The enteroendocrine cell (EEC) lineage is important for intestinal homeostasis and systemic energy balance. Notably, progenitors of EECs exhibit stem cell potential and contribute to intestinal epithelial proliferation and renewal; however, the molecular mechanisms are not well understood. In this study, we first report that miR-7 and miR-375 (previously thought to be specific to pancreatic beta cells) are very highly expressed along the EEC lineage trajectory and are among the most enriched miRNAs in Prox1+ EEC progenitors relative to Lgr5+ intestinal stem cells. Next, by studying intestinal stem/progenitor cell responses to microbiota, high-fat diet, and bariatric surgery, we show that miR-7 and miR-375 expression levels are inversely correlated with intestinal epithelial proliferative status. We then demonstrate by both loss- and gain-of function assays in ex vivo mouse enteroids that both miRNAs exert robust control of intestinal epithelial proliferation and enteroendocrine cell maturation. We also show by single cell RNA-sequencing, intestinal phenotyping, and metabolic phenotyping in a miR-375 knockout mouse model, that miR-375 controls intestinal stem/progenitor cell dynamics, especially with increasing age. Overall, this study demonstrates for the first time that two miRNAs highly enriched in the EEC lineage are critical regulators of intestinal epithelial proliferation and likely mediators of the effects of high-fat diet on the intestinal crypt. Ongoing studies are focused on the role of these two miRNAs in the rescue of intestinal crypt behavior after bariatric surgery.
P. Sethupathy: None.
American Diabetes Association/Pathway to Stop Diabetes (1-16-ACE-47)