Cellular and molecular basis of intestinal barrier dysfunction in the irritable bowel syndrome

Abstract

The etiopathogenesis of the irritable bowel syndrome (IBS), one of the most prevalent gastrointestinal disorders, is not well known. The most accepted hypothesis is that IBS is the result of the disturbance of the 'brain-gut axis.' Although the pathophysiological mechanisms of intestinal dysfunction are complex and not completely understood, stress, infections, gut flora, and altered immune response are thought to play a role in IBS development. The intestinal barrier, composed of a single-cell layer, forms a physical barrier that separates the intestinal lumen from the internal milieu. The loss of integrity of this barrier is related with mucosal immune activation and intestinal dysfunction in IBS. The number of mast cells and T lymphocytes is increased in the intestinal mucosa of certain IBS patients, and the mediators released by these cells could compromise the epithelial barrier function and alter nerve signaling within the enteric nervous system. The association of clinical symptoms to structural and functional abnormalities of the mucosal barrier in IBS patients highlights the importance of understanding the physiological role of the gut barrier in the pathogenesis of this disorder. This review summarizes the clinical and experimental evidences indicating the cellular and molecular mechanisms of IBS symptomatology, and its relevance for future translational research.

Keywords: Intestinal barrier function; Irritable bowel syndrome; Mast cells; Tight junctions.

Fig. 1

The apical junctional complex. Transmission electron micrograph showing the apical junctional complex (AJC) between two adjacent enterocytes in the human jejunal mucosa. Just below the base of the microvilli (Mv), the plasma membranes of adjacent cells are in intimate contact at the tight junction (TJ), followed by the adherens junction (AJ) and desmosomes (D). Bar, 1 µm; amplified area bar, 150 nm.

Fig. 2

Molecular components of the tight junction. Tight junctions are composed of integral transmembrane proteins (claudins, occludin and junctional adhesion molecules [JAM]-A, -B and -C) that interact in the paracellular space with proteins on adjacent cells. These transmembrane proteins are connected to the actomyosin cytoskeleton filaments through scaffolding proteins (zonula occludens [ZO] [ZO-1, ZO-2, and ZO-3]).

Fig. 3

Neuro-immune regulation of intestinal barrier function. In the intestinal mucosa, mast cells are strategically located in close proximity to epithelial cells and nerve endings, establishing a bidirectional communication through the release of specific mediators. In addition, mast cells can recruit and activate other immune cells. The interaction of all these elements is crucial to assure an appropriate intestinal barrier homeostatic balance. However, chronic stimulation and the consequent release of inflammatory mediators may lead to tight junction disruption and intestinal barrier dysfunction through myosin light chain kinase-mediated phosphorylation of myosin light chain and subsequent changes in the expression and localization of tight junction proteins. IL, interleukin; IFNγ, interferon gamma; TNF-α, tumor necrosis factor alpha; NGF, nerve growth factor; CRF, corticotropin releasing factor; SP, substance P; ZO, zonula occludens.