No abstract

Clostridium difficile infection (CDI) is mediated by two major exotoxins, toxin A (TcdA) and toxin B (TcdB), which damage the colonic epithelial barrier and induce inflammatory responses. The function of the colonic vascular barrier during CDI has not been studied. Here we report increased colonic vascular permeability in CDI mice and elevated vascular endothelial growth factor A (VEGF-A) which was induced by infection with a TcdA and/or TcdB-producing strain in vivo but not with a TcdA−TcdB− isogenic mutant. TcdA or TcdB also induced VEGF-A in human colonic mucosal biopsies. Hypoxia-inducible factor (HIF) signaling appeared to mediate toxin-induced VEGF production in colonocytes, which can further stimulate human intestinal microvascular endothelial cells. Neutralization of VEGF-A and inhibition of its signaling pathway each attenuated CDI in vivo. Compared to healthy controls, CDI patients had significantly higher serum VEGF-A, which subsequently decreased after treatment. Our findings indicate critical roles for toxin-induced VEGF-A and colonic vascular permeability in CDI pathogenesis. It may also implicate the pathophysiological significance of gut vascular barrier in response to virulence factors of enteric pathogens. As an alternative to pathogen-targeted therapy, this study may enable new host-directed therapeutic approach for severe, refractory CDI.

Clostridium difficile is well recognized as the leading cause of antibiotic-associated diarrhea, having a significant impact in both health-care and community settings. Central to predisposition to C. difficile infection is disruption of the gut microbiome by antibiotics. Being a Gram-positive anaerobe, C. difficile is intrinsically resistant to a number of antibiotics. Mobile elements encoding antibiotic resistance determinants have also been characterized in this pathogen. While resistance to antibiotics currently used to treat C. difficile infection has not yet been detected, it may be only a matter of time before this occurs, as has been seen with other bacterial pathogens. This review will discuss C. difficile disease pathogenesis, the impact of antibiotic use on inducing disease susceptibility, and the role of antibiotic resistance and mobile elements in C. difficile epidemiology.