Serotonin Activity Is Correlated with Intestinal Stem Cell Proliferation in Small Intestinal Crypts

Abstract

INTRODUCTION: Increased serotonin activity enhances small intestinal (SI) mucosal growth and nutrient absorption, but the mechanism behind this observation is unknown. This study evaluated the effect of serotonin signaling on intestinal stem cell (ISC) number and proliferation in mouse SI crypts. We hypothesized that alterations in serotonin activity correspond to changes in ISC proliferation. METHODS: Lgr5-EGFP-reporter mice were administered intraperitoneal citalopram, a selective serotonin reuptake inhibitor (SSRI), to potentiate serotonin activity, or para-chlorophenylalanine (PCPA), to inhibit serotonin synthesis. Control animals received saline alone. After 14 days, mice were injected intraperitoneally with bromodeoxyuridine (BrdU) to label actively dividing cells, followed by SI harvest 1 hour later. Immunofluorescence staining and microscopy identified Lgr5-positive ISC and BrdU-positive proliferating cells in epithelial crypts. ISC proliferation was quantified by calculating the proportion of crypts per animal with ≥1 cell expressing Lgr5 and labeled with BrdU. RESULTS: Compared with controls, SSRI treatment was associated with more Lgr5-positive cells per crypt (4.8 ± 0.9 vs 3.1 ± 0.6 cells/crypt; p < 0.01), and PCPA treatment resulted in no difference (3.5 ± 1.3 vs 3.1 ± 0.6 cells/crypt; p = 0.11); 66.6% of crypts in control animals did not contain proliferating stem cells. SSRI treatment was associated with a greater number of crypts exhibiting ISC proliferation (60.0% vs 33.3%; p < 0.01), and PCPA treatment was associated with fewer crypts containing proliferating ISCs (16.7% vs 33.3%; p < 0.01) compared with controls (Figure).FigureCONCLUSION: Serotonin activity is directly correlated with ISC proliferation in SI crypts. Modulation of stem cell activity with SSRIs may have therapeutic potential in patients who undergo SI resection.