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Review
. 2013 Sep;11(9):1075-83.
doi: 10.1016/j.cgh.2013.07.001. Epub 2013 Jul 12.

Intestinal permeability defects: is it time to treat?

Matthew A Odenwald  1 , Jerrold R Turner
Affiliations
Review

Intestinal permeability defects: is it time to treat?

Matthew A Odenwald et al. Clin Gastroenterol Hepatol. 2013 Sep.

Abstract

An essential role of the intestinal epithelium is to separate luminal contents from the interstitium, a function primarily determined by the integrity of the epithelium and the tight junction that seals the paracellular space. Intestinal tight junctions are selectively permeable, and intestinal permeability can be increased physiologically in response to luminal nutrients or pathologically by mucosal immune cells and cytokines, the enteric nervous system, and pathogens. Compromised intestinal barrier function is associated with an array of clinical conditions, both intestinal and systemic. Although most available data are correlative, some studies support a model where cycles of increased intestinal permeability, intestinal immune activation, and subsequent immune-mediated barrier loss contribute to disease progression. This model is applicable to intestinal and systemic diseases. However, it has not been proven, and both mechanistic and therapeutic studies are ongoing. Nevertheless, the correlation between increased intestinal permeability and disease has caught the attention of the public, leading to a rise in popularity of the diagnosis of "leaky gut syndrome," which encompasses a range of systemic disorders. Proponents claim that barrier restoration will cure underlying disease, but this has not been demonstrated in clinical trials. Moreover, human and mouse studies show that intestinal barrier loss alone is insufficient to initiate disease. It is therefore uncertain whether increased permeability in these patients is a cause or effect of the underlying disorder. Although drug targets that may mediate barrier restoration have been proposed, none have been proven effective. As such, current treatments for barrier dysfunction should target the underlying disease.

Keywords: CA-MLCK; CD; Claudin; Crohn’s disease; GVHD; Graft vs Host Disease; IBD; IBS; IL; Inflammatory Bowel Disease; Irritable Bowel Syndrome; Leaky Gut Syndrome; MLCK; Myosin Light Chain Kinase; TNF; Tight Junction; constitutively active–myosin light chain kinase; graft-versus-host disease; inflammatory bowel disease; interleukin; irritable bowel syndrome; myosin light chain kinase; tumor necrosis factor.

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Figures

Figure 1
Figure 1. Intestinal permeability: Pathophysiological mechanisms and methods of analysis
a) The intestinal epithelium normally provides an effective barrier to macromolecules, bacterial products, and food antigens, but a small percentage can cross the tight junction (dashed arrow). In genetically susceptible individuals, translocation of luminal materials has been proposed to trigger exaggerated mucosal immune activation and cytokine release (e.g. IL-13, TNF, IFN-γ), which subsequently activates two distinct pathways of trans-tight junction flux. These are referred to as the pore (thin arrow) and leak (bold arrow) pathways, and are selectively activated by IL-13 and TNF, respectively. Increased tight junction permeability may lead to further translocation of macromolecules from the lumen into the lamina propria and amplification of mucosal immune activation. In the absence of appropriate regulatory signals, this vicious cycle may progress to disease. b) Intestinal permeability is most commonly measured by fractional urinary excretion of orally ingested probes. These probes can cross the intestinal epithelium by the paracellular pathway and enter the blood stream. They are then filtered by the glomerulus and excreted in the urine. Ideal probes are not metabolized in the intestinal lumen or blood, are readily filtered by the glomerulus, and are not actively absorbed or secreted in the kidney. Fractional urinary excretion can therefore be used as an indirect measure of intestinal permeability.
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