Breaching the mucosal barrier by stealth: an emerging pathogenic mechanism for enteroadherent bacterial pathogens

The clinical and molecular understanding of bacterial diseases of the gastrointestinal tract, developed largely over the past 50 years, has led to our current assignment of these causative agents into an evolving set of mechanistic categories (see Table ​Table1).1). Early studies revealed that some organisms (Staphylococcus aureus among them) produce toxins in contaminated foods and that, upon ingestion, these preformed toxins trigger a rapid-onset, net jejunal secretion of electrolytes and water, typically lasting less than 24 hours. In these illnesses, the causative organism need not be present in the intestine. In contrast, the “enterotoxigenic” pathogens, typified by Vibrio cholerae and enterotoxigenic Escherichia coli (ETEC), are noninflammatory and must colonize the gastrointestinal tract in order to deliver toxins to the mucosa. These toxins typically effect cAMP- or cGMP-mediated net Cl– secretion, often resulting in a large-volume diarrhea. Recent studies of certain strains of Bacteroides fragilis indicate that these agents can serve as large bowel mediators of enterotoxigenic disease via a toxin that disrupts the mucosal barrier (1). Table 1 Pathogenic mechanisms used by diarrheogenic bacteria Another long-recognized grouping of enteric bacterial diseases is the “invasive” category, which can be subdivided based upon the extent of dissemination within the host. The most superficial invaders, Shigella spp. and enteroinvasive E. coli, have similar, if not identical, virulence properties. These organisms invade the epithelium of the colon and terminal ileum, spread intercellularly via actin-filament projections (2), and cause focal microulcerations of the ileocecal mucosa. The submucosal group is exemplified by Yersinia enterocolitica and Yersinia pseudotuberculosis, which transcytose across the mucosal epithelium and proceed to the regional lymph nodes, causing severe abdominal pain and, occasionally, mesenteric lymphadenitis. Recent clinical and experimental data suggest that Campylobacter jejuni is an invasive pathogen that can translocate across the mucosa, and that may survive submucosally, but does not typically reach the bloodstream (3). The third invasive subgroup is typified by certain Salmonella serovars (e.g., Typhi and Paratyphi) that invade and translocate across the epithelium. These organisms enter and apparently survive for many hours in submucosal monocytes, which may serve to transport these pathogens to distal sites in the host (e.g., spleen, liver, and bone marrow). The characterization of a previously unrecognized group of pathogenic E. coli (i.e., enteropathogenic E. coli [EPEC], enteroaggregative E. coli [EAEC], diffusely adherent E. coli [DAEC], and enterohemmorhagic E. coli [EHEC]) since the 1950s has led to the establishment of the enteroadherent category of disease. These agents colonize the small and/or large intestine, do not appear to be invasive to any appreciable extent in vivo, and, with the exception of shiga-like toxins of EHEC, are not known to elaborate any of the classical enterotoxins, yet they cause diarrheal illness. Classical EPEC serotypes are known to induce “pedestal” or “cup-like” rearrangements, referred to as attaching and effacing lesions, of epithelial cell membranes. The attaching bacteria erode the microvilli via a rearrangement of cytoskeletal actin into host membrane pedestal structures that support the organism. EAEC and DAEC display characteristic, but different, adherence patterns on cultured intestinal cells and have not been shown to cause any striking membrane effacement. Although certain aspects of EPEC pathogenesis, such as adherence and the attaching and effacing phenotype, have been studied elegantly and in detail (4), the mechanisms by which these and other enteroadherent organisms induce inflammation and diarrhea have only recently started to emerge (5). Salmonella enterica serovar Typhimurium (now abbreviated S. Typhimurium) have previously been considered members of the invasive category, because of their invasiveness in cultured cells and their ability to cause a typhoid-like illness in mice. Indeed, S. Typhimurium may occasionally be isolated from extraintestinal sites in humans including the bloodstream, particularly in immunocompromised hosts. However, these pathogens are more typically associated in humans with diarrheal illness of mild to moderate severity accompanied by fever and the appearance of fecal leukocytes. Although S. Typhimurium may trigger limited invasion of the intestine, as may occur with other enteroadherent pathogens, mucosal invasion does not appear to be a prominent aspect of normal disease. As now shown in this issue of the JCI (6), S. Typhimurium appear to be prime examples of organisms that cause diarrheal disease through a general mechanism that may characterize many bacteria commonly placed in the enteroadherent category of intestinal diseases.