Intestinal Barrier Dysfunction: The Primary Driver of IBD?

Abstract

The healthy gastrointestinal tract is functionally maintained by an epithelial barrier, a monocellular layer that acts as a critical interface between the “outside” lumen and host tissues. This selectively permeable barrier controls the equilibrium between tolerance and immunity to microbes and non-self antigens. It is physically composed of epithelial cells linked through tight junctions, and it is reinforced by a mucus layer and the secretion of antimicrobial peptides such as defensins, cathelicidins and lysozymes. Intestinal epithelial cells are also responsible for the transport of water and nutrients while simultaneously preventing the uptake of noxious agents and luminal flora. Pathogens are selectively eradicated and should therefore be distinguished from the commensal flora to elicit a balanced inflammatory response. This capacity is tightly governed by pathogen recognition receptors, such as NOD proteins and the Toll-like receptors (TLRs). To avoid immunologic hyper-responsiveness against harmless intra-luminal food and bacterial antigens, the selective transport of small quantities of these antigens takes place by dendritic cells and M cells in Peyer's patches, leading to oral tolerance. Several defects related to intestinal barrier function have been found in patients with inflammatory bowel disease (IBD), but for many, it remains to be clarified whether these are primary defects or secondary bystander effects of the inflammatory state. Nevertheless, evidence suggests that a “leaky gut” is an early and possibly primary defect in IBD pathogenesis. It has been demonstrated that increased intestinal epithelial permeability in Crohn’s disease (CD) may indeed precede clinical relapse by as much as 1 year and that unaffected first-degree relatives of CD patients may also have barrier dysfunction. In addition, it is well known that mucosal barrier-breaking substances, such as non-steroidal anti-inflammatory drugs (NSAIDs), may cause flare-ups in IBD patients. Finally, transgenic animal models have clearly demonstrated that a unique defect in the intestinal epithelial barrier is a sufficient trigger of the development of chronic gut inflammation. The recent advances in genotyping technology have greatly improved the knowledge base regarding genetic susceptibility for IBD and have revealed several IBD-associated single nucleotide polymorphisms (SNPs) in genes involved in intestinal barrier function. In this chapter, we first describe the components of the normal intestinal barrier. Next, we focus on the different barrier anomalies found in IBD both at the genetic and molecular level. The current evidence for a role of these barrier disturbances in the inflammatory process is extensively discussed. As a final point, the different therapeutic strategies for protecting or restoring the barrier function of the gut during IBD are discussed.