Deciphering internal and external factors influencing intestinal junctional complexes

Abstract

The intestinal barrier, an indispensable guardian of gastrointestinal health, mediates the intricate exchange between internal and external environments. Anchored by evolutionarily conserved junctional complexes, this barrier meticulously regulates paracellular permeability in essentially all living organisms. Disruptions in intestinal junctional complexes, prevalent in inflammatory bowel diseases and irritable bowel syndrome, compromise barrier integrity and often lead to the notorious "leaky gut" syndrome. Critical to the maintenance of the intestinal barrier is a finely orchestrated network of intrinsic and extrinsic factors that modulate the expression, composition, and functionality of junctional complexes. This review navigates through the composition of key junctional complex components and the common methods used to assess intestinal permeability. It also explores the critical intracellular signaling pathways that modulate these junctional components. Lastly, we delve into the complex dynamics between the junctional complexes, microbial communities, and environmental chemicals in shaping the intestinal barrier function. Comprehending this intricate interplay holds paramount importance in unraveling the pathophysiology of gastrointestinal disorders. Furthermore, it lays the foundation for the development of precise therapeutic interventions targeting barrier dysfunction.

Keywords: C. elegans; Drosophila; Gastrointestinal diseases; Gut barrier; extrinsic modulators; intrinsic modulators; junctional complex; microbes; mouse model.

Figure 1.

Comparative analysis of junctional complexes across evolutionary models of intestinal barriers. (a), in the vertebrate intestine, junctional complexes comprise tight junction, adherens junction, and desmosomes, with each complex containing multiple key junctional proteins. (b), in the Drosophila intestine, adherens junctions and septate junctions form the protective junctional complex among intestinal epithelial cells. Many evolutionarily conserved junctional proteins are expressed in the fly intestinal barrier. (c), the C. elegans apical junction consists of the cadherin-catenin complex and DLG-1/AJM-1 complex, with many junctional proteins sharing homology with higher species.

Figure 2.

Popular methods for assessing intestinal permeability. (a), the oral probe excretion assay is a widely employed indirect method where probe molecules traverse the gastrointestinal system and potentially cross the intestinal barrier, subsequently quantified through renal excretion assays to gauge intestinal permeability. (b), the transepithelial electrical resistance (TEER) assay measures the electrical resistance across a cell monolayer, commonly used to assess the integrity and barrier function of epithelial or endothelial cell layers. (c), the gut permeability staining assay involves the visualization of fluorescently labeled molecules or tracers that permeate through the gut epithelium, thus providing insights into intestinal barrier integrity and permeability. This method is commonly used in model organisms with transparent anatomy.

Figure 3.

A summary scheme of the intrinsic cellular signaling pathways modulating intestinal permeability.

Figure 4.

Gut microbes and common chemicals regulate intestinal junctional complexes in a complex manner. (a), many beneficial microbes (e.g., L. plantarum, A. muciniphila, B. longum) promote the gut barrier integrity and reduce cytokine release and inflammation. (b), detrimental microbes (e.g., C. albicans, E. faecalis, S. aureus) undermine gut barrier integrity by diminishing junctional protein expression and organization. (c), a summary of microbes and chemicals that are known to affect gut barrier permeability through diverse mechanisms.