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

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          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.

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          Author and article information

          Journal
          Free Radic. Biol. Med.
          Free radical biology & medicine
          Elsevier BV
          1873-4596
          0891-5849
          May 2017
          : 106
          Affiliations
          [1 ] College of Pharmacy Yeungnam University, 280 Daehak-ro, Gyeongsan 38541, Republic of Korea.
          [2 ] Department of Anatomy and Histology, College of Korean Medicine, Daegu Hany University, Gyeongsan 38610, Republic of Korea.
          [3 ] School of Chemical Engineering, Yeungnam University, Gyeongsan 38541, Republic of Korea.
          [4 ] Department of Histology, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, Republic of Korea.
          [5 ] College of Pharmacy Yeungnam University, 280 Daehak-ro, Gyeongsan 38541, Republic of Korea. Electronic address: jakim@yu.ac.kr.
          Article
          S0891-5849(17)30106-5
          10.1016/j.freeradbiomed.2017.02.034
          28216386
          3fa92425-48eb-464f-b3b8-3f9ba8448875
          History

          Adherent-invasive E. coli,IL-8,Inflammatory Bowel Disease (IBD),NADPH oxidase (NOX) 2,TNFα,Toll-like receptor (TLR)

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