Gut permeability and mucosal inflammation: bad, good or context dependent

Abstract

Inflammatory bowel disease (IBD) is a multifactorial disease. A breach in the mucosal barrier, otherwise known as "leaky gut," is alleged to promote mucosal inflammation by intensifying immune activation. However, interaction between the luminal antigen and mucosal immune system is necessary to maintain mucosal homeostasis. Furthermore, manipulations leading to deregulated gut permeability have resulted in susceptibility in mice to colitis as well as to creating adaptive immunity. These findings implicate a complex but dynamic association between mucosal permeability and immune homeostasis; however, they also emphasize that compromised gut permeability alone may not be sufficient to induce colitis. Emerging evidence further supports the role(s) of proteins associated with the mucosal barrier in epithelial injury and repair: manipulations of associated proteins also modified epithelial differentiation, proliferation, and apoptosis. Taken together, the role of gut permeability and proteins associated in regulating mucosal inflammatory diseases appears to be more complex than previously thought. Herein, we review outcomes from recent mouse models where gut permeability was altered by direct and indirect effects of manipulating mucosal barrier-associated proteins, to highlight the significance of mucosal permeability and the non-barrier-related roles of these proteins in regulating chronic mucosal inflammatory conditions.

Conflict of interest statement

DISCLOSURE

The authors declared no conflict of interest.

Figures

Figure 1

The intestinal epithelium constitutes a physical and biochemical barrier to separate effectively the luminal antigens and mucosal immune system. (a) A pathological breach in the mucosal barrier induces hyperactivation of the mucosal immune system and chronic inflammation. (b) However, a leaky gut due to opening of the tight junctions alone may not be sufficient to induce mucosal inflammation, but rather can induce adaptive immune response due to the heightened immune system. The ultimate outcome may depend on potential non-junctional effect/s of the barrier-associated protein/s modified under inflammatory conditions.

Figure 2

Alterations in tight junction proteins expression/cellular distribution may influence mucosal inflammatory conditions by modulating mucosal homeostasis and gut permeability. (a) Pathological (upregulated) expression of claudin-1 in mouse gut epithelium hyperactivates Notch-signaling to inhibit goblet cell/Mucin-2 synthesis, which in turn increases susceptibility to chronic inflammation. (b) Increased claudin-2 expression in mouse gut epithelium, similar to IBD patients, increases gut permeability and colonocyte proliferation. Presence of anergic macrophages and increased numbers of regulatory T cells (Treg cells) in the lamina propria of claudin-2 transgenic mice suggest immune compensation. As expected, these mice are resistant to experimentally induced colitis.