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.

Porcine circovirus type 2 exploits JNK-mediated disruption of tight junctions to facilitate Streptococcus suis translocation across the tracheal epithelium

“…TJ are responsible for the integrity and function of the epithelial barrier, and once damaged, the risk of infection with exogenous pathogens will greatly increase; ZO-1 and occludin are known to play a primary role in the maintenance of the epithelial barrier [31,32]. In the present study, we demonstrate that PCV2 infection downregulated the expression of TJ ZO-1 and occludin in the respiratory epithelium, increased the barrier permeability and contributed to the translocation of the bacterial pathogen SS2.…”

The early life microbiota protects neonatal mice from pathological small intestinal epithelial cell shedding

“…The intestinal epithelium is the first line of defence between the luminal gut contents and the host. IEC integrity is maintained by a delicate balance of proliferation and cell shedding in the intestinal crypts and tips of the villi, respectively [8]. As such, regulation and maintenance of barrier integrity at the intestinal epithelial interface is vital to prevent entry of luminal microbes into the systemic circulation that may induce detrimental inflammatory responses.…”

“…Indeed, recent studies indicate that the microbiota, and certain microbiota members, modulate transcriptional and functional intestinal epithelial cell (IEC) responses through pathological and immune-mediated mechanisms [6,7]. A central output of these interactions is the reinforcement of the gut barrier, which is achieved through constant replenishment of cells [8]. Intestinal epithelial cells are 'born' in the crypts of Lieberkuhn from where they migrate to the tips of the intestinal villi and are lost into the intestinal lumen through a homeostatic process known as cell shedding [9,10].…”

Intestinal intermediate filament polypeptides in C. elegans: Common and isotype-specific contributions to intestinal ultrastructure and function

“…Surface-covering epithelia separate the hostile exterior from the body interior while facilitating regulated exchange between both compartments [1][2][3][4] . The functional dichotomy becomes particularly relevant in the intestine.…”