Serotonin disturbs colon epithelial tolerance of commensal E. coli by increasing NOX2-derived superoxide

• Published in: Free radical biology & medicine 2017-05, Vol.106, p.196-207
• Main Authors: Banskota, Suhrid, Regmi, Sushil Chandra, Gautam, Jaya, Gurung, Pallavi, Lee, Yu-Jeong, Ku, Sae Kwang, Lee, Jin-Hyung, Lee, Jintae, Chang, Hyeun Wook, Park, Sang Joon, Kim, Jung-Ae
• Format: Article
• Language: English
• Subjects: Adherent-invasive E. coli; Animals; Colon - metabolism; Colon - microbiology; Colon - pathology; Epithelial Cells - metabolism; Epithelial Cells - microbiology; Epithelial Cells - pathology; Escherichia coli - metabolism; Escherichia coli - pathogenicity; Humans; IL-8; Inflammatory Bowel Disease (IBD); Inflammatory Bowel Diseases - drug therapy; Inflammatory Bowel Diseases - metabolism; Inflammatory Bowel Diseases - microbiology; Inflammatory Bowel Diseases - pathology; Mice; NADPH oxidase (NOX) 2; NADPH Oxidase 2 - genetics; NADPH Oxidase 2 - metabolism; Serotonin - metabolism; Serotonin - pharmacology; Superoxides - metabolism; TNFα; Toll-like receptor (TLR); Toll-Like Receptor 2 - genetics; Toll-Like Receptor 2 - metabolism; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2017.02.034

Adherent-invasive E. coli colonization and Toll-like receptor (TLR) expression are increased in the gut of inflammatory bowel disease (IBD) patients. However, the underlying mechanism of such changes has not been determined. In the current study, it was examined whether gut serotonin (5-hydroxytryptamine, 5-HT) can induce adherent-invasive E. coli colonization and increase TLR expression. In a co-culture system, commensal E. coli strain (BW25113, BW) adhered minimally to colon epithelial cells, but this was significantly enhanced by 5-HT to the level of a pathogenic strain (EDL933). Without inducing bacterial virulence, such as, biofilm formation, 5-HT enhanced BW-induced signaling in colon epithelial cells, that is, NADPH oxidase (NOX)-dependent superoxide production, the up-regulations of IL-8, TLR2, TLR4, and ICAM-1, and the down-regulations of E-cadherin and claudin-2. In a manner commensurate with these gene modulations, BW induced an increase in NF-κB and a decrease in GATA reporter signals in colon epithelial cells. However, 5-HT-enhanced BW adhesion and colon epithelial responses were blocked by knock-down of NOX2, TLR2, or TLR4. In normal mice, 5-HT induced the invasion of BW into gut submucosa, and the observed molecular changes were similar to those observed in vitro, except for significant increases in TNFα and IL-1β, and resulted in death. In dextran sulfate sodium-induced colitis mice (an IBD disease model), in which colonic 5-HT levels were markedly elevated, BW administration induced death in along with large amount of BW invasion into colon submucosa, and time to death was negatively related to the amount of BW injected. Taken together, our results demonstrate that 5-HT induces the invasion of commensal E. coli into gut submucosa by amplifying commensal bacteria-induced epithelial signaling (superoxide production and the inductions of NOX2 and TLR2/TLR4). The authors suggest that these changes may constitute the molecular basis for the pathogenesis of IBD. [Display omitted] •5-HT induces adhesive invasion of commensal E. coli to colon epithelial cells.•Commensal E. coli induces colon epithelial NOX2 activation via TLR-2 and TLR-4.•5-HT amplifies commensal E. coli-induced up-regulation of TLR2/TLR4, IL-8, and ICAM-1 via NOX2.•5-HT enhances E. coli-induced down-regulation of E-cadherin.•Inoculation of commensal E.coli with high 5-HT levels induces fatal colon inflammation in mice.