Leaky gut: mechanisms, measurement and clinical implications in humans

Abstract

The objectives of this review on 'leaky gut' for clinicians are to discuss the components of the intestinal barrier, the diverse measurements of intestinal permeability, their perturbation in non-inflammatory 'stressed states' and the impact of treatment with dietary factors. Information on 'healthy' or 'leaky' gut in the public domain requires confirmation before endorsing dietary exclusions, replacement with non-irritating foods (such as fermented foods) or use of supplements to repair the damage. The intestinal barrier includes surface mucus, epithelial layer and immune defences. Epithelial permeability results from increased paracellular transport, apoptosis or transcellular permeability. Barrier function can be tested in vivo using orally administered probe molecules or in vitro using mucosal biopsies from humans, exposing the colonic mucosa from rats or mice or cell layers to extracts of colonic mucosa or stool from human patients. Assessment of intestinal barrier requires measurements beyond the epithelial layer. 'Stress' disorders such as endurance exercise, non-steroidal anti-inflammatory drugs administration, pregnancy and surfactants (such as bile acids and dietary factors such as emulsifiers) increase permeability. Dietary factors can reverse intestinal leakiness and mucosal damage in the 'stress' disorders. Whereas inflammatory or ulcerating intestinal diseases result in leaky gut, no such disease can be cured by simply normalising intestinal barrier function. It is still unproven that restoring barrier function can ameliorate clinical manifestations in GI or systemic diseases. Clinicians should be aware of the potential of barrier dysfunction in GI diseases and of the barrier as a target for future therapy.

Keywords: mucus; permeability; tight junctions.

Figure 1:. Anatomy of the mucosal barrier.

Left panel: In the human intestinal mucosa, composed of columnar epithelial cells, lamina propria (with its immune cells) and muscular mucosa, the goblet cells synthesize and release mucin, and the unstirred layer is immediately above the epithelial cells. The tight junction is a component of the apical junctional complex, and it seals paracellular spaces between epithelial cells. Middle and Right Panels show an electron micrograph and the corresponding line drawing of the junctional complex of an intestinal epithelial cell. The key elements of the tight junction are the zona occludens and zona adherens, each of which is made up of different components. Just below the base of the microvilli (Mv), the plasma membranes of adjacent cells seem to fuse at the tight junction (TJ), where claudins, zonula occludens 1 (ZO1), occludin and F-actin interact. E-cadherin, α-catenin 1, β-catenin, catenin δ1 (also known as p120 catenin; not shown) and F-actin interact to form the adherens junction (AJ). Myosin light chain kinase (MLCK) is associated with the peri-junctional actomyosin ring. Desmosomes, located beneath the apical junctional complex, are formed by interactions between desmoglein, desmocollin, desmoplakin and keratin filaments. In general, diffusion through claudins and occludin within the membrane is energy-independent, whereas ZO-1 facilitates exchange between tight junction and cytosolic pools through energy –dependent mechanisms Reproduced from ref. 17.

Figure 2.

Intestinal barrier and its dysfunctions. The intestinal barrier includes the mucus layer preventing bacterial adhesion by secretion of chemicals such as α-defensins and IgA secretion, epithelial cells, connected at the tight junctions (tj) by junctional complexes, having the ability to transport luminal content and react to noxious stimuli by secretion of chloride and antimicrobial peptides, and the lamina propria innate and acquired immunity cells secreting Ig and cytokines. Intestinal permeability measurements are determined by the marker molecules used for measurement, since the type of molecules that pass the intestinal barrier depends on the type of lesion. Reproduced from ref. 18.