Paracellular permeability and tight junction regulation in gut health and disease

Abstract

Epithelial tight junctions define the paracellular permeability of the intestinal barrier. Molecules can cross the tight junctions via two distinct size-selective and charge-selective paracellular pathways: the pore pathway and the leak pathway. These can be distinguished by their selectivities and differential regulation by immune cells. However, permeability increases measured in most studies are secondary to epithelial damage, which allows non-selective flux via the unrestricted pathway. Restoration of increased unrestricted pathway permeability requires mucosal healing. By contrast, tight junction barrier loss can be reversed by targeted interventions. Specific approaches are needed to restore pore pathway or leak pathway permeability increases. Recent studies have used preclinical disease models to demonstrate the potential of pore pathway or leak pathway barrier restoration in disease. In this Review, we focus on the two paracellular flux pathways that are dependent on the tight junction. We discuss the latest evidence that highlights tight junction components, structures and regulatory mechanisms, their impact on gut health and disease, and opportunities for therapeutic intervention. Increased intestinal permeability occurs in a wide range of disorders, including inflammatory bowel disease, coeliac disease and graft-versus-host disease, but the relative contributions of barrier dysfunction and immune responses are unclear. Intestinal barrier loss can be a consequence of tight junction dysfunction or of epithelial damage; in most studies, these mechanisms are not distinguished. Paracellular transport across the tight junction can occur via the pore pathway or the leak pathway, which have distinct size-selectivity and charge-selectivity and are differentially regulated by immune signalling. Claudin-2 increases Na^+ and water flux across the pore pathway but larger molecules are unable to traverse claudin-2 channels. The leak pathway allows macromolecules to cross the epithelial barrier and is regulated by the cytoskeleton and epithelial long myosin light chain kinase splice variant 1 (MLCK1). Blocking MLCK1 recruitment to the tight junction limits tight junction barrier loss without interfering with essential MLCK functions in epithelial cells and cells of other types. Increased intestinal permeability owing to tight junction barrier loss could be targeted in gastrointestinal diseases associated with increased permeability. In this Review, the authors discuss the molecular components and regulation of the tight junction, and consider the relevance to gut diseases and therapeutic opportunities.