Intestinal Permeability & Associated Diseases

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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 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 that direct or indirect communication occurs between intestinal bacteria and the central nervous system.4

Dietary changes, chronic alcohol consumption, stress, the use of antibiotics, and other environmental 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 A recent systematic review also identified consumption of a Western-style diet, insulin resistance, dyslipidemia, hyperglycemia, and elevated levels of proinflammatory markers as among the strongest risk factors for altered intestinal integrity.5 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.6 Increased intestinal permeability has been shown to play a central role in the pathogenesis of IBD.6 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.7 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.7,8

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.

(Video Time: 2 minutes) 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. Probiotics can help shift the balance of the gut microbiome from less beneficial and potentially pathogenic organisms to commensal and beneficial species. Probiotics also modulate the immune response, decreasing intestinal inflammation and preventing infection.9 Another way to improve a dysbiotic microbiota is 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 A recent randomized controlled trial (n=51 adults 60 years or older) found that an eight-week polyphenol-rich diet reduced intestinal permeability measures by inducing changes to the gut microbiota.10 As a specific example, theobromine and methylxanthines, derived from cocoa and/or green tea, were positively correlated with butyrate-producing bacteria and inversely correlated with serum zonulin levels.10,11

Additionally, studies suggest that glutamine supplementation may be an effective treatment for patients with diarrhea-predominant IBS (IBS-D).12 A 2019 randomized, double-blind, placebo-controlled, eight-week trial (n=106) suggests that in patients with IBS-D with intestinal hyperpermeability following an enteric infection, oral dietary glutamine supplements (five grams three times per day) 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.12

The functional medicine model 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 intestinal permeability in IFM’s Applying Functional Medicine in Clinical Practice (AFMCP).

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Related Articles

Rise of Autoimmune Disease Linked to Intestinal Permeability

Intestinal Permeability and Inflammatory Triggers

The Connection Between Leaky Gut and Arthritis

The Microbiome and Immune-Related Disease


  1. de J R De-Paula V, Forlenza AS, Forlenza OV. Relevance of gut microbiota 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
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  8. 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.
  9. Gagliardi A, Totino V, Cacciotti F, et al. Rebuilding the gut microbiota ecosystem. Int J Environ Res Public Health. 2018;15(8):1679. doi:10.3390/ijerph15081679
  10.  Peron G, Gargari G, Meroño T, et al. Crosstalk among intestinal barrier, gut microbiota and serum metabolome after a polyphenol-rich diet in older subjects with “leaky gut”: The MaPLE trial. Clin Nutr. 2021;40(10):5288-5297. doi:10.1016/j.clnu.2021.08.027
  11.  Del Bo’ C, Bernardi S, Cherubini A, et al. A polyphenol-rich dietary pattern improves intestinal permeability, evaluated as serum zonulin levels, in older subjects: the MaPLE randomised controlled trial. Clin Nutr. 2021;40(5):3006-3018. doi:10.1016/j.clnu.2020.12.014
  12.  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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