Central role of the gut epithelial barrier in the pathogenesis of chronic intestinal inflammation: lessons learned from animal models and human genetics

Abstract

The gut mucosa is constantly challenged by a bombardment of foreign antigens and environmental microorganisms. As such, the precise regulation of the intestinal barrier allows the maintenance of mucosal immune homeostasis and prevents the onset of uncontrolled inflammation. In support of this concept, emerging evidence points to defects in components of the epithelial barrier as etiologic factors in the pathogenesis of inflammatory bowel diseases (IBDs). In fact, the integrity of the intestinal barrier relies on different elements, including robust innate immune responses, epithelial paracellular permeability, epithelial cell integrity, as well as the production of mucus. The purpose of this review is to systematically evaluate how alterations in the aforementioned epithelial components can lead to the disruption of intestinal immune homeostasis, and subsequent inflammation. In this regard, the wealth of data from mouse models of intestinal inflammation and human genetics are pivotal in understanding pathogenic pathways, for example, that are initiated from the specific loss of function of a single protein leading to the onset of intestinal disease. On the other hand, several recently proposed therapeutic approaches to treat human IBD are targeted at enhancing different elements of gut barrier function, further supporting a primary role of the epithelium in the pathogenesis of chronic intestinal inflammation and emphasizing the importance of maintaining a healthy and effective intestinal barrier.

Keywords: Crohn’s disease; animal models of intestinal inflammation; gut immune homeostasis; inflammatory bowel disease genetics; innate immunity; intestinal barrier function; intestinal epithelial cells; ulcerative colitis.

Figure 1

Murine loci and genes associated with gut inflammation that are potentially related to intestinal epithelial barrier dysfunction. Colitis susceptibility loci, Cdcs, and Dssc, are identified by red bold font. Genes potentially involved in the epithelial barrier defect characteristic of SAMP mice are italicized. Genes deleted in mouse models of intestinal inflammation that affect epithelial function are underscored. The potential role of each gene in the pathogenesis of epithelial dysfunction associated with chronic intestinal inflammation is discussed within the text. Cdcs, cytokine deficiency-induced colitis susceptibility; Dssc, DSS colitis locus.

Figure 2

Epithelial innate immune function is a key factor in maintaining gut homeostasis. IECs express PRRs, such as TLRs and NOD-like receptors, whose signaling activates NF-κB, leading to reinforcement of the epithelial barrier through release of anti-microbial peptides (i.e., defensins) and paracellular secretion of proinflammatory cytokines (e.g., TNF, IL-1, and IL-18) that enhance mucosal defense to bacterial penetration and the production of trophic factors, such as intestinal TFF3 that can block IEC apoptosis. Autophagy, perhaps due to ATG16L1, also contributes to the effectiveness of the epithelial barrier, controlling intracellular pathogens, and inducing lysozyme production. Breakdown of PRR/NF-κB signaling pathways via critical components, including MyD88, TAK1, and NEMO, facilitates penetrance of luminal microorganisms, triggering an exaggerated adaptive immune response. Similarly, defects in autophagy lead to less effective bacterial clearance and production of proinflammatory molecules, such as adipokines and acute phase reactants from Paneth cells.

Figure 3

The intestinal epithelial barrier plays a central role in gut homeostasis. IECs form an semi-permeable lining, with barrier function modulated by the presence of TJs, AJs, and desmosomes. Expression and assembly of these protein complexes are finely regulated by several intracellular pathways. Polymorphisms in MYO9B, PARD3, and MAGI2 and impairment of the Gαi2/adenylate cyclase axis result in defective TJ assembly; phosphorylation of myosin II through MLCK activation by TNF leads to TJ disassembly. Lack of junctional proteins, such as JAM-A, or altered expression and/or pairing (e.g., dominant negative N-cadherin, claudin-2 overexpression) leads to increased epithelial permeability, facilitating translocation of luminal bacteria, and antigens and exposure to the mucosal adaptive immune system.

Figure 4

Role of epithelial cell integrity and mucus production in gut health and disease. Proteins regulating cell structure (e.g., DLG5) or metabolic functions (e.g., XBP1) maintain IEC integrity. IECs in constant contact with luminal toxins and xenobiotics dispose of these harmful molecules by means of several transporter proteins, such as MDR1, OCTN1, and 2. IECs secrete a thick layer of mucus, whose production is finely regulated by different proteins, including MUC family members and POFUT1. Loss of control over ER stress, resulting from XBP1 dysfunction and accumulation of toxic molecules inside IECs, secondary to transporter molecule loss of function, cause IEC damage, defective defensin secretion from Paneth cells, and release of proinflammatory mediators leading to immune activation. Direct exposure of IEC to luminal toxins/antigens is increased by deletion of MUC2, 3, and 4, which leads to dramatic reduction of mucus production, and eventually to intestinal inflammation. Conversely, overproduction of mucus is also harmful, leading to bacterial overgrowth in intestinal crypts, as seen in POFUT1 deficiency, causing a dysregulation of the epithelial transcription factor, NOTCH that controls IEC proliferation and differentiation.

Figure 5

Therapeutic agents that enhance epithelial barrier function. Several drugs can potentially improve different components of intestinal barrier function by (from left to right): (1) enhancing mucosal innate immunity through increased expression of TLRs and production of anti-microbial peptides, (2) decreasing epithelial permeability through the expression and assembly of TJ and AJ proteins, and (3) restoring epithelial cell and mucus layer integrity by reducing IEC apoptosis and inducing mucus production.