Intestinal permeability

Intestinal permeability is the phenomenon of the gut wall in the gastrointestinal tract exhibiting permeability. It is a normal function of the intestine to exhibit some permeability, to allow nutrients to pass through the gut, while also maintaining a barrier function to keep potentially harmful substances (such as antigens) from leaving the intestine and migrating to the body more widely. In a healthy human intestine, small particles (< 4 Å in radius) can migrate through tight junction claudin pore pathways, and particles up to 10-15 Å (3.5 kDa) can transit through the paracellular space uptake route.

Modulation and effects

One way in which intestinal permeability is modulated is via CXCR3 receptors in the gut wall, which respond to zonulin. Gliadin (glycoprotein present in wheat) activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules. Bacterial pathogens such as cholera, select enteric viruses, and parasites modulate intestinal tight junction structure and function, and these effects may contribute to the development of chronic intestinal disorders.

Excessive intestinal permeability is a factor in several autoimmune conditions such as Crohn's disease, celiac disease, type 1 diabetes, inflammatory bowel disease, and irritable bowel syndrome but it is not clear if increased intestinal permeability is a cause or a consequence of these conditions. Stress and infections also seem to cause perturbations in intestinal permeability. Larazotide acetate (previously known as AT-1001) is a zonulin receptor antagonist drug candidate that is in clinical trials for celiac disease, based on the hypothesis that increased intestinal permeability in coeliac is harmful to health.

Pathophysiology

Experimental evidence from animal models links gut flora, an increase in intestinal permeability and endotoxemia of intestinal origin to low-grade chronic inflammation and obesity in animals. In mice with increased gut permeability, more of the endotoxins released by the gut flora reach the plasma, leading to further effects relating to obesity and insulin resistance. Furthermore, the composition of gut flora can change the intestinal permeability in mice. It is not clear whether these results from animal experiments have any relevance to human health.

A review of 2014 highlights the relevance of differences between experimental results obtained on animals and results of clinical observations on humans and points out a need for further studies and randomized controlled trials.

Research directions

Research has found some evidence that glutamine may be an effective treatment for reducing excessive intestinal permeability. It is known that nutritional depletion results in increased intestinal permeability. Low levels of glutamine can lead to excessive intestinal permeability and excessive intestinal permeability itself is known to lower levels of glutamine. Glutamine is the preferred food source for enterocytes which are cells that are found in the intestine. Prebiotics and certain probiotics such as Escherichia coli Nissle 1917 have also been found to reduce increased intestinal permeability.

Alternative medicine

Main article: Leaky gut syndrome

A proposed medical condition called leaky gut syndrome has been popularized which theorizes that restoring normal functioning of the gut wall can cure many systemic health conditions, but there is little evidence to support this theory, and no evidence that so-called 'treatments' for 'leaky gut syndrome', such as nutritional supplements and a gluten-free diet, have any beneficial effect for most of the conditions they are claimed to help.

See also

• Environmental enteropathy