Layered defense: how mucus and tight junctions seal the intestinal barrier

Abstract

The colonic mucosa provides a vital defensive barrier separating the body from the microbial populations residing in the intestinal lumen. Indeed, growing evidence shows that loss of this barrier may cause disease or exacerbate disease progression. The loss of barrier integrity increases the translocation of bacterial antigens and stimulates inflammation in the intestinal mucosa, which is the central pathological feature of inflammatory bowel diseases (IBDs). This review focuses on how intestinal mucus and intercellular tight junctions (TJs) act together to maintain the integrity of the colonic barrier and how barrier integrity is dysregulated in IBD.

Keywords: Epithelial barrier; IBD; Inflammation; Mucus; Tight junction.

Fig. 1

Protective layers of the colonic mucosal barrier. The outer mucus layer, composed of Muc2 and various carbohydrate modifications, interacts with colonic microflora, while the density of the inner layer prevents bacterial penetration. The innermost mucus layer, the glycocalyx, is attached to the plasma membrane. Together, the inner and outer mucus layer limit abrasion and trap bacteria, thereby restricting their contact with the epithelia. In general, the mucus limits contact of bacteria with underlying epithelial cells but does not restrict access of bacterial metabolites. The epithelial paracellular barrier is composed of intercellular contacts called tight junctions (TJs). TJ strands, composed of proteins called claudins, connect apposing cells and occlude the paracellular space. Some claudins form ion pores within the TJ (pore pathway, inset), which selectively permit ion and water exchange. However, bacterial products may breach TJ defenses upon separation (a) or rupture of the TJ strands (b). Epithelial cell turnover likely helps to remove attached bacteria, and mucus flux ensures trapped bacteria are eliminated. Stem cells residing in the crypt bases produce progeny that migrate toward the lumen surface. While doing so they differentiate, producing goblet cells that secrete mucins. Differentiating cells also change the complement of claudins that they express, such that pore forming claudins are more highly expressed in the crypt-base compared to the luminal surface [54]