title: Pathophysiological mechanisms of diarrhea caused by the Vibrio cholerae O1 El Tor variant: an in vivo study in mice.
abstract: Cholera is caused by infection with Vibrio cholerae. This study aimed to investigate the pathophysiology of diarrhea caused by the V. cholerae O1 El Tor variant (EL), a major epidemic strain causing severe diarrhea in several regions. In the ligated ileal loop model of EL-induced diarrhea in the ICR mice, a cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor and a calcium-activated chloride channel (CaCC) inhibitor similarly inhibited intestinal fluid secretion. In addition, barrier disruption and NF-κB-mediated inflammatory responses, e.g., iNOS and COX-2 expression, were observed in the infected ileal loops. Interestingly, intestinal fluid secretion and barrier disruption were suppressed by NF-κB and COX-2 inhibitors, whereas an iNOS inhibitor suppressed barrier disruption without affecting fluid secretion. Furthermore, EP2 and EP4 PGE2 receptor antagonists ameliorated the fluid secretion in the infected ileal loops. The amount of cholera toxin (CT) produced in the ileal loops by the EL was ∼2.4-fold of the classical biotype. The CT transcription inhibitor virstatin, a toll-like receptor-4 (TLR-4) antibody and a CT antibody suppressed the EL-induced intestinal fluid secretion, barrier disruption and COX-2 expression. The CT at levels detected during EL infection induced mild intestinal barrier disruption without inducing inflammatory responses in mouse intestine. Collectively, this study indicates that CT-induced intestinal barrier disruption and subsequent TLR-4-NF-κB-mediated COX-2 expression are involved in the pathogenesis of EL-induced diarrhea and represent promising novel therapeutic targets of cholera.
authors.affiliation: a Department of Physiology , Faculty of Science, Mahidol University , Ratchathewi , Bangkok , Thailand.
authors.forename: Saravut
authors.initials: S
authors.lastname: Satitsri
authors.affiliation: b Graduate Program in Translational Medicine, Research Center, Faculty of Medicine, Ramathibodi Hospital, Mahidol University , Ratchathewi , Bangkok , Thailand.
authors.forename: Pawin
authors.initials: P
authors.lastname: Pongkorpsakol
authors.affiliation: c Graduate Studies, Faculty of Allied Health Science, Thammasat University , Rangsit , Prathumthani , Thailand.
authors.forename: Potjanee
authors.initials: P
authors.lastname: Srimanote
authors.affiliation: a Department of Physiology , Faculty of Science, Mahidol University , Ratchathewi , Bangkok , Thailand.|d Excellent Center for Drug Discovery, Faculty of Science, Mahidol University , Ratchathewi , Bangkok , Thailand.|e Center of Excellence on Medical Biotechnology (CEMB), S&T Postgraduate Education and Research Development Office (PERDO), Ministry of Education , Bangkok , Thailand.
authors.forename: Varanuj
authors.initials: V
authors.lastname: Chatsudthipong
authors.affiliation: a Department of Physiology , Faculty of Science, Mahidol University , Ratchathewi , Bangkok , Thailand.|b Graduate Program in Translational Medicine, Research Center, Faculty of Medicine, Ramathibodi Hospital, Mahidol University , Ratchathewi , Bangkok , Thailand.|d Excellent Center for Drug Discovery, Faculty of Science, Mahidol University , Ratchathewi , Bangkok , Thailand.|e Center of Excellence on Medical Biotechnology (CEMB), S&T Postgraduate Education and Research Development Office (PERDO), Ministry of Education , Bangkok , Thailand.
authors.forename: Chatchai
authors.initials: C
authors.lastname: Muanprasat
mesh_terms: D000818:Animals; D015373:Bacterial Typing Techniques; D002087:Butyrates / Q000494:pharmacology; D018118:Chloride Channels / Q000037:antagonists & inhibitors; D002771:Cholera / Q000382:microbiology* / Q000503:physiopathology*; D002772:Cholera Toxin / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics; D003967:Diarrhea / Q000209:etiology / Q000382:microbiology* / Q000503:physiopathology*; D015232:Dinoprostone / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D004751:Enteritis / Q000276:immunology / Q000382:microbiology / Q000503:physiopathology; D014644:Genetic Variation; D005838:Genotype; D007422:Intestines / Q000187:drug effects / Q000382:microbiology* / Q000821:virology; D051379:Mice; D018181:Mice, Inbred CFTR; D008813:Mice, Inbred ICR; D053644:Naphthalimides / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D041241:Vibrio cholerae O1 / Q000235:genetics / Q000302:isolation & purification / Q000472:pathogenicity*
chemical_list: D002087:Butyrates; D018118:Chloride Channels; D053644:Naphthalimides; C505381:virstatin; D002772:Cholera Toxin; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone
keywords: CFTR; El Tor variant; PGE2; Vibrio cholera; cholera; diarrhea; inflammation