Inflammatory and Microbiota-Related Regulation of the Intestinal Epithelial Barrier

Abstract

The intestinal epithelial barrier (IEB) is one of the largest interfaces between the environment and the internal milieu of the body. It is essential to limit the passage of harmful antigens and microorganisms and, on the other side, to assure the absorption of nutrients and water. The maintenance of this delicate equilibrium is tightly regulated as it is essential for human homeostasis. Luminal solutes and ions can pass across the IEB via two main routes: the transcellular pathway or the paracellular pathway. Tight junctions (TJs) are a multi-protein complex responsible for the regulation of paracellular permeability. TJs control the passage of antigens through the IEB and have a key role in maintaining barrier integrity. Several factors, including cytokines, gut microbiota, and dietary components are known to regulate intestinal TJs. Gut microbiota participates in several human functions including the modulation of epithelial cells and immune system through the release of several metabolites, such as short-chain fatty acids (SCFAs). Mediators released by immune cells can induce epithelial cell damage and TJs dysfunction. The subsequent disruption of the IEB allows the passage of antigens into the mucosa leading to further inflammation. Growing evidence indicates that dysbiosis, immune activation, and IEB dysfunction have a role in several diseases, including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and gluten-related conditions. Here we summarize the interplay between the IEB and gut microbiota and mucosal immune system and their involvement in IBS, IBD, and gluten-related disorders.

Keywords: IBD; IBS; celiac disease; gut microbiota; intestinal epithelial barrier; mucosal immune system; non-celiac gluten sensitivity.

Figure 1

Schematic representation of the junctional complex in intestinal epithelium. Molecules can cross the intestinal epithelial monolayer through the intercellular space (paracellular route) or through the cells (transcellular route). The junctional complex involved in paracellular pathway includes tight junctions, adherens junctions, gap junctions and desmosomes. Tight junctions are composed of transmembrane proteins such as claudins, occludin, junctional adhesion molecule (JAM), and zonula occludens proteins (ZOs). ZOs, act as scaffold proteins, connecting claudins and occludin to cytoskeletal actin.

Figure 2

Alteration of IEB in irritable bowel syndrome, inflammatory bowel disease and celiac disease. (A) In irritable bowel syndrome (IBS), tryptase, histamine, and interferon-γ (IFN-γ) are increased and can contribute to TJ disruption. In addition, IL-9 is produced by innate lymphoid cells, T helper cells and mast cells. This latter cell population has a key role in IBS pathophysiology, and can modify TJ protein expression. In addition, immune mediators, including histamine, serotonin and proteases evoke sensory afferent over-stimulation and contribute to symptom generation. In celiac disease (CD), intestinal epithelial cells recognize gluten peptides through CXCR3, which increases IEB permeability through zonulin release and its transactivation of epidermal growth factor receptor (EGFR) and protease activated receptor 2 (PAR-2). Transcytosis of gluten peptides occurs after peptide recognition by secretory immunoglobulin A (SIgA). A reduction in the expression of E-cadherin and β-catenin was found in intestinal biopsies of CD patients. Active tissue transglutaminase2 (tTG2) deamidates gluten peptides, contributing to the development of a cell mediated pro-inflammatory immune response. (B) Genetics, environment, diet, immune system dysregulation and dysbiosis represent some of the complex mechanisms responsible for inflammatory bowel diseases (IBD). Inflammation down-regulates TJs proteins contributing to IEB alteration. In IBD patients has been reported an upregulation of the pore-forming claudin-2 and downregulation of occludin. Channel-forming claudins are up-regulated by cytokines including TNF-α and IL-13, leading to an increased permeability for ions and water. Occludin is down-regulated by inflammatory processes (e.g., TNF-α and IFN-γ), leading to increased paracellular permeability for macromolecules. Moreover, it has been shown a downregulation of claudin-5 and -8 in Crohn's disease and claudin-4 and -7 in Ulcerative Colitis (UC). In Crohn's disease, the stimulation of NOD2, a sensor of Gram-positive bacteria, induces the production of pro-inflammatory mediators, which concur to IEB dysfunction. Differently from UC, in Crohn's disease the mucus layer is thicker, suggesting an increase in MUC2 expression and goblet cells hyperplasia. In patients with Crohn's disease, intestinal epithelial cells (IECs) failed to produce thymic stromal lymphopoietin (TSLP), with consequent inability to control IL-12, produced by dendritic cells and involved in the development of Thelper 2 cells, resulting in alteration of intestinal homeostasis. Compared to UC, in which the antimicrobial peptides (AMPs) system seems to be adequately induced, Crohn's disease is characterized by lower levels of AMPs. Contrasting evidence are available on the role of smoking in UC and Crohn's disease.