Roles of gut microbes in the gut-to-brain axis controlling hedonic/reward responses to food intake in physiological condition and in the pathology of obesity

Overweight and obesity are now considered as multifactorial pathologies, affecting 39% of the world’s population. The dysregulation of food intake in favor of hedonic food intake (based on the pleasure, and linked to the brain reward system) rather than food intake based on the energy needs of the body (homeostatic), has been identified as one of the main cause of body weight gain. Identifying factors contributing to this dysregulation of food intake would limit the obesity epidemic, the prevalence of metabolic disease associated with obesity, and healthcare costs. Our team and others have broadly described the roles and mechanisms by which the gut microbiota influences hunger and satiety to regulate food intake in function of the energy needs. However, the roles of gut microbes in the hedonic food intake have been poorly investigated so far. The mechanisms behind the dysregulations of hedonic food intake associated with obesity are still unknown. The aim of this PhD work is to investigate the roles of the gut microbiota as a potential therapeutic target to tackle dysregulations of the hedonic/reward system in the context of obesity. We aim to know if the gut microbiota is involved in the hedonic responses to food intake in physiological and pathological conditions (obesity). Our objective is to prove the causal role of the gut microbiota in reward dysregulations associated with obesity. After that, we investigated the mediators of the gut-brain axis influencing the reward responses to food intake. Finally, we studied the underlying mechanisms of the roles of the gut microbiota in hedonic/reward responses to food intake. We used the fecal material transplantation model in mice to prove the causal role of the gut microbiota in the reward system on a behavioral and neuronal points of view. Thanks to metabolomics studies, we were able to identify a gut-derived metabolite as a potential mediator in the gut-brain axis influencing the reward system. Moreover, we have demonstrated that the modulation of the gut microbiota following the administration of Akkermansia muciniphila allows to restore the reward alterations in obese rodents, potentially through a decrease in neuro-inflammation. In conclusion, the therapeutic approach based on the modulation of the gut microbiota and in particular, the administration of beneficial bacteria would represent a promising strategy to treat the food intake alterations linked to the pleasure. Our results demonstrate that the gut microbiota represents an important therapeutic target in the treatment of food intake dysregulations associated with obesity.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 202