Plasticity of gastro-intestinal mucosa in nutritional pathologies and after surgery PIMS
Maude Le Galle et Andre Bado
Our team focus on the contribution of the gastrointestinal tract to nutritional pathologies including obesity, which is often associated with comorbidities such as type 2 diabetes or non-alcoholic fatty liver disease (NAFLD). The pharmacotherapy of obesity remains inconstant and today bariatric surgeries that are remodeling of the gastrointestinal tract are the only effective treatments when obesity becomes morbid. While these surgeries are generally extremely beneficial, we have reported that they can lead to intestinal failure, with severe malnutrition, microvesicular steatosis, and acute liver failure (Lancet. 2013). These clinical observations are reminiscent of the short bowel syndrome (SBS) resulting from an extensive resection of the small intestine and responsible for the main cause of intestinal failure.
Managing these pathologies – obesity and malnutrition resulting from intestinal failure – with increasing human, social and economic costs, requires research efforts to better understand their origins and identify new targets and therapeutic strategies.
To meet these social needs, our team gathers physiologists of the gastro-intestinal tract, basic scientists and clinicians (digestive surgeons, gastroenterologists and nutritionists) to develop basic and transitional researches to study gastrointestinal adaptations in response to obesity, surgical remodeling, and nutritional status (undernutrition / malnutrition).
We set up unique rat models of bariatric surgeries as vertical sleeve gastrectomy (VSG), Roux-en-Y gastric bypass (RYGB) and one-anastomosed gastric bypass (OAGB) (PLoS One 2015, Am J Physiol 2016, J Vis Exp. 2018) and rat models of Short Bowel Syndrome (jejuno-colonic or jejunum-ileum anastomosis) (Sci. Rep. 2016).
Combining experimental research in these preclinical models with clinical studies, we identified differences in intestinal adaptation that contribute to improved glucose homeostasis after RYGB vs VSG-type bariatric surgeries (Gastroenterology 2016; Trends Endocrinol Metab. 2017). We also characterized the structural and functional adaptations of residual intestinal mucosa and microbiota in humans and rats with short bowel syndrome (Sci. Rep. 2016, Microorganisms 2016, Front. Physiol. 2017).
In all these studies, we highlighted the plasticity of the gastrointestinal tract epithelial cells and its consequences on intestinal functions (Nutr Rev. 2018).
We are now extending our studies to both side of the intestinal epithelium: the mucosa layers containing the enteric nervous system (ENS) and immune cells versus the luminal microbiota. Our goal is to determine the functional consequences of changes in enteric neuronal and immune cells and microbiota on intestinal epithelial cell function.
Finally, “omics” studies of the intestinal mucosa in preclinical models and in patients will allow to identify new biomarkers and therapeutic targets to complement or replace surgery
Gastrointestinal tract anatomy in physiology and after remodeling by surgery.
A. Normal gastrointestinal tract anatomy.
B. Gastrointestinal tract anatomy after bariatric surgerie as vertical sleeve gastrectomy (VSG), Roux-en-Y gastric bypass (RYGB), or one-anastomosis gastric bypass (OAGB).
B. Gastrointestinal tract anatomy after massive resection of the intestine leading to short bowel syndrome (SBS). Three categories are recognized: end-jejunostomy with no colon and ileum (type 1); jejuno-colic anastomosis with no ileum and no ileocecal valve (type 2); and jejuno-ileal anastomosis preserving colon, ileo-cecal valve, and distal part of the ileum (type 3). Adapted from Nutr Rev. 2018.
Intestinal reprogramming and improvement of glucose homeostasis after bariatric surgery.
After RYGB, the jejunal mucosa in the alimentary limb becomes hyperplasic in rats, as well as in RYGB-operated obese subjects (compared to obese subjects). This hyperplasia is associated with a metabolic hyperactivity of the alimentary limb and results in increased glucose consumption, which can be visualized by PET / CT Scan analyses in humans. Adapted from Gastroenterology 2016
The gut connectome
Both sides of the gastro-intestinal epithelium could contribute to the adaptations in response to surgery readouts. In the mucosa, glial and neurons of the enteric nervous system and immune cells directly communicate with epithelial cells. In the outer side, microbiota-produced metabolites feed or signal intestinal epithelial cells
Translational research within the PIMS team
Our team gathers physiologists of the gastro-intestinal tract, basic scientists and clinicians (digestive surgeons, gastroenterologists and nutritionists) to develop bench-to-bedsides as well as bedside-to-bench researches.