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Altres ajuts: Supported in part by the Fondo de Investigación Sanitaria and CIBERehd, Instituto Carlos III, Subdirección General de Investigación Sanitaria, Ministerio de Ciencia e Innovación (CP10/00502, MV; EC07/90148 & PI/080940 JS; CB06/04/0021, JS), the International Foundation for Functional Gastrointestinal Disorders (2008 IFFGD) and the 2010 Rome Foundation Award (JS). CIBERehd is funded by the Instituto de Salud Carlos III The etiopathogenesis of the irritable bowel syndrome (IBS), one of the most prevalent gastrointestinal disorders, is not well known. The most accepted hypothesis is that IBS is the result of the disturbance of the 'brain-gut axis.' Although the pathophysiological mechanisms of intestinal dysfunction are complex and not completely understood, stress, infections, gut flora, and altered immune response are thought to play a role in IBS development. The intestinal barrier, composed of a single-cell layer, forms a physical barrier that separates the intestinal lumen from the internal milieu. The loss of integrity of this barrier is related with mucosal immune activation and intestinal dysfunction in IBS. The number of mast cells and T lymphocytes is increased in the intestinal mucosa of certain IBS patients, and the mediators released by these cells could compromise the epithelial barrier function and alter nerve signaling within the enteric nervous system. The association of clinical symptoms to structural and functional abnormalities of the mucosal barrier in IBS patients highlights the importance of understanding the physiological role of the gut barrier in the pathogenesis of this disorder. This review summarizes the clinical and experimental evidences indicating the cellular and molecular mechanisms of IBS symptomatology, and its relevance for future translational research.

The gastrointestinal mucosal surface is lined with epithelial cells representing an effective barrier made up with intercellular junctions that separate the inner and the outer environments, and block the passage of potentially harmful substances. However, epithelial cells are also responsible for the absorption of nutrients and electrolytes, hence a semipermeable barrier is required that selectively allows a number of substances in while keeping others out. To this end, the intestine developed the "intestinal barrier function", a defensive system involving various elements, both intra- and extracellular, that work in a coordinated way to impede the passage of antigens, toxins, and microbial byproducts, and simultaneously preserves the correct development of the epithelial barrier, the immune system, and the acquisition of tolerance against dietary antigens and the intestinal microbiota. Disturbances in the mechanisms of the barrier function favor the development of exaggerated immune responses; while exact implications remain unknown, changes in intestinal barrier function have been associated with the development of inflammatory conditions in the gastrointestinal tract. This review details de various elements of the intestinal barrier function, and the key molecular and cellular changes described for gastrointestinal diseases associated with dysfunction in this defensive mechanism. La superficie de la mucosa del tracto gastrointestinal está revestida de células epiteliales que establecen una barrera efectiva, mediante uniones intercelulares, entre el medio interno y el medio externo, impidiendo el paso de sustancias potencialmente nocivas. Sin embargo las células epiteliales también son responsables de la absorción de nutrientes y electrolitos, por lo que se requiere una barrera semipermeable que permita el paso selectivo a ciertas sustancias, mientras que evite el acceso a otras. Para ello, el intestino ha desarrollado la "función barrera intestinal", un sistema defensivo compuesto por diferentes elementos, tanto extracelulares como celulares, que actúan de forma coordinada para impedir el paso de antígenos, toxinas y productos microbianos y, a la vez, mantiene el correcto desarrollo de la barrera epitelial, el sistema inmunitario y la adquisición de tolerancia hacia los antígenos de la dieta y la microbiota intestinal. La alteración de los mecanismos que componen la función barrera favorece el desarrollo de respuestas inmunitarias exageradas, y, aunque se desconoce su implicación exacta, la alteración de la función barrera intestinal se ha asociado al desarrollo de enfermedades inflamatorias en el tracto digestivo. En esta revisión se detallan los diferentes elementos que componen la función barrera intestinal y las alteraciones moleculares y celulares más características descritas en enfermedades digestivas asociadas a la disfunción de este mecanismo de defensa.

The interface between the intestinal lumen and the mucosa is the location where the majority of ingested immunogenic particles face the scrutiny of the vast gastrointestinal immune system. Upon regular physiological conditions, the intestinal micro-flora and the epithelial barrier are well prepared to process daily a huge amount of food-derived antigens and non-immunogenic particles. Similarly, they are ready to prevent environmental toxins and microbial antigens to penetrate further and interact with the mucosal-associated immune system. These functions promote the development of proper immune responses and oral tolerance and prevent disease and inflammation. Brain-gut axis structures participate in the processing and execution of response signals to external and internal stimuli. The brain-gut axis integrates local and distant regulatory networks and super-systems that serve key housekeeping physiological functions including the balanced functioning of the intestinal barrier. Disturbance of the brain-gut axis may induce intestinal barrier dysfunction, increasing the risk of uncontrolled immunological reactions, which may indeed trigger transient mucosal inflammation and gut disease. There is a large body of evidence indicating that stress, through the brain-gut axis, may cause intestinal barrier dysfunction, mainly via the systemic and peripheral release of corticotropin-releasing factor. In this review, we describe the role of stress and corticotropin-releasing factor in the regulation of gastrointestinal permeability, and discuss the link to both health and pathological conditions.