title: Serotonin disturbs colon epithelial tolerance of commensal E. coli by increasing NOX2-derived superoxide.
abstract: 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.
authors.affiliation: College of Pharmacy Yeungnam University, 280 Daehak-ro, Gyeongsan 38541, Republic of Korea.
authors.forename: Suhrid
authors.initials: S
authors.lastname: Banskota
authors.affiliation: College of Pharmacy Yeungnam University, 280 Daehak-ro, Gyeongsan 38541, Republic of Korea.
authors.forename: Sushil Chandra
authors.initials: SC
authors.lastname: Regmi
authors.affiliation: College of Pharmacy Yeungnam University, 280 Daehak-ro, Gyeongsan 38541, Republic of Korea.
authors.forename: Jaya
authors.initials: J
authors.lastname: Gautam
authors.affiliation: College of Pharmacy Yeungnam University, 280 Daehak-ro, Gyeongsan 38541, Republic of Korea.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Gurung
authors.affiliation: College of Pharmacy Yeungnam University, 280 Daehak-ro, Gyeongsan 38541, Republic of Korea.
authors.forename: Yu-Jeong
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Department of Anatomy and Histology, College of Korean Medicine, Daegu Hany University, Gyeongsan 38610, Republic of Korea.
authors.forename: Sae Kwang
authors.initials: SK
authors.lastname: Ku
authors.affiliation: School of Chemical Engineering, Yeungnam University, Gyeongsan 38541, Republic of Korea.
authors.forename: Jin-Hyung
authors.initials: JH
authors.lastname: Lee
authors.affiliation: School of Chemical Engineering, Yeungnam University, Gyeongsan 38541, Republic of Korea.
authors.forename: Jintae
authors.initials: J
authors.lastname: Lee
authors.affiliation: College of Pharmacy Yeungnam University, 280 Daehak-ro, Gyeongsan 38541, Republic of Korea.
authors.forename: Hyeun Wook
authors.initials: HW
authors.lastname: Chang
authors.affiliation: Department of Histology, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, Republic of Korea.
authors.forename: Sang Joon
authors.initials: SJ
authors.lastname: Park
authors.affiliation: College of Pharmacy Yeungnam University, 280 Daehak-ro, Gyeongsan 38541, Republic of Korea. Electronic address: jakim@yu.ac.kr.
authors.forename: Jung-Ae
authors.initials: JA
authors.lastname: Kim
mesh_terms: D000818:Animals; D003106:Colon / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D004926:Escherichia coli / Q000378:metabolism / Q000472:pathogenicity; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D000074662:NADPH Oxidase 2 / Q000235:genetics* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics* / Q000378:metabolism
chemical_list: C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D013481:Superoxides; D012701:Serotonin; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2
keywords: Adherent-invasive E. coli; IL-8; Inflammatory Bowel Disease (IBD); NADPH oxidase (NOX) 2; TNFα; Toll-like receptor (TLR)