Modulation of Gut Microbiota Composition by Serotonin Signaling Influences Intestinal Immune Response and Susceptibility to Colitis

Feb 5, 2019Cellular and molecular gastroenterology and hepatology

Serotonin’s influence on gut bacteria affects intestinal immunity and risk of colitis

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Abstract

A significant difference in microbial composition was observed between Tph1 and Tph1 littermates.

Gut-derived serotonin (5-HT) may influence microbiota and susceptibility to colitis.
5-HT directly stimulated and inhibited the growth of specific commensal bacteria in a concentration-dependent manner.
5-HT is associated with the inhibition of antimicrobial peptide production in colonic epithelial cells.
Transferring gut microbiota between Tph1 and Tph1 littermates altered the severity of colitis.
Germ-free mice colonized with microbiota from Tph1 mice exhibited reduced severity of colitis induced by dextran sulfate sodium.

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BACKGROUND & AIMS: Serotonin (5-hydroxytryptamine [5-HT]) is synthesized mainly within enterochromaffin (EC) cells in the gut, and tryptophan hydroxylase 1 (Tph1) is the rate-limiting enzyme for 5-HT synthesis in EC cells. Accumulating evidence suggests the importance of gut microbiota in intestinal inflammation. Considering the close proximity of EC cells and the microbes, we investigated the influence of gut-derived 5-HT on the microbiota and the susceptibility to colitis.

METHODS: Gut microbiota of Tph1and Tph1mice were investigated by deep sequencing. Direct influence of 5-HT on bacteria was assessed by using in vitro system of isolated commensals. The indirect influence of 5-HT on microbiota was assessed by measuring antimicrobial peptides, specifically β-defensins, in the colon of mice and HT-29 colonic epithelial cells. The impact of gut microbiota on the development of dextran sulfate sodium-induced colitis was assessed by transferring gut microbiota from Tph1mice to Tph1littermates and vice versa, as well as in germ-free mice. -/-+/--/-+/-

RESULTS: A significant difference in microbial composition between Tph1and Tph1littermates was observed. 5-HT directly stimulated and inhibited the growth of commensal bacteria in vitro, exhibiting a concentration-dependent and species-specific effect. 5-HT also inhibited β-defensin production by HT-29 cells. Microbial transfer from Tph1to Tph1littermates and vice versa altered colitis severity, with microbiota from Tph1mice mediating the protective effects. Furthermore, germ-free mice colonized with microbiota from Tph1mice exhibited less severe dextran sulfate sodium-induced colitis. -/-+/--/-+/--/--/-

CONCLUSIONS: These findings demonstrate a novel role of gut-derived 5-HT in shaping gut microbiota composition in relation to susceptibility to colitis, identifying 5-HT-microbiota axis as a potential new therapeutic target in intestinal inflammatory disorders.

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Modulation of Gut Microbiota Composition by Serotonin Signaling Influences Intestinal Immune Response and Susceptibility to Colitis

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