Intestinal Epithelial Barrier Dysfunction in Disease and Possible Therapeutical Interventions

The intestinal epithelial monolayer constitutes a physical and functional barrier between the organism and the external environment. It regulates nutrients absorption, water and ion fluxes, and represents the first defensive barrier against toxins and enteric pathogens. Epithelial cells are linked together at the apical junctional complex by tight junctions that reduce the extracellular space and the passage of charge entities while forming a physical barrier to lipophilic molecules. Cultured intestinal epithelial cells have been extensively used to study intestinal absorption of newly synthesized drugs and the regulation of tight junctions structure and function. In vitro mild irritants, proinflammatory cytokines, toxins and pathogens, and adverse environmental conditions open tight junctions and increase paracellular permeability, an effect often accompanied by immune activation of the enterocytes. Conversely, inhibition of proinflammatory cytokines, exposure to growth factors and probiotics, among others, exert a protective effect. Impaired barrier function results from activation of signalling pathways that lead to alteration of junctional proteins expression and/or distribution. In vivo, intestinal barrier dysfunction is associated with various intestinal and non-intestinal disorders including inflammatory bowel disease, celiac disease, and diarrhoeal infection. This review will describe the current knowledge of the mechanisms regulating tight junctions and intestinal permeability, how these findings have lead to a better understanding of barrier alteration in human intestinal disorders, and what the emerging therapies to treat these pathologies are. Keywords: Growth factors, inflammatory bowel disease, intestinal epithelial cells, myosin light chain kinase, NF-κB, probiotics, protease activated receptor-2, tight junction, cellular polarity, pathogens, xenobiotics, absorption, hydrophilic molecules, Apical Junctional Complex, ytoplasmic plaque, actin-myosin cytoskeleton, microdomains, detergent-insoluble, diffusion, intestinal permeability, disease, protein kinase, phosphoinositide, perijunctional actomyosin ring, basolateral factors, cytoskeleton, Barrier dysfunction, myosin light, cytoskeleton reorganization, epithelial permeability, exogenous stimuli, bacterial attachment, endogenous factors, neuro-endocrine, immune cells, sealing, gastrointestinal, diarrhoea, Vibrio cholera, zonula occludens toxin, ileum, jejunum, macropinocytosis, proinflammatory cytokines, interferon(, tumour necrosis, toxins, calcium depletion, microfilaments, caveolae-vesicles, ctomyosin ring, polymerization, trypsin-lik, EPITHELIAL BARRIER, enteropathies, ulcerative colitis, inflammatory bowel syndrome, colitis, luminal antigens, bacteria translocation, neutrophils, proinflammatory cytokine, electrical resistance, subepithelial electrical, lactulose/mannitol, pouchitis, epithelial resistance, polymorphonuclear, transepithelial migration, colonic crypt, polymorphisms, predisposition, nucleotide, pathogenic strains, mucosal infiltration, epithelial injury, sulfonic acid, non-intestinal disorders, alcoholic, nonalcoholic, gluten proteins, hyperplasia, immu-noglobulin, auto-antibodies, endotoxaemia, seru, myosin IX, Bio-breeding diabetic, glycaemia, horseradish peroxidase, Antigen, sucrase isomaltase, cholesterol, sphingolipid, enterocytes, exosomes, E. coli, apoptosis, proinflammatory, Shigella flex- neri, ethanol, placebo