Role of Stress on Driving the Intestinal Paracellular Permeability

Abstract

The gut epithelium is a polarized monolayer that exhibits apical and basolateral membrane surfaces. Monolayer cell components are joined side by side via protein complexes known as tight junction proteins (TJPs), expressed at the most apical extreme of the basolateral membrane. The gut epithelium is a physical barrier that determinates intestinal permeability, referred to as the measurement of the transit of molecules from the intestinal lumen to the bloodstream or, conversely, from the blood to the gut lumen. TJPs play a role in the control of intestinal permeability that can be disrupted by stress through signal pathways triggered by the ligation of receptors with stress hormones like glucocorticoids. Preclinical studies conducted under in vitro and/or in vivo conditions have addressed underlying mechanisms that account for the impact of stress on gut permeability. These mechanisms may provide insights for novel therapeutic interventions in diseases in which stress is a risk factor, like irritable bowel syndrome. The focus of this study was to review, in an integrative context, the neuroendocrine effects of stress, with special emphasis on TJPs along with intestinal permeability.

Keywords: claudins; corticosterone; gut epithelium; occludin; paracellular permeability; stress.

Figure 1

Intestinal transcellular and paracellular permeability. Transport mechanisms of the epithelial cell monolayer involve the passage of particles through (1) endocytosis and (2) phagocytosis or solutes via (3) facilitated transport. The paracellular route allows the passage of ions and small molecules between the spaces of the lateral membrane of the epithelial cells (4). JAM, junctional adhesion protein; ZO, zonula occludens. Created at Biorender.com.

Figure 2

Stress mediators and their effects in intestinal paracellular permeability. Stress response activates both hypothalamic–pituitary–adrenal (HPA) and sympathetic adrenomedullary axis to promote the secretion of hormones and neurotransmitters that induce paracellular permeability disruption. CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone; VIP, vasoactive intestinal peptide; JAM, junctional adhesion molecule; ZO, zonule occludens. Created at Biorender.com.

Figure 3

Cellular and molecular mechanisms of stress on intestinal paracellular permeability. (1) Corticotropin-releasing hormone (CRH) and other stress mediators induce mast cell degranulation, generating the release of tumor necrosis factor α (TNFα) and tryptase that promote proteinase-activated-receptor-2 (PAR2) degradation. This results in the re-localization of zonula occludens-1 (ZO-1) within the epithelial cell, increasing the intestinal paracellular permeability. (2) TNFα promotes the increase in myosin light chain kinase (MLCK) expression and, subsequently, the phosphorylation of myosin light chain (MLC). This pathway modifies actin filaments and internalizes claudins, increasing intestinal paracellular permeability. (3) Dysbiosis and the disruption of permeability allow the entrance of pathogenic bacteria and their components such as lipopolysaccharide (LPS) and lipoteichoic acid toward the basolateral side of the epithelial monolayer cell. Lipopolysaccharides and lipoteichoic acid interact with receptors, resulting in NOD-like receptor family pyridine-domain-containing (NLRP) inflammasome activation that promote the oxidative stress and autophagia, promoting a decrease in the mucus layer. (4) LPS interaction with the epithelial cell toll-like receptor 4 (TLR-4) results in its activation and the induction of the cytokine production such as TNFα. This facilitates the inflammatory state in the intestinal barrier. ROS, reactive oxygen species; LTA, lipoteichoic acid; JNK, Jannus kinase; VIP, vasoactive intestinal peptide; HSP70, heat shock protein 70; Cldn, claudin; TNFR, TNF receptor. Created at Biorender.com.