Enhanced serotonin signaling stimulates ordered intestinal mucosal growth

Significant quantities of serotonin (5-hydroxytryptamine; 5-HT) are found in the intestine, and studies have demonstrated that 5-HT can stimulate enterocyte cell division, suggesting regulatory roles in mucosal homeostasis and intestinal adaptation. We hypothesized that excess enteric 5-HT signaling enhances mucosal growth without changing intestinal villous cellular makeup.

Mice lacking the serotonin reuptake transporter (SERT) and wild-type littermates (WTLM) were euthanized and their ileum analyzed. Villus height (VH), crypt depth (CD), and enterocyte height (EH) were measured. Enterocyte cell division was measured using Ki-67 immunofluorescence to calculate crypt proliferation index (CPI). Cellular distribution along villi was investigated by immunofluorescent staining for enterocytes, enteroendocrine cells, and goblet cells. Group measurements were compared using t-test and chi-squared test.

SERT knock-out (SERTKO) mice had significantly taller villi, deeper crypts, and taller enterocytes compared with WTLM (P < 0.0001). Similarly, enterocyte proliferation was greater in SERTKO compared with WTLM (P < 0.01). For SERTKO, mean values were: VH, 255.6 μm; CD, 66.7 μm; EH, 21.2 μm; and CPI, 52.8%. For WTLM, corresponding values were: VH, 207.8 μm; CD, 56.1 μm; EH, 19.5 μm; and CPI, 31.9%. The cellular composition along villi was not significantly different between genotypes (P > 0.05).

Enhancing 5-HT signaling in mice increases VH, CD, EH, and crypt cell proliferation in the intestinal mucosa. 5-HT-associated growth did not alter the cellular composition of the villi. Serotonin may represent an important physiologic regulator of intestinal growth and adaptation and holds promise as a target for therapies aimed at enhancing intestinal recovery after injury or mucosal surface area loss.