Proximal and Distal Gut Mucosa Adapt Differently to Westernized Diet, Promoting an Insulin-Resistant Dysmetabolic State

SUMMARY The intestine adapts to local nutrient exposure, but little is known about the effect of high-fat diets (HFDs) on topographically distinct segments of the gut. Here, we show obesogenic diets induce different effects on proximal versus distal intestinal mucosa in vivo and mouse and human organoid models. Notably, we demonstrate proximal gut hyperplasia and distal gut hypoplasia in response to HFD in rodents and show that surgical and pharmacologic interventions that circumvent this altered mucosal physiology improve glucose metabolism. In addition, organoids derived from the duodenum of mice or humans demonstrate increased stemness (self-renewal and differentiation) and growth response to increasing amounts of lipid or glucose, while ileal organoids displayed a functionally different and often opposite growth response profile. These results highlight the important role of the small intestinal mucosa in regulating metabolic homeostasis in health and disease and open new avenues and therapeutic approaches to treat metabolic diseases. GRAPHICAL ABSTRACT