment of eating-related disorders. Indeed, it is known that insufficient stimulation of the appetitive components of the reward system leads to increased food consumption to achieve pleasurable stimuli, and as a result, succinate can be useful to reduce food consumption in eating-related disorders (e.g., obesity-related disorders, binge eating, and the like). The effect of succinate on appetitive components may also be interesting for the treatment of other reward system dysregulations in which appetitive components are dysregulated.

[0215] 3. Effects of succinate on the appetitive component of the food reward system To further characterize the different components of the food reward system, in particular the mouse's motivation to obtain a food reward (i.e., the "want" component of food intake), the operant wall test was performed to assess mouse motivation during progressive ratio sessions (Figure 19).

[0216] This study showed a significant decrease in the number of active lever presses to obtain sucrose pellets in HFD mice compared to ND mice during PR2 (P<0.05), PR3 (P<0.01) and PR4 sessions (P<0.001), reflecting a lack of behavior related to the "appetitive" component of the reward system in the context of obesity. Separate analyses during the different progressive ratio sessions also show a significant increase in the number of active lever presses between HFD SUC and HFD mice during PR1 and PR2, and a significant decrease in the number of active lever presses in ND SUC mice compared to ND mice during PR2.

[0217] This study demonstrates the effect of succinate on the appetitive component of the reward system in obese and lean states.

[0218] These results support the use of succinate to treat eating-related disorders, and more generally, the reward system, in which the appetitive component is overstimulated, typically in patients with compulsive behavior toward rewarding stimuli.

Claims

1. A composition for use in preventing and / or treating reward system disorders, comprising one or more bacteria of the genus Parabacteroides and / or an extract thereof and / or a metabolite thereof.

2. The composition for use according to claim 1, wherein the bacteria of the genus Parabacteroides are selected from the group consisting of P. distasonis, P. goldsteinii, P. merdae, P. acidifaciens, P. bethesdaerhonensis, P. chartae, P. chinchilla, P. congius, P. faecis, P. goldnii, P. johnsonii, P. massiliensis, P. paucimobilis, P. provencensis, P. timonensis, Parabacteroides spp., and combinations thereof.

3. The composition for use according to claim 1, wherein the reward system disorder is selected from the group consisting of mental disorders, neurological disorders, and combinations thereof.

4. The composition for use according to claim 3, wherein the mental disorder is selected from the group consisting of addiction-related disorders, eating-related disorders, mood disorders, obsessive-compulsive disorder, schizophrenia, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, major depressive disorder (MDD), and anxiety disorders.

5. The composition for use according to claim 4, wherein the eating-related disorder is selected from the group consisting of anorexia nervosa, bulimia nervosa, binge eating, overweight-related disorders, and obesity-related disorders.

6. The composition for use according to claim 4, wherein the addiction-related disorder is selected from the group consisting of alcohol-related addiction, drug-related addiction, and game-related addiction.

7. The composition for use according to claim 3, wherein the neurological disorder is selected from the group consisting of Parkinson's disease and Tourette syndrome.

8. The composition for use according to any one of claims 1 to 7, wherein the composition is administered to a human individual.

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

10. The bacteria are administered in a dosage comprising from about 1×10 ２ CFU / g composition to about 1×10 １２ CFU / g composition, a composition for use according to any one of claims 1 to 7.

11. The composition for use according to any one of claims 1 to 7, wherein the composition further comprises one or more beneficial microorganisms (plural available).

12. The composition for use according to claim 11, wherein the one or more beneficial microorganisms are selected from the group consisting of bacteria of the families Clostridiaceae, Peptostreptococcaceae, Prevotellaceae, Methylobacteriaceae, the genus Turicibacter, the genus Coprococcus, the genus Noeria, the genus Prevotella, the genus Staphylococcus, and the genus Akkermansia.

13. The composition for use according to any one of claims 1 to 7, wherein the composition is in the form of a pharmaceutical composition further comprising a pharmaceutically acceptable carrier.

14. The composition for use according to any one of claims 1 to 7, wherein the composition is in the form of a nutritional composition further comprising a nutritionally acceptable carrier.

15. The composition for use according to any one of claims 1 to 7, wherein the composition is included in a kit further comprising means for administering the composition.

16. The composition for use according to claim 1, wherein the reward system disorder is a mental disorder selected from the group consisting of anorexia nervosa and bulimia nervosa.

17. The composition for use according to claim 1, wherein the reward system disorder is a mental disorder, and the mental disorder is compulsive overeating.

18. The composition for use according to claim 1, wherein the reward system disorder is a mental disorder, and the mental disorder is an eating-related disorder that is not an overweight-related disorder or an obesity-related disorder.

19. A composition comprising succinate for use in preventing and / or treating a reward system disorder.

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