The main research activities performed upon the last five years were devoted:
- to develop experimental models mimicking metabolic and behavioral (including food behavior disorders and stress) disturbances occurring during obesity, cancer development, and addiction; as well as models of fecal material transfer (FMT) from human to mice for mechanistic studies
- to evaluate the implication and therapeutic interest of the gut microbiota and related microbial metabolites in the occurrence of metabolic and behavioral disorders, cancer progression and related cachexia, disturbed control of food intake and reward, alcohol dependence, anxiety and depression
- to investigate the role of the endocannabinoid system and of specific receptors responding to gut microbial components or metabolites
- to decipher the role of the immune system in the development of obesity, inflammation, insulin resistance, oxidative stress, type 2 diabetes, hepatic steatosis, infectious diseases (e.g. malaria) or behavior in mice
- to evaluate the involvement of key gut function alterations in the occurrence of behavioral and metabolic disorders associated to obesity, alcohol consumption and cancer progression
- to develop specific surgical interventions in mice and techniques of real-time imagery (i.e., mouse colonoscopy), in order to evaluate the role of the mucosal microbiota on wound healing
- to evaluate how drugs such as immunosuppressive agents can affect the gut microbiota and conversely how the gut microbiota can affect the pharmaco-kinetics and pharmacodynamics of drugs
- to study how nutrients targeting the gut microbiota may affect metabolic homeostasis, gut functions, behavior, immune system (including infectious di and organs (liver, muscle, brain, adipose tissue)
- to use untargeted and targeted metabolomics in biological fluids and breath to analyze the relevance of microbial metabolites in the changes in behavior (depression, social behavior and food related behavior), and metabolic disorders related to cancer or obesity
- to isolate novel bacteria/metabolites to tackle obesity, diabetes, inflammation, cancer cachexia and some cancers
A link exists between the composition of the gut microbiota – that is profoundly modified in genetic (ob/ob) and dietary models of obesity – and the control of body weight, insulin secretion/response, inflammation and appetite. The gut microbiota may also be involved in the hepatic steatosis and vascular disorders induced by nutritional deficiency in essential polyunsaturated fatty acids, as well as in the occurrence of cachexia and inflammation linked to systemic cancer development. Non digestible carbohydrates such as inulin-type fructans are defined as prebiotics since they are highly fermented by certain bacterial species and thereby improve host health. We have tested the influence of several non-digestible dietary carbohydrates (e.g., fructans, cereal subfractions, and/or glucans derivatives, pectooligocaccharides…) and polyphenolic compounds on gut microbiota composition, activity and systemic metabolism.
Our experimental data suggest their potential to improve metabolic disorders associated with obesity. In rodents, changing the gut microbiota composition using fructans reduces food intake, improves glucose homeostasis and steatosis, and decreases fat mass development, these events being clearly related to the modulation of endogenous gut peptides production. Indeed, changing the microbiota with dietary prebiotics administration leads to an increase in the differentiation of stem cells into endocrine L cells in the proximal colon of rats, and therefore promotes the production of glucagon-like peptide-1 and 2 (GLP-1 and GLP-2) in this organ. The relevance of the GLP-1 in the improvement of metabolic disorders is shown through experiments performed in mice lacking functional GLP-1 receptor: those mice are resistant to the beneficial effect of fructans on obesity and glucose metabolism. In addition, the GLP-2 is known to improve gut barrier function, here we found that the endogenous production of GLP-2 is a key event responsible for the reduced gut permeability observed upon severe obesity and type 2 diabetes.
Some of these metabolic alterations are modulated by the gut microbiota through specific bacteria-derived compounds such as pathogen-associated molecular patterns (PAMPs). Among them, we have identified the key role played by the lipopolysaccharides (LPS) in the onset of metabolic inflammation and glucose homeostasis disorders in the context of obesity and associated disorders, as well as in the inflammation linked to alcohol dependence in humans. The alteration of the gut barrier is one important cause of the translocation of bacterial elements (e.g., LPS, peptidoglycans) and metabolites which promote inflammation and metabolic disorders, which occur in nutritional or behavioral disorders (diabetes and obesity, cancer cachexia, alcohol dependence).
High-throughput molecular analysis of bacterial 16S rRNA gene allowed to point out novel interesting bacteria (Bifidobacteria, Akkermansia muciniphila, Roseburia spp., Lactobacillus spp., …) or yeast (Saccharomyces boulardii) in the control of host metabolic status, adiposity and immunity.