The main research activities performed upon the last five years were devoted:
- to develop experimental models mimicking metabolic and behavioural disturbances occurring during obesity, cancer development, addiction;
- to evaluate the implication and therapeutic interest of the gut microbiota and associated microbial metabolites in the occurrence of tmetabolic and behavioral disorders and the progression of cancer;
- to investigate the role of the gut microbiota in the control of food intake, food reward, alcohol dependence, 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 innate immune system in the development of obesity, inflammation, insulin resistance, oxidative stress, type 2 diabetes, hepatic steatosis, or behaviour in mice;
- to evaluate the involvement of key gut functions (endocrine, immune, endothelial, barrier functions) alterations in the occurrence of behavioural 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 how conversely the gut microbiota can affect the pharmacokinetics and pharmacodynamics of such drugs.
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 occurring in nutritional or behavioural disorders (diabetes and obesity, cancer cachexia, alcohol dependence…) (For reviews, Cani et al Nature Metabolism 2019; Delzenne et al Proc. Nutr. Soc. 2019; Cani Gut 2018 ; Bindels et al, Clin Nutr Exp 2016 ; Delzenne et al, Diabetologia 2015)
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. 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.