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Intestinal Permeability & Associated Diseases

Approximately 95% of the symbiotic microbes in the human body are located in the gut.1 In a homeostatic state, this highly diverse population of microbiota promotes overall health.2,3 However, in the event that the gut reaches a state of dysbiosis, a variety of diseases ranging from type 2 diabetes to inflammatory bowel disease may develop.4 More recently, intestinal microbial dysbiosis has been associated with a number of brain pathologies, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, suggesting a direct or indirect communication between intestinal bacteria and the central nervous system.4

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Dietary changes, chronic alcohol consumption, stress, the use of antibiotics, and other environmental factors, as well as genetic factors, can lead to alterations in the microbiota, which in turn may induce intestinal inflammation and increase intestinal permeability.2,4

When intestinal inflammation becomes chronic, the integrity of the epithelial barrier is altered; this is often referred to as “leaky gut.”2,3

Crohn’s disease and ulcerative colitis, collectively called inflammatory bowel disease (IBD), are immune-mediated conditions characterized by a chronic inflammation of the gut.5 Increased intestinal permeability has been shown to play a central role in the pathogenesis of IBD.5

What are the mechanisms by which intestinal permeability contributes to the pathophysiology of disease? The intestinal epithelial barrier (with its intercellular tight junctions) controls the equilibrium between tolerance and immunity to non-self antigens.6 The protein zonulin is the modulator of intercellular tight junctions, and when the zonulin pathway is deregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune, inflammatory, and neoplastic disorders can occur.6,7

In the following video, IFMCP Robert Sheeler, MD, talks about three levels of red flags for intestinal permeability: sensitivity to foods, environmental sensitivities, and autoimmune disease.

Caption: Robert Sheeler, MD, is board certified in family medicine, holistic medicine, integrative medicine, and headache medicine, and is a certified Functional Medicine practitioner.

A dysbiotic microbiota may be ameliorated with certain probiotics or by boosting the growth and metabolism of beneficial commensals in the colon with fiber-rich food, especially targeting butyrate production.3 Butyrate is produced by microbial fermentation in the large intestine and is a cellular mediator regulating multiple functions of gut cells and beyond, including gene expression, cell differentiation, gut tissue development, immune modulation, oxidative stress reduction, and diarrhea control.3

Additionally, studies suggest that glutamine supplementation may be an effective treatment for patients with diarrhea-predominant IBS (IBS-D).8 A 2018 study found that in patients with IBS-D with intestinal hyperpermeability following an enteric infection, oral dietary glutamine supplements dramatically and safely reduced all major IBS-related end points. This included a reduction of greater than 50 points on the Irritable Bowel Syndrome Severity Scoring System and changes in daily bowel movement frequency, stool form, and intestinal permeability.8

Intestinal permeability plays a central role in many chronic conditions, and Functional Medicine offers clinicians a range of practical applications to help bring the gut back into balance. It is often the first place to start improving overall health. 



Learn More About Functional Medicine

Is the rise of autoimmune disease linked to intestinal permeability? Read more.

What is the role of the microbiome in immune-related diseases?

References 
  1. de J R De-Paula V, Forlenza AS, Forlenza OV. Relevance of gutmicrobiota in cognition, behavior, and Alzheimer’s disease. Pharmacol Res. 2018;136:29-34. doi:10.1016/j.phrs.2018.07.007
  2. Brandl K, Schnabl B. Is intestinal inflammation linking dysbiosis to gut barrier dysfunction during liver disease? Expert Rev Gastroenterol Hepatol. 2015;9(8):1069-1076. doi:10.1586/17474124.2015.1057122
  3. Hiippala K, Jouhten H, Ronkainen A, et al. The potential of gut commensals in reinforcing intestinal barrier function and alleviating inflammation. Nutrients. 2018;10(8):E988. doi:10.3390/nu10080988
  4. Spielman LJ, Gibson DL, Klegeris A. Unhealthy gut, unhealthy brain: the role of the intestinal microbiota in neurodegenerative diseases. Neurochem Int. 2018;120:149-163. doi:10.1016/j.neuint.2018.08.005
  5. Vanuytsel T, Vermeire S, Cleynen I. The role of haptoglobin and its related protein, zonulin, in inflammatory bowel disease. Tissue Barriers. 2013;1(5):e27321. doi:10.4161/tisb.27321
  6. Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev. 2011;91(1):151-175. doi:10.1152/physrev.00003.2008
  7. Wang W, Uzzau S, Goldblum SE, Fasano A. Human zonulin, a potential modulator of intestinal tight junctions. J Cell Sci. 2000;113(Pt 24):4435-4440.
  8. Zhou Q, Verne ML, Fields JZ, et al. Randomised placebo-controlled trial of dietary glutamine supplements for postinfectious irritable bowel syndrome. Gut. 2019;68(6):996-1002. doi:10.1136/gutjnl-2017-315136

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