int-777 and Colitis

Renewal and patterning of the intestinal epithelium is coordinated by intestinal stem cells (ISCs); dietary and metabolic factors provide signals to the niche that control ISC activity. Bile acids (BAs), metabolites in the gut, signal nutrient availability by activating the G protein-coupled bile acid receptor 1 (GPBAR1, also called TGR5). TGR5 is expressed in the intestinal epithelium, but it is not clear how its activation affects ISCs and regeneration of the intestinal epithelium. We studied the role of BAs and TGR5 in intestinal renewal, and regulation of ISC function in mice and intestinal organoids.. We derived intestinal organoids from wild-type mice and Tgr5. BAs and TGR5 agonists promoted growth of intestinal organoids. Administration of cholecystokinin to mice resulted in acute release of BAs into the intestinal lumen and increased proliferation of the intestinal epithelium. BAs and Tgr5 expression in ISCs were required for homeostatic intestinal epithelial renewal and fate specification, and for regeneration after colitis induction. Tgr5. BAs promote regeneration of the intestinal epithelium via activation of TGR5 in ISCs, resulting in activation of SRC and YAP and activation of their target genes. Release of endogenous BAs in the intestinal lumen is sufficient to promote ISC renewal and drives regeneration in response to injury.

Topics: Adaptor Proteins, Signal Transducing; Adult Stem Cells; Animals; Bile Acids and Salts; Cell Cycle Proteins; Cell Self Renewal; Cells, Cultured; Cholic Acids; Colitis; Dextran Sulfate; Disease Models, Animal; Epithelial Cells; Humans; Intestinal Mucosa; Male; Mice; Mice, Knockout; Organoids; Primary Cell Culture; Receptors, G-Protein-Coupled; Regeneration; Signal Transduction; src-Family Kinases; YAP-Signaling Proteins