Modulation of Gut Microbiota Composition by Serotonin Signaling Influences Intestinal Immune Response and Susceptibility to Colitis.
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 Tph1-/- and Tph1+/- mice 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 Tph1-/- mice to Tph1+/- littermates and vice versa, as well as in germ-free mice.


RESULTS
A significant difference in microbial composition between Tph1-/- and Tph1+/- littermates 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 Tph1-/- to Tph1+/- littermates and vice versa altered colitis severity, with microbiota from Tph1-/- mice mediating the protective effects. Furthermore, germ-free mice colonized with microbiota from Tph1-/- mice 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.
['Kwon|Yun Han|YH|', 'Wang|Huaqing|H|', 'Denou|Emmanuel|E|', 'Ghia|Jean-Eric|JE|', 'Rossi|Laura|L|', 'Fontes|Michelle E|ME|', 'Bernier|Steve P|SP|', 'Shajib|Md Sharif|MS|', 'Banskota|Suhrid|S|', 'Collins|Stephen M|SM|', 'Surette|Michael G|MG|', 'Khan|Waliul I|WI|']
D000818:Animals D000900:Anti-Bacterial Agents D001419:Bacteria D003092:Colitis D003106:Colon D016264:Dextran Sulfate D004198:Disease Susceptibility D015536:Down-Regulation D004847:Epithelial Cells D000069196:Gastrointestinal Microbiome D005856:Germ-Free Life D006579:Heterozygote D007249:Inflammation D007413:Intestinal Mucosa D007422:Intestines D008297:Male D008810:Mice, Inbred C57BL D047495:PPAR gamma D011985:Receptors, Serotonin D012701:Serotonin D015398:Signal Transduction D014365:Tryptophan Hydroxylase D015854:Up-Regulation D023083:beta-Defensins
Microbiota Colitis Tph1 β-defensins 5-Hydroxytryptamine (5-HT)