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

Cell Mol Gastroenterol Hepatol. 2019;7(4):709-728. doi: 10.1016/j.jcmgh.2019.01.004. Epub 2019 Feb 1.

Abstract

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.

Keywords: 5-Hydroxytryptamine (5-HT); Colitis; Microbiota; Tph1; β-defensins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Bacteria / drug effects
  • Bacteria / growth & development
  • Colitis / immunology*
  • Colitis / pathology*
  • Colon / pathology
  • Dextran Sulfate / administration & dosage
  • Disease Susceptibility
  • Down-Regulation / drug effects
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Gastrointestinal Microbiome* / drug effects
  • Germ-Free Life
  • Heterozygote
  • Inflammation / pathology
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / metabolism
  • Intestines / immunology*
  • Intestines / pathology
  • Male
  • Mice, Inbred C57BL
  • PPAR gamma / metabolism
  • Receptors, Serotonin / metabolism
  • Serotonin / metabolism*
  • Signal Transduction* / drug effects
  • Tryptophan Hydroxylase / deficiency
  • Tryptophan Hydroxylase / metabolism
  • Up-Regulation / drug effects
  • beta-Defensins / metabolism

Substances

  • Anti-Bacterial Agents
  • PPAR gamma
  • Receptors, Serotonin
  • beta-Defensins
  • Serotonin
  • Dextran Sulfate
  • Tph1 protein, mouse
  • Tryptophan Hydroxylase

Grant support