Intestinal permeability

Intestinal permeability is a term describing the control of material passing from inside the gastrointestinal tract through the cells lining the gut wall, into the rest of the body. The intestine normally exhibits some permeability, which allows 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.[1] In a healthy human intestine, small particles (< 4 Å in radius) can migrate through tight junction claudin pore pathways,[2] and particles up to 10-15 Å (3.5 kDa) can transit through the paracellular space uptake route.[3]

Modulation

One way in which intestinal permeability is modulated is via CXCR3 receptors in cells in the intestinal epithelium, which respond to zonulin.[4] Gliadin (a glycoprotein present in wheat) activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules.[4][5] 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.[4][6]

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.[7][8][9] 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.[8] Furthermore, the composition of gut flora can change the intestinal permeability in mice.[9] 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.[9]

Clinical significance

Excessive intestinal permeability is a factor in several autoimmune conditions such as Crohn's disease, celiac disease, type 1 diabetes,[10] rheumatoid arthritis, spondyloarthropathies,[11] inflammatory bowel disease,[4][12] and irritable bowel syndrome[5] but it is not clear if increased intestinal permeability is a cause or a consequence of these conditions.[13] Stress and infections also seem to cause perturbations in intestinal permeability.[5]

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..[5] Glutamine is an important energy source for enterocytes, which are the cells that line the intestine.[14]

Prebiotics and certain probiotics such as Escherichia coli Nissle 1917 have also been found to reduce increased intestinal permeability.[5]

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.[15]

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.[12]

See also

References

  1. ↑ M. Campieri; C. Fiocchi; S.B. Hanauer (31 March 2002). Inflammatory Bowel Disease: A Clinical Case Approach to Pathophysiology, Diagnosis, and Treatment. Springer. p. 7. ISBN 978-0-7923-8772-5.
  2. ↑ Thoma YM, Anderson JM, Turner JR (2012). Johnson LR; et al., eds. Tight Junctions and the Intestinal Barrier. Physiology of the Gastrointestinal Tract 1 (Academic Press). pp. 1043–. ISBN 978-0-12-382027-3.
  3. ↑ Fasano, A. (February 2012). "Leaky Gut and Autoimmune Diseases". Clinical Reviews in Allergy & Immunology (Review) 42 (1): 71–78. doi:10.1007/s12016-011-8291-x. PMID 22109896.
  4. 1 2 3 4 Fasano A (Jan 2011). "Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer". Physiol Rev. (Review) 91 (1): 151–75. doi:10.1152/physrev.00003.2008. PMID 21248165.
  5. 1 2 3 4 5 Rapin JR, Wiernsperger N (2010). "Possible links between intestinal permeability and food processing: A potential therapeutic niche for glutamine". Clinics (Sao Paulo) (Review) 65 (6): 635–43. doi:10.1590/S1807-59322010000600012. PMC 2898551. PMID 20613941.
  6. ↑ O'Hara, JR; Buret, AG (2008). "Mechanisms of intestinal tight junctional disruption during infection". Frontiers in Bioscience 13: 7008–21. doi:10.2741/3206. PMID 18508712.
  7. ↑ Frazier TH, DiBaise JK, McClain CJ (September 2011). "Gut microbiota, intestinal permeability, obesity-induced inflammation, and liver injury". JPEN J Parenter Enteral Nutr (Review) 35 (5 Suppl): 14S–20S. doi:10.1177/0148607111413772. PMID 21807932.
  8. 1 2 Teixeira TF, Collado MC, Ferreira CL, Bressan J, Peluzio Mdo C (September 2012). "Potential mechanisms for the emerging link between obesity and increased intestinal permeability". Nutr Res (Review) 32 (9): 637–47. doi:10.1016/j.nutres.2012.07.003. PMID 23084636.
  9. 1 2 3 Festi D, Schiumerini R, Eusebi LH, Marasco G, Taddia M, Colecchia A (November 2014). "Gut microbiota and metabolic syndrome". World J. Gastroenterol. (Review) 20 (43): 16079–16094. doi:10.3748/wjg.v20.i43.16079. PMC 4239493. PMID 25473159.
  10. ↑ Bischoff SC, Barbara G, Buurman W, Ockhuizen T, Schulzke JD, Serino M, Tilg H, Watson A, Wells JM (Nov 18, 2014). "Intestinal permeability--a new target for disease prevention and therapy". BMC Gastroenterol (Review) 14: 189. doi:10.1186/s12876-014-0189-7. PMC 4253991. PMID 25407511.
  11. ↑ Yeoh N, Burton JP, Suppiah P, Reid G, Stebbings S (Mar 2013). "The role of the microbiome in rheumatic diseases". Curr Rheumatol Rep (Review) 15 (3): 314. doi:10.1007/s11926-012-0314-y. PMID 23378145.
  12. 1 2 "Leaky gut syndrome". NHS Choices. 9 April 2013. Retrieved 24 October 2013.
  13. ↑ Heyman M, et al. (Sep 2012). "Intestinal permeability in coeliac disease: insight into mechanisms and relevance to pathogenesis". Gut (Review) 61 (9): 1355–64. doi:10.1136/gutjnl-2011-300327. PMID 21890812.
  14. ↑ Blachier, François; Boutry, Claire; Bos, Cécile; Tomé, Daniel (2009-09-01). "Metabolism and functions of l-glutamate in the epithelial cells of the small and large intestines". The American Journal of Clinical Nutrition 90 (3): 814S–821S. doi:10.3945/ajcn.2009.27462S. ISSN 0002-9165. PMID 19571215.
  15. ↑ Crespo Pérez L, et al. (Jan 2012). "Non-dietary therapeutic clinical trials in coeliac disease". Eur J Intern Med. (Review) 23 (1): 9–14. doi:10.1016/j.ejim.2011.08.030. PMID 22153524.
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