A porous defense: the leaky epithelial barrier in intestinal disease

Abstract

A critical function of the intestinal mucosa is to form a barrier that separates luminal contents from the interstitium. This intestinal barrier is compromised in a number of intestinal diseases, most notably inflammatory bowel disease. In vitro studies have demonstrated that cytokines elaborated by immune cells can cause the mucosal barrier to become leaky; these cytokines are known to be increased in intestinal mucosa involved in inflammatory bowel disease. Detailed information describing the mechanisms by which altered cytokine signaling occurs is not available, but recent data implicate the cytoskeleton within epithelial cells as a critical regulator of the mucosal barrier under physiological and pathophysiological conditions. Using available data, we describe a model of intestinal disease where an initial insult to the epithelial barrier may trigger a selfamplifying cycle of immune activation, cytokine release, and further barrier dysfunction. This model is supported by the observation that pharmacological abrogation of cytokine signaling corrects both barrier defects and clinical disease in animal models and human patients, although such therapy clearly has multiple mechanisms. Other therapeutic targets that represent strategies to prevent or reverse disease processes are also considered. The overarching hypothesis is that modulation of the mucosal epithelial barrier plays a critical role in the initiation and propogation of inflammatory intestinal diseases.

Alcohol, intestinal bacterial growth, intestinal permeability to endotoxin, and medical consequences: Summary of a symposium

“…This was initially recognized in patients with Crohn's disease (Hollander, 1988;Ukabam, 1983), but has subsequently been reported in patients or experimental models of a spectrum of inflammatory, immune-mediated, and infectious intestinal diseases (Clayburgh et al, 2004). Tumor necrosis factor-α (TNF-α) appears to play an important role in regulating intestinal epithelial barrier function since TNFα-neutralizing antibodies restored barrier function in Crohn's disease patients (Suenaert et al, 2002).…”

Epithelial myosin light chain kinase expression and activity are upregulated in inflammatory bowel disease

“…While the relevance of epithelial barrier dysfunction to disease pathogenesis remains a subject of active investigation, it is well accepted that compromised barrier function is a common feature of infectious, ischemic, and immune-mediated intestinal disease. 1 This has been well defined in Crohn's disease (CD), where barrier defects can be detected in patients as well as a subset of their healthy relatives. [2][3][4] Moreover, barrier dysfunction may precede clinical evidence of disease 5 and may serve as a marker of impending disease reactivation.…”

Enterotoxigenic Bacteroides fragilis: A potential instigator of colitis

“…1 IBD patients exhibit excess epithelial permeability that enhances direct contact between the colonic flora and the immune system possibly permitting disease initiation. [2][3][4] In fact, Crohn's disease is partially responsive to antibiotic treatment (e.g., metronidazole, ciprofloxacin, or rifaximin), suggesting that enteric bacteria are important in disease pathogenesis.…”