The main research activities performed upon the last five years were devoted:
- to develop experimental models mimicking metabolic disturbances occurring upon obesity and cancer development
- to test for the implication of gut microbiota in the occurrence of those metabolic disorders
- 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 and cancer cachexia in mice.
- to evaluate the involvement of key gut functions (endocrine, immune, endothelial, barrier functions) alterations in the occurrence of behavioural and metabolic disorders.
- to explore the potential links between oxidative stress, inflammation and cancer cell metabolism.
These alterations are mainly dependent on the gut microbiota and specific bacterial 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 (LPS, peptidoglycans..) which promotes inflammation and metabolic disorders occurring in nutritional or behavioural disorders (diabetes and obesity, cancer cachexia, alcohol dependence…) (For review, Delzenne et al, Diabetologia 2015; Cani and Everard, Molecular Nutrition Food Research 2016; Bindels et al, Clin Nutr Exp 2016)
There is a link 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 could 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 and selectively 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…) on gut fermentation and systemic metabolism.
Our experimental data suggest their potential to improve metabolic disorders associated with obesity (insulin sensitivity, immunomodulation, fat mass development). In rodents and humans, changing the gut microbiota composition by using fructans improves glucose homeostasis, steatosis and decrease fat mass development, and these events being clearly related to the modulation of endogenous gut peptides production. The gut microbiota participate to specific intestinal metabolic responses, for instance, 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. Recent data obtained following high-throughput molecular analysis of bacterial 16S rRNA allowed to point out novel interesting bacteria (Bifidobacteria, Akkermansia muciniphila, Roseburia spp., Lactobacillus spp., …) or yeast (Saccharomyces boulardii) in the control of host hormonal status, adiposity, and immunity.