Zonulin & Leaky Gut: A discovery that changed the way we view inflammation, autoimmune disease and cancer!

An amazing discovery a few years ago revolutionized our ability to understand the gut and permeability and how this impacts a wide range of health conditions from cancer to autoimmune disease to inflammation and food sensitivities.

This little molecule, zonulin, has quite a story...

Zonulin is the "doorway" to leaky gut

Zonulin opens up the spaces between the cells of the intestinal lining. That normally occurs, in order for nutrient and other molecules to get in and out of the intestine. However, when leaky gut is present, the spaces between the cells open up too much allowing larger protein molecules to get into the bloodstream where an immunologic reaction can take place. Once that happens, the body is primed to react to those proteins each and every time they appear.  It can also cause leakage of intestinal contents, like bacteria into the immune system creating inflammation and overloading the liver's ability to filter out this garbage.

Triggers that open the zonulin doorway

Based on Dr. Fasano's research, we know that the two most powerful triggers to open the zonulin door are gluten and gut bacteria in the small intestine.  Gliadin causes zonulin levels to increase both in those people who have celiac disease and those who do not.  As the zonulin level rises, the seal  between the intestinal cells diminishes, opening up spaces between cells that allow all sorts of things to pass right through.  This is called "leaky gut".  Its as if the security guard that keeps the bad guys out is taking a nap! Sometimes large food molecules will pass through to the immune system.  The immune system thinks they are foreign invaders and will mount and immune response leading to food sensitivities.  In addition this immune activation leads to more damage to the intestinal cells (called enterocytes) and the gut becomes more inflamed and more permeable or "leaky".  As the damage continues, the microvilli that line the intestines and absorb nutrients become damaged, leading to other nutrient deficiencies.

Top causes of increased zonulin and development of leaky gut:

1. Overgrowth of harmful organisms, like bacteria or yeast in the intestine

A. SIBO = small intestinal bacterial overgrowth
B. Fungal dysbiosis or candida overgrowth
C. Parasite infections

Gliadin in the diet (gluten containing foods)

Gliadin is a protein in wheat, that like gluten, is a trigger for people with celiac disease. However, a study published in the Scandiavian Journal of Gastroenterology in 2006 clearly showed that gliadin can affect zonulin even in people without the gene for celiac. The researchers concluded that

Based on our results, we concluded that gliadin activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules.

The significance of this is that gluten affects intestinal permeability in all persons to different extents.  It also means that 100% of patients with autoimmune disease or leaky gut could potentially benefit from a gluten-free diet.

Elevated zonulin levels and leaky gut are also associated with the following:

  1. Crohn's disease
  2. Type 1 Diabetes
  3. Multiple Sclerosis
  4. Asthma
  5. Glioma
  6. Inflammatory Bowel Disease

In conclusion the article states:

Genetic predisposition, miscommunication between innate and adaptive immunity, exposure to environmental triggers, and loss of intestinal barrier function secondary to the activation of the zonulin pathway by food-derived environmental triggers or changes in gut microbiota all seem to be key ingredients involved in the pathogenesis of inflammation, autoimmunity, and cancer. This new theory implies that [once this path is activated] it can be... reversed by preventing the continuous interplay between genes and the environment.

Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer

Alessio Fasano



The primary functions of the gastrointestinal tract have traditionally been perceived to be limited to the digestion and absorption of nutrients and to electrolytes and water homeostasis. A more attentive analysis of the anatomic and functional arrangement of the gastrointestinal tract, however, suggests that another extremely important function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non-self antigens. Zonulin is the only physiological modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance. When the finely tuned zonulin pathway is deregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune, inflammatory, and neoplastic disorders can occur. This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by reestablishing the zonulin-dependent intestinal barrier function. This review is timely given the increased interest in the role of a “leaky gut” in the pathogenesis of several pathological conditions targeting both the intestine and extraintestinal organs.

