Microbial Metabolite Regulation of Epithelial Cell-Cell Interactions and Barrier Function

Abstract

Epithelial cells that line tissues such as the intestine serve as the primary barrier to the outside world. Epithelia provide selective permeability in the presence of a large constellation of microbes, termed the microbiota. Recent studies have revealed that the symbiotic relationship between the healthy host and the microbiota includes the regulation of cell-cell interactions at the level of epithelial tight junctions. The most recent findings have identified multiple microbial-derived metabolites that influence intracellular signaling pathways which elicit activities at the epithelial apical junction complex. Here, we review recent findings that place microbiota-derived metabolites as primary regulators of epithelial cell-cell interactions and ultimately mucosal permeability in health and disease.

Keywords: SCFAs; bacterial metabolites; hypoxanthine; indoles; inflammation; intestinal epithelial cells; intestinal mucosal barrier; polyamines; secondary bile acids; tight junctions.

Figure 1

The contribution of the microbiota to “physiologic hypoxia”. Shown here are histologic sections of healthy colon derived from colonized (A) or germ-free (B) mice documenting low-oxygen regions (red) visualized by staining with pimonidazole, a dye that stains only in low-oxygen tensions. Nuclear counter-stain with DAPI is shown in blue. Note the near total lack of pimonidazole localization in the absence of microbial colonization.

Figure 2

Microbial-derived butyrate regulates epithelial tight junction expression and function. Shown here is the influence of butyrate on tight junction protein expression. Through the actions of butyrate on HDACs and HIF, butyrate influences the expression of multiple TJ-associated proteins, including those indicated here. See text for further clarification.

Figure 3

Microbe-derived indole regulates epithelial tight junction function. Indoles act through the aryl hydrocarbon receptor (AHR) to inhibit ezrin and myosin light-chain (MLC) kinase activity.

Figure 4

Purines derived from microbial sources influence the epithelial apical tight junction actin complex. Purines such as hypoxanthine are derived, in part, from microbial sources and are salvaged as templates for ATP generation that supports actin polymerization of G-actin to F-actin in the apical epithelial TJ complex.