Mechanisms regulating intestinal barrier integrity and its pathological implications

Abstract

The gastrointestinal tract is a specialized organ in which dynamic interactions between host cells and the complex environment occur in addition to food digestion. Together with the chemical barrier of the mucosal layer and the cellular immune system, the epithelial cell layer performs a pivotal role as the first physical barrier against external factors and maintains a symbiotic relationship with commensal bacteria. The tight junction proteins, including occludin, claudins, and zonula occludens, are crucial for the maintenance of epithelial barrier integrity. To allow the transport of essential molecules and restrict harmful substances, the intracellular signaling transduction system and a number of extracellular stimuli such as cytokines, small GTPases, and post-translational modifications dynamically modulate the tight junction protein complexes. An imbalance in these regulations leads to compromised barrier integrity and is linked with pathological conditions. Despite the obscurity of the causal relationship, the loss of barrier integrity is considered to contribute to inflammatory bowel disease, obesity, and metabolic disorders. The elucidation of the role of diseases in barrier integrity and the underlying regulatory mechanisms have improved our understanding of the intestinal barrier to allow the development of novel and potent therapeutic approaches.

Fig. 1. Intestinal epithelial barrier.

Epithelial cells form a layer that functions as a physical barrier facilitated by tight connections between each cell. A number of tight junction protein components seal the paracellular pathway and conduct gate and fence functions. The mucosal layer is a chemical barrier that is critical to limit the contact between the microbiome and epithelial cells. Immune cells are also a major participant in the immune response and the tolerance of the host against external substances. The graphical illustration was drawn by using the images from Servier Medical Art by Servier, with slight modifications (http://www.servier.com/Powerpoint-image-bank, https://creativecommons.org/licenses/by/3.0/)

Fig. 2. Factors affecting intestinal barrier integrity and pathological implications.

Genetic susceptibility, diet, and a number of environmental conditions affect barrier integrity directly or indirectly through changes in microbiota. Compromised barrier integrity leads to an immune response and contributes to several pathological conditions