Role of Cytolethal Distending Toxin in Altered Stool Form and Bowel Phenotypes in a Rat Model of Post-infectious Irritable Bowel Syndrome

Abstract

Background/AimsCampylobacter jejuni infection is a leading cause of acute gastroenteritis, which is a trigger for post-infectious irritable bowel syndrome (PI-IBS). Cytolethal distending toxin (CDT) is expressed by enteric pathogens that cause PI-IBS. We used a rat model of PI-IBS to investigate the role of CDT in long-term altered stool form and bowel phenotypes.MethodsAdult Sprague-Dawley rats were gavaged with wildtype C. jejuni (C+), a C. jejuni cdtB knockout (CDT-) or saline vehicle (controls). Four months after gavage, stool from 3 consecutive days was assessed for stool form and percent wet weight. Rectal tissue was analyzed for intraepithelial lymphocytes, and small intestinal tissue was stained with anti-c-kit for deep muscular plexus interstitial cells of Cajal (DMP-ICC).ResultsAll 3 groups showed similar colonization and clearance parameters. Average 3-day stool dry weights were similar in all 3 groups, but day-to-day variability in stool form and stool dry weight were significantly different in the C+ group vs both controls (P < 0.01) and the CDT- roup (P < 0.01), but were not different in the CDT- vs controls. Similarly, rectal lymphocytes were significantly higher after C. jejuni (C+) infection vs both controls (P < 0.01) and CDT-exposed rats (P < 0.05). The counts in the latter 2 groups were not significantly different. Finally, c-kit staining revealed that DMP-ICC were reduced only in rats exposed to wildtype C. jejuni.ConclusionsIn this rat model of PI-IBS, CDT appears to play a role in the development of chronic altered bowel patterns, mild chronic rectal inflammation and reduction in DMP-ICC.

Cytolethal Distending Toxin in Salmonella and Campylobacter spp. Isolated from Food Animals and Gastroenteritis Cases in Qatar

“…isolates had a similar rate of occurrence of the genes as gastroenteritis cases, none of the live animals showed any clinical signs of disease. By virtue of its toxicity, CDT has been incriminated in the risk of chronic gastroenteritis sequelae, including Inflammatory Bowel Disease and Inflammatory Bowel Syndrome as shown in studies on rats (Pokkunuri et al, 2012). Knowledge gained on the occurrence of these foodborne pathogens in the food supply system and the presence of the virulence factor could be used to introduce intervention strategies to mitigate their associated risk.…”

“…In a few cases, around 6-7%, patients with gastrointestinal illness may develop sequelae with serious consequences (Hoffmann et al, 2012). Many factors could play roles in exacerbating the risk of gastroenteritis including CDT (Smith & Bayles, 2006;Pokkunuri et al, 2012).…”

“…We used a multidisciplinary epidemiological approach to investigate the occurrence of these foodborne pathogens in diverse populations (non-humans and humans) and determined the presence of the CDT among the pathogens in order to shed light on one of the putative mechanisms of pathogenicity (Smith & Bayles, 2006;Pokkunuri et al, 2012). Qatar was chosen due to its diverse social and cultural population which includes diverse food and methods of food preparation.…”

“…However, the role of the CDT in the pathogenesis of gastroenteritis is not fully understood. By virtue of its toxicity, CDT has been incriminated in the risk of chronic gastroenteritis sequelae, including Inflammatory Bowel Disease as shown in studies on rats (Pokkunuri et al, 2012). CDT has the ability to attack the cells of intestinal villi, which allows normal bacterial biota to enter and cause infection.…”

“…The mechanisms by which these pathogens predispose hosts to these sequelae are poorly understood. Several studies hypothesize the role of CDT (cytolethal distending toxin) in the pathogenesis (Smith & Bayles, 2006;Jindasa, Bloom, Weiss, & Duhamel, 2011;Pokkunuri et al, 2012). However, the data remains scarce.…”