The intestinal barrier: a fundamental role in health and disease

Abstract

The gastrointestinal mucosa constitutes a critical barrier where millions of microbes and environmental antigens come in close contact with the host immune system. Intestinal barrier defects have been associated with a broad range of diseases and therefore denote a new therapeutic target. Areas covered: This review is based on an extensive literature search in PubMed of how the intestinal barrier contributes to health and as a trigger for disease. It discusses the anatomy of the intestinal barrier and explains the available methods to evaluate its function. Also reviewed is the importance of diet and lifestyle factors on intestinal barrier function, and three prototypes of chronic diseases (inflammatory bowel disease, celiac disease and nonalcoholic fatty liver disease) that have been linked to barrier defects are discussed. Expert commentary: The intestinal barrier has been investigated by various methods, but correlation of results across studies is difficult, representing a major shortcoming in the field. New upcoming techniques and research on the effect of barrier-restoring therapeutics may improve our current understanding of the gut barrier, and provide a step forward towards personalised medicine.

Keywords: Intestinal mucosal barrier; extraintestinal disease; gut health; intestinal epithelial cells; intestinal inflammation; intestinal permeability; mucus layer; tight junctions.

Figure 1. Schematic representation of the main components of the intestinal barrier

The intestinal barrier is a semipermeable structure that allows the uptake of essential nutrients and immune sensing, while being restrictive against pathogenic molecules and bacteria. Both structural and molecular components act together to fulfil this complex, but essential function of the gastrointestinal tract. The mucus layer forms a sieve-like structure overlying the intestinal epithelium. Antimicrobial peptides (AMPs) and secretory IgA molecules (sIgA) are secreted in the mucus layer as immune-sensing and regulatory proteins. The intestinal epithelial cells (IECs) form a continuous monolayer and are tightly attached to each other by junctional complexes. The tight junctions (TJs) are located at the apical side of the cells, and regulate the transport of small molecules and ions. The adherens junctions (AJs) and desmosomes provide strict cell-adhesion bonds and aid in the maintenance of the integrity of the intestinal barrier. The lamina propria contains immune cells (e.g. T cells, B cells, macrophages and dendritic cells) from the adaptive and innate immune system that take part in the immunological defence mechanisms of the intestinal barrier. AMP, antimicrobial peptide; sIgA, secretory immunoglobulin A; IECs, intestinal epithelial cells; TJ, tight junction; AJ, adherens junction

Figure 2. Ex vivo and in vitro methods to assess epithelial barrier function

(A) Ussing chamber assay: An endosopic intestinal biopsy is placed on one half of the chamber with the mucosal side facing upwards. The tissue is gently placed in-between plastic films for mounting. After equilibration of the tissue for 30 minutes, fluorescently labelled dextrans (FD4) are added to the mucosal side of the chamber. Serosal samples are taken every 30 minutes for 2 hours to evaluate the passage through the biopsy. The transepithelial electrical resistance (TEER) is recorded every 30 minutes by the electrodes. (B) Transwell assay: Intestinal cells are grown on permeable filter supports. Medium is changed every two days after seeding the cells. TEER measurements are performed using chopstick electrodes to measure confluency of the cells. FD4, FITC-dx4, fluorescein isothiocyanate, dextran 4000 Da; TEER, transepithelial electrical resistance