Intestinal epithelial responses to enteric pathogens: effects on the tight junction barrier, ion transport, and inflammation

Abstract

The effects of pathogenic organisms on host intestinal epithelial cells are vast. Innumerable signalling pathways are triggered leading ultimately to drastic changes in physiological functions. Here, the ways in which enteric bacterial pathogens utilise and impact on the three major physiological functions of the intestinal epithelium are discussed: alterations in the structure and function of the tight junction barrier, induction of fluid and electrolyte secretion, and activation of the inflammatory cascade. This field of investigation, which was virtually non-existent a decade ago, has now exploded, thus rapidly expanding our understanding of bacterial pathogenesis. Through increased delineation of the ways in which microbes alter host physiology, we simultaneous gain insight into the normal regulatory mechanisms of the intestinal epithelium.

Figure 1

Epithelial tight junctions (TJ) can be altered by various pathogens, as well as by their elaborated toxins. These effects may result from direct modification of TJ proteins such as occludin, claudin, and ZO-1, or by alteration of the perijunctional actomyosin ring. The intermediary signalling steps in these processes have not been fully characterised, and the exact relationship between TJ protein disruption and actomyosin ring disruption is presently not clear. PKCα, protein kinase Cα; PKCβ, protein kinase Cβ; EPEC, enteropathogenic Escherichia coli; MLC, myosin light chain; HA, haemagglutinin.

Figure 2

Various enteric pathogens elicit a chloride secretory response by stimulating either of the two apical chloride secretory channels, cystic fibrosis transmembrane conductance regulator (CFTR) or calcium activated chloride channel (CaCC). In addition to the various mechanisms that directly activate these channels, proinflammatory processes induced by various pathogens also have the ability to stimulate chloride secretion. Thus induction of the proinflammatory cytokine interleukin 8 stimulates the transmigration of neutrophils to the lumen where they secrete 5′AMP. Conversion of this nucleotide to the secretagogue adenosine leads to chloride secretion. Similarly, induction of nitric oxide by various pathogens leads to cGMP dependent chloride secretion. DAG, diacylglycerol; TDH, thermostable direct haemolysin; TRH, TDH related haemolysin; NO, nitric oxide; PGE₂, prostaglandin E₂; Cox-2, cyclooxygenase 2; ETEC, enterotoxigenic E coli; EAEC, enteroaggregative E coli; PLC, phospholipase C; CaMKII, calmodulin dependent protein kinase; PIP2, phosphatidyl inositol 4,5-bisphosphate; IP3, inositol 1,4,5-trisphosphate.

Figure 3

The key proinflammatory pathway induced by enteric pathogens results in nuclear factor κB (NFκB) mediated transcription of interleukin 8 (IL-8). Secreted IL-8, in addition to factors such as pathogen elicited epithelial derived chemoattractant (PEEC), stimulates the transepithelial migration of neutrophils. Intraluminal neutrophils target the pathogens for destruction. The precise bacterial components involved in evoking the inflammatory response and the details of the signalling pathways involved have not been determined in all cases. The mitogen activated protein kinases (p38, c-Jun NH2 terminal kinase (JNK), and ERK1/2) play a central role in many of these pathways. Pathogen associated molecular patterns, such as lipopolysaccharide (LPS) and flagellin, bind to cognate toll-like receptors (TLRs) to elicit a response. Finally, non-IL-8 mediated proinflammatory pathways also exist in epithelial cells. PKC, protein kinase C; EPEC, enteropathogenic Escherichia coli; IκB, inhibitory protein κB; IKK, IκB kinase; NIK, NFκB inducing kinase; AP-1, activating protein 1.