Irritable Bowel Syndrome: Role of Gut Bacteria and Bacterial Toxins

Irritable bowel syndrome (IBS) is a common condition affecting 10-15% of the population. While the precise aetiology remains unknown, our group has focused on the contributions of altered gut flora to IBS, including links between acute gastroenteritis and post-infectious IBS (PI-IBS) and the role of small intestinal bacterial overgrowth (SIBO). Breath testing and culture of small intestinal aspirates indicate that SIBO is present in over one-third of IBS subjects and almost two-thirds of diarrhoea-predominant IBS (D-IBS) subjects, but only one-tenth of non-IBS subjects. The success of antibiotic therapies in impacting IBS phenotypes also supports a bacterial role in IBS. Four large-scale multi-centre trials indicate that rifaximin significantly reduces SIBO and non-constipation IBS with little bacterial resistance or reduction of benefit in successive retreatments. To elucidate the mechanisms underlying PI-IBS, we developed a rat model using Campylobacter jejuni, the most common identified cause of acute gastroenteritis. This model mirrors many findings in human IBS subjects, including altered stool form more than three months after clearing initial infection, SIBO, increased intraepithelial lymphocytes (IELs), reductions in deep muscular plexus interstitial cells of Cajal (DMPICCs), required for normal intestinal motility, and increases in specific mucosal defence mediators. Common to all pathogens causing gastroenteritis is cytolethal distending toxin (Cdt). We developed a rat model using a mutant C. jejuni lacking Cdt, which demonstrated significantly ameliorated bowel phenotypes including SIBO and IELs and no reduction in DMP-ICCs, strongly implicating Cdt in the development of IBS phenotypes. Further, early exposure to C. jejuni appears to mitigate the acute effects of second infections, which suggested immunity might play a role in IBS development. Our recent data indicating molecular mimicry between Cdt and neural elements of the gut support this hypothesis and may form the basis for future biomarkers and potential therapies directed at the underlying causes of IBS.