The role of gut inflammation in recurrent Clostridium difficile-associated disease.

Clostridium difficile is a scourge of nursing-home and hospital-based medicine. The bacterium itself is a grampositive, spore-forming, toxin-producing anaerobic gastrointestinal pathogen.With the development of NAP1 variants, it has developed a clinical impact of some significance with estimated annual costs to the national healthcare system of upward of half a million hospital and nursinghome infections, at least $1 billion in patient costs, and 14 000 deaths per year in the United States [1, 2]. The personal costs are not trivial. Recurrent disease is common and life threatening. Antibiotic therapy fails in up to 25% of patients even after 10–15 days of therapy. Despite these statistics, we are only now beginning to understand the reasons for recurrent infection. The article by El Feghaly et al in the current issue of Clinical Infectious Diseases is the first to study cellular inflammatory components involved in persistent diarrhea in Clostridium difficile infection (CDI) [3]. The concept that bacteria persist and benefit from inflammation in their host is not a new one. Another gastrointestinal bacteria that triggers inflammation, as part of a nutritional strategy, is Helicobacter pylori. Much like C. difficile, this bacteria is commonly found among humans and produces a range of response from asymptomatic colonization to complicated, severe disease. The crux of CDI lies with the toxins produced by these bacteria. Clostridium difficile toxins TcdA, Tcdb, and CDT/ binary toxin initiate the host’s humoral response. Kelly et al have shown CDI resolution as well as protective immunity is related to level of serum immunoglobulin G (IgG) antitoxin [4, 5]. However, the antitoxin A IgG level at day 12 of the CDI did not appear to increase the predictability of continued, recurrent CDI in their cohort of patients [5, 6]. Several current clinical trials are examining the protective nature of the humoral response. The host’s immediate cellular response following onset of CDI and TcdA and TcdB secretion is the cytokine release of interleukin 8 (IL-8) from colonic epithelial cells and mobilization of regional immune effector cells (similar to H. pylori in the stomach). Onderdonk et al’s elegant study, with gnotobiotic mice monoassociated with C. difficile, demonstrated that the primary cellular immune response to toxin was edema and polymorphonuclear cell infiltrate, while also demonstrating the effectiveness of vancomycin and the rapid generation of resistance to clindamycin [7]. The resulting intense immune activation (primarily neutrophilic) results in the clinically classic endoscopic findings of the volcano lesion and pseudomembranes. Similar disruption in gut homeostasis is found in acute, active inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, where mucosal pathology is characterized by an influx of innate immune effector cells (primarily neutrophils, macrophages, dendritic cells, and natural killer T cells) producing an adaptive immune response cells including T and B cells. The immune response in these conditions is characterized by an imbalance of T-cell subgroups, including Th1, Th2, Th17, and Treg lymphocytes. With the increased evidence of bacterial dysbiosis and antigen processing in the pathogenesis of IBD, it is not surprising that similar aspects of gut inflammation are shared by both inflammatory diseases of the bowel characterized by gut flora changes and infectious diseases of the intestine characterized by often-times persistent inflammation of the intestine. Received 21 February 2013; accepted 25 February 2013; electronically published 13 March 2013. Correspondence: Bruce Yacyshyn, MD, Department of Medicine, University of Cincinnati School of Medicine, 231 Albert B. Sabin Way, ML 0595, Cincinnati, OH 45267 (bruce. yacyshyn@uc.edu). Clinical Infectious Diseases 2013;56(12):1722–3 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/cid/cit151