C. J. Greig1, R. A. Cowles1 1Yale School Of Medicine,Department Of Surgery,New Haven, CT, USA
Introduction:
Intestinal adaptation is regulated by a variety of factors and is thought to be most robust in the ileum. In patients with short bowel syndrome (SBS), resection of the distal intestine is associated with more severe disease and worse outcomes which may be explained by the regional differences in adaptive potential. Enteric serotonin (5-HT) signaling is known to induce mucosal growth in the distal small bowel but its actions at other sites have not been characterized. We hypothesized that enhanced 5-HT signaling would stimulate mucosal growth in all areas of the small intestine, potentially allowing for the development of novel therapies for SBS patients with distal resections.
Methods:
The serotonin reuptake transporter (SERT) inactivates 5-HT. Knockout or pharmacologic inhibition of SERT results in enhanced 5-HT signaling. P-chlorophenylalanine (PCPA) is an inhibitor of 5-HT biosynthesis. With institutional approval, C57Bl/6 wild-type (WT), SERT knockout (SERTKO), and selective serotonin reuptake inhibitor (SSRI)-treated WT mice were used for experiments. Four small bowel segments were harvested from proximal jejunum to distal ileum. Histologic sections were H&E-stained and villus height (VH), crypt depth (CD) and crypt proliferation index (CPI) were measured (n=40 per parameter). Values were compared using Student’s t-test and significance assumed when p≤0.05.
Results:
At baseline, morphometric (VH/CD) and proliferative (CPI) parameters varied from jejunum to ileum. Enhanced 5-HT signaling resulted in significant increases in morphometric and proliferative parameters for nearly every region of the small intestine (see table). Inhibition of 5-HT synthesis with PCPA resulted in reversal of the 5-HT-mediated effects, confirming the role of 5-HT in stimulating mucosal growth.
Conclusion:
Morphometric and proliferative parameters vary throughout the small intestine of WT mice. Enhanced 5-HT signaling resulted in taller villi, deeper crypts and increased crypt proliferation throughout the small bowel. The ability of this model to stimulate mucosal growth from the jejunum to the ileum suggests serotonergic signaling is a viable target for therapies aimed at increasing mucosal surface area in the residual bowel of SBS patients.
