The impact of three-way crosstalk between intestinal epithelium, immunity and microbiota on bariatric surgery clinical outcomes – IMAT

The intestinal epithelium is a constantly renewing tissue that quickly adapts to its environment. The microbiota and immune cells, in contact with intestinal epithelial cells, can impact their functions and thus modulate nutrient absorption, hormone secretion and barrier function of the gastrointestinal tract. This triad is thus an interesting target to prevent or fight the global obesity pandemic.
Studies of bariatric surgical procedures have yielded important data on their efficacy and safety for obesity and related metabolic disorders. The most commonly used surgical techniques in France are Vertical Sleeve Gastrectomy (VSG) and Roux-en-Y Gastric Bypass (RYGB). Beyond decrease in food intake and absorptive surface, different mechanisms have been reported to explain their beneficial effects: enterohormonal changes (including incretin GLP-1), increased intestinal glucose uptake and changes in the microbiota composition. Surprisingly the intestinal immune cells are still poorly characterized after theses surgeries

We hypothesize that cytokines produced by intestinal immune cells (IIC) are key mediators of the crosstalk between immune cells and intestinal epithelial cells (IEC), controlling intestinal adaptation in response to bariatric surgery and that microbiota-derived metabolites modulate this three way crosstalk.

The objectives of this research program are to characterize the phenotype and functions of IIC in response to bariatric surgery (Task1), their relationships with the microbiota and its derived metabolites (Task2) and the role of IIC and microbiota in the reprograming of IEC (Task3).
As readouts of the reprograming of IEC, we will focus on intestinal adaptations that we have already showed to be of great clinical importance: differentiation of EEC and notably GLP-1 secreting cells after both surgeries (VSG and RYGB) and glucose metabolism switch in relation to the hyperplasia reported in the alimentary limb after RYGB. To investigate the potential role of IIC in these adaptations we will work on preclinical models (Tasks 1-3) but also on a cohort of obese subjects, candidates for bariatric surgery (Task4).

The strength of the Intestinal Ménage À Trois (IMAT) consortium is to gather researchers and clinicians with complementary and synergic expertise in intestinal physiopathology (Partners 1-3), obesity & bariatric surgery (Partner 1), intestinal immunology (Partner 2) and microbiota (Partner 3).

Our project will provide a necessary foundation for future identification of new intestinal, and therefore orally accessible, therapeutic targets that modulate the epithelium, intestinal immunity and/or the microbiota in order to prevent / limit the harmful effects of obesity or alternatively to induce the same beneficial consequences as bariatric surgery while limiting its negative effect.