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.

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

“…Therefore, proinflammatory cytokine signaling may further enhance the ''leakiness'' of the epithelial layer, which may promote the perpetuation of the local inflammation. However, mice expressing the constitutive active form of MLCK show increased epithelial permeability but does not develop spontaneous colitis in vivo [39], suggesting that leakiness of the epithelial layer alone may not lead to spontaneous development of colitis but requires another ''deleterious hit'' for the onset of the disease [40].…”

Interleukin-37: A Peacekeeper at the Intestinal Borders

“…1). Indeed, most IL-1 family members when produced by the epithelium (vs. immune cells) during early innate events possess protective functions in the regulation of the interplay between the host and the gut microbiome [1,7]. In individuals unable to mount appropriate immune responses against harmful factors, perhaps due to deficits in IL-37 production, a homeostatic imbalance can ensue that promotes chronic intestinal inflammation (Fig.…”

“…Ulcerative colitis and Crohn's disease, the two main idiopathic forms of IBD, are chronic, relapsing inflammatory conditions of the gut, characterized by acute and chronic immune cell infiltrates in the epithelium [7]. In the previously cited manuscript from Gunaltay et al [8], IL-37 was decreased during active ulcerative colitis and upregulated when disease was quiescent, consistent with its anti-inflammatory activities.…”

“…Using CRISPR/Cas9 technology in a human colonic epithelial cell line, the authors demonstrate that even a modest reduction in IL-37 expression augments production of chemokines following activation of the Toll-like receptor (TLR)5 signaling pathway after exposure to bacterial-derived flagellin. These findings are notable since they once again emphasize the central importance of the intestinal epithelium in contributing to the regulation of both innate and adaptive immune responses triggered by the gut microbiome [7]. Indeed, the intestinal epithelium is constantly barraged by components of commensal and pathogenic bacteria, as well as by other potentially harmful insults.…”

“…Indeed, the intestinal epithelium is constantly barraged by components of commensal and pathogenic bacteria, as well as by other potentially harmful insults. Depending on the immunological status and genetic predisposition of the host, intestinal epithelial cells respond by producing several proinflammatory molecules, including not only IL-1a, IL-18, and IL-8, and other chemotactic factors [7], but also anti-inflammatory molecules (e.g., IL1Ra, IL-11) that counterbalance innate mucosal immune activation, as it appears to be the case for IL-37.…”