Potentiated serotonin signaling in serotonin re‐uptake transporter knockout mice increases enterocyte mass and small intestinal absorptive function

Genetic knockout of the serotonin reuptake transporter (SERT) potentiates serotonin signaling and increases crypt‐cell proliferation, neuroplasticity, and mucosal surface area. However, it remains unknown whether these changes occur throughout the small intestine and whether they increase nutrient absorption. We hypothesized that serotonin‐mediated mucosal growth would occur throughout the intestine and would increase enterocyte mass and absorptive function. Following institutional approval, intestinal segments spanning the bowel were harvested from 10 to 12 week‐old SERT knockout (SERTKO) and wild‐type (WT) C57Bl/6 mice. Histologic sections were used to measure villus height (VH), crypt depth (CD), and crypt proliferation index (CPI). Plasma citrulline was measured colorimetrically. Glucose and peptide absorption in isolated segments of small bowel were calculated using a previously described method for quantification after luminal instillation of substrate. At baseline, morphometric (VH/CD) and proliferative (CPI) parameters varied from jejunum to ileum. Enhanced 5‐HT signaling significantly increased plasma citrulline levels and morphometric/proliferative parameters in all regions analyzed. Glucose absorption in WT mice varied throughout the small intestine, and SERTKO mice demonstrated significant increases in the middle and distal bowel. WT peptide absorption was similar throughout the small bowel, and SERTKO mice had significant increases in the proximal and distal bowel. Enhanced serotonin signaling results in increased morphometric and proliferative parameters throughout the small intestine, and results in increased enterocyte mass and intestinal absorptive function. These data further advance the concept that the serotonin system is an attractive therapeutic target for increasing functional intestinal mucosa.