Interactions of the intestinal epithelium with the pathogen and the indigenous microbiota: a three-way crosstalk

Abstract

The mucosal surfaces of the gastrointestinal tract harbor a vast number of commensal microbiota that have coevolved with the host, and in addition display one of the most complex relationships with the host. This relationship affects several important aspects of the biology of the host including the synthesis of nutrients, protection against infection, and the development of the immune system. On the other hand, despite the existence of several lines of mucosal defense mechanisms, pathogenic organisms such as Shigella and Salmonella have evolved sophisticated virulence strategies for breaching these barriers. The constant challenge from these pathogens and the attempts by the host to counter them set up a dynamic equilibrium of cellular and molecular crosstalk. Even slight perturbations in this equilibrium may be detrimental to the host leading to severe bacterial infection or even autoimmune diseases like inflammatory bowel disease. Several experimental model systems, including germ-free mice and antibiotic-treated mice, have been used by various researchers to study this complex relationship. Although it is only the beginning, it promises to be an exciting era in the study of these host-microbe relationships.

Figure 1

(a) Healthy epithelial surface. A healthy intestinal epithelial surface acts as a physical and biochemical barrier with key features including the apical brush border, the mucus layer, the presence of antimicrobial peptides (blue black dots) in the lumen, the glycocalyx, and the epithelial tight junctions. Also seen in the illustration are numerous commensal bacteria and a dendritic cell sampling the lumen with its extended dendrites (yellow). (b) Key features of S. typhimurium infected epithelium. Such host pathogen interactions involve translocation of bacterial effectors (green circles) into the epithelial cells, membrane ruffling, bacterial endocytosis, and SCV formation. Chemoatractants are secreted by the epithelial surface that leads to PMN influx. SCV: Salmonella containing vacuole. (c) Intestinal epithelial surface of an antibiotic-treated patient showing enrichment of a set of antibiotic resistant members of the commensal microflora (light blue and brown) such as C. difficle and E. faecalis. The C. difficle proteins, TcdA and Tcdb (red circles) act intracellularly as glycosyltransferases and inhibit Rho, Rac, and Cdc42. The effect of these modifications lead to actin condensation, transcriptional activation of several genes and apoptosis. Other mechanisms that are triggered include basolateral IL8 secretion, apical Hepoxillin A synthesis, and PMN influx in the apical surface.