Cholera toxin disrupts barrier function by inhibiting exocyst-mediated trafficking of host proteins to intestinal cell junctions.

Cholera toxin (CT), a virulence factor elaborated by Vibrio cholerae, is sufficient to induce the severe diarrhea characteristic of cholera. The enzymatic moiety of CT (CtxA) increases cAMP synthesis in intestinal epithelial cells, leading to chloride ion (Cl(-)) efflux through the CFTR Cl(-) channel. To preserve electroneutrality and osmotic balance, sodium ions and water also flow into the intestinal lumen via a paracellular route. We find that CtxA-driven cAMP increase also inhibits Rab11/exocyst-mediated trafficking of host proteins including E-cadherin and Notch signaling components to cell-cell junctions in Drosophila, human intestinal epithelial cells, and ligated mouse ileal loops, thereby disrupting barrier function. Additionally, CtxA induces junctional damage, weight loss, and dye leakage in the Drosophila gut, contributing to lethality from live V. cholerae infection, all of which can be rescued by Rab11 overexpression. These barrier-disrupting effects of CtxA may act in parallel with Cl(-) secretion to drive the pathophysiology of cholera.

The role of anti(myco)bacterial interventions in the management of IBD: is there evidence at all?

BACKGROUND/AIMS: The etiology of IBD is unknown but may relate to an unidentified bacterial pathogen or an immunological reaction to gut microbiota. Antibiotics have therefore been proposed as a therapy for Crohn's disease (CD) and ulcerative colitis (UC). The aim of this review was to compel the evidence for the use of antibiotics in the treatment of IBD. METHODS: We performed a systematic review of the literature regarding the use of antibiotics for inducing or maintaining remission in IBD. RESULTS: Current data are conflicting, but a recent systematic review of randomized controlled trials has shown a statistically significant effect of antibiotics being superior to placebo for active, perianal and quiescent CD and for active UC. These data have been poorly translated in clinical practice and the place of antibiotics is restricted to certain specific situations in the international guidelines. This is first linked to the difficulties in interpreting clinical trials because of their heterogeneity in study design, endpoints, type of antibiotic and concomitant therapies. The exception to this is the use of either ciprofloxacin or metronidazole for treating CD perianal fistulas. CONCLUSION: The pathology of CD, the likely primary and known secondary pathogens in this disease and the successful responses in animal models all plead for new trials of antibiotics in IBD. This is a call to select patients more carefully, and to continue antibiotics for longer than is customary. Beside antibiotics, new therapeutic approaches that can balance gut dysbiosis should be tested.