Microbial stimulation of oxytocin release from the intestinal epithelium via secretin signaling

Abstract

AbstractIntestinal microbes impact the health of the intestine and organs distal to the gut.Limosilactobacillus reuteriis a human intestinal microbe that promotes normal gut transit1, the anti-inflammatory immune system2–4, wound healing5–7, normal social behavior in mice8–10, and prevents bone reabsorption11–17. Each of these functions is impacted by oxytocin18–22, and oxytocin signaling is required forL. reuteri-mediated wound healing5and social behavior9; however, the initiating events in the gut that lead to oxytocin stimulation and related beneficial functions remain unknown. Here we found evolutionarily conserved oxytocin production in the intestinal epithelium through analysis of single-cell RNA-Seq datasets and imaging of human and mouse intestinal tissues. Moreover, human intestinal organoids produce oxytocin, demonstrating that the intestinal epithelium is sufficient to produce oxytocin. We subsequently found thatL. reuterifacilitates oxytocin secretion directly from human intestinal tissue and human intestinal organoids. Finally, we demonstrate that stimulation of oxytocin secretion byL. reuteriis dependent on the gut hormone secretin, which is produced in enteroendocrine cells23, while oxytocin itself is produced in enterocytes. Altogether, this work demonstrates that oxytocin is produced and secreted from enterocytes in the intestinal epithelium in response to secretin stimulated byL. reuteri. This work thereby identifies oxytocin as an intestinal hormone and provides mechanistic insight into avenues by which gut microbes promote host health.