Antibiotic-induced microbial depletion enhances murine small intestinal epithelial growth in a serotonin-dependent manner.

Regulation of small intestinal epithelial growth by endogenous and environmental factors is critical for intestinal homeostasis and recovery from insults. Depletion of the intestinal microbiome increases epithelial proliferation in small intestinal crypts, similar to the effects observed in animal models of serotonin potentiation. Based on prior evidence that the microbiome modulates serotonin activity, we hypothesized that microbial depletion-induced epithelial proliferation is dependent on host serotonin activity. A mouse model of antibiotic-induced microbial depletion (AIMD) was employed. Serotonin potentiation was achieved through either genetic knockout of the serotonin transporter (SERT) or pharmacological SERT inhibition, and inhibition of serotonin synthesis was achieved with para-chlorophenylalanine. AIMD and serotonin potentiation increased intestinal villus height and crypt proliferation in an additive manner, but the epithelial proliferation observed after AIMD was blocked in the absence of endogenous serotonin. Using Lgr5-EGFP-reporter mice, we evaluated intestinal stem cell (ISC) quantity and proliferation. AIMD increased the number of ISCs per crypt and ISC proliferation compared with controls, and changes in ISC number and proliferation were dependent on the presence of host serotonin. Furthermore, Western blotting demonstrated that AIMD reduced epithelial SERT protein expression compared with controls. In conclusion, host serotonin activity is necessary for microbial depletion-associated changes in villus height and ISC proliferation in crypts, and microbial depletion produces a functional serotonin-potentiated state through reduced SERT protein expression. These findings provide an understanding of how changes to the microbiome contribute to intestinal pathology and can be applied therapeutically. Antibiotic-induced microbial depletion of the murine small intestine results in a state of potentiated serotonin activity through reduced epithelial expression of the serotonin transporter. Specifically, serotonin-dependent mechanisms lead to increased intestinal surface area and intestinal stem cell proliferation. Furthermore, the absence of endogenous serotonin leads to blunting of small intestinal villi, suggesting that serotonin signaling is required for epithelial homeostasis.