  • AUjewel

    My former accupuncturist, a doctor of Chinese medicine diagnosed me with leaky gut 15-20 yrs ago, but I moved. I am very ill and have been for 50 yrs. They removed my tonsils, thyroid, gall bladder, and operated on most of my joints, and spine. I have recently removed gluten from my diet and am very weak and depressed. Western medicine has let me down, (currently on 17 prescriptions daily) and I believe the only cure for me is to treat my leaky gut. I take caprylic acid, Probiotics, acidophylis and b complex, fish oil, multi, magnesium D3, CoQ10. Can you recommend anything to help me get rid of this gut problem?? Any thoughts would be appreciated more than you can imagine.

    • Archie

      Have you read the GAPS diet, or SCD diet?

    • Arnetta

      You can take Slippery elm, L Glutamin, & there is a miracle product called (VSL #3) Vitamin A. Also there is a probotic that is supposed to be just as good as the VSL #3 it’s called Garden of life- primal defense .

    • jean

      My husband and I are in a similiar situation. Have had chronic digestive issues for 30 plus years. We have found that the research from Ray Peat is amazing and makes so much sense. We are on a new way of eating. Only eating foods that are digestable and do not cause inflamation. So far so good. We are being coached by Josh Rubin at Please check it out, it is working for us. There is tons of research….. check out Josh Rubins you tube videos to understand how given the right foods, our bodies can heal themselves. Good luck and may God bless you!

    • Honey Koria

      Hi AUjewel, if you really want to get well then first visit & if possible visit him at his clinic (you’ll get all info on his website). His modus operandi is Paleo diet but he practices functional medicine & he is thorough in his observation of his patients’s clinical issues. Good luck & get healthy soon!

    • Sally Oh

      If you are serious about getting well, hire a good functional nutrition practitioner, get some lab tests done to determine the root causes (it won’t be just gluten at this point) and which systems need to be addressed and in what order. I spent years chasing symptoms, taking this fix-it and that fix-it until I was good and sick… then I discovered functional nutrition. What a difference!

  • This is great! I tested negative for celiac but positive for a wheat allergy (as well as a plethora of other food allergies). I’ve been on a grain free diet for 15 months and my health has vastly improved, especially in digestion, fibromyalgia and chronic fatigue symptoms. It’s not always easy but definitely worth it.

  • J R Fibonacci Hunn

    The basic idea, as I understand it, is that eating a lot of carbohydrates causes the gut to inflame and leak, which leads to a variety of forms of systemic inflammation. All of the “catalysts” listed in the article, like of pathogens in the first few feet of the small intestines, are a direct and unaviodable result of eating lots of carbs. That is why the populations of bacteria soar in that region- because the carbs fuel that growth. If we provide the excess fuel, something will thrive there to eat it, since we can’t use it. All of those carbs also can alter the pH of the gut, creating what we might call micro-ulcers. An ulcer is a leaky stomach right? For more, see

    • Gen

      Not all carbs. Just ones with gluten such as wheat, barley, oat

      • Your Everything

        ALL carbs especially sugar

  • AUjewel

    I have good D3 levels and take a good bit of fish oil high in Om3ga 3. I have recently tried the paleo diet but eat so little now. I will def look into my multi. I do take probiotics of several diff kinds; also Caprylic Acid, Magnesium Citrate, Zinc, Boswellia & Curcumin, Milk Thistle,Selenium…, I am taking a dozen prescriptions, including prednisone and Plaquenil daily and have for 3 years. It keeps inflammation at bay but the side effects (esp the Plaquenil) are terrible.I know for a fact I am gluten sensitive if not full blown Celiac disease. it is near impossible to cut out gluten. I had to retire early and go on disability so a nutritionist or specialized anybody for testing, etc. Down but not defeated.

    • Bluesky

      AUjewel I can relate to you and your situation. I too have been suffering with IBS (in other words they don’t know what’s wrong) for 18 years now after a food poisoning incident. I’ve got high inflammation readings but I’m now getting this under control. I’ve been to every type of Dr, Nutritionist, Dietition, Chinese practitioner etc. My best help has been taking Acacia powder to settle the gut down. I’m on the FODMAP diet and it has really helped with food choices. I also listen to a hypnotherapy course, very helpful too. I’ve given up gluten and it has helped. Now I also take nutritional supplements as I was malnourished and they have been absolutely fabulous. Private PM me if you would like more information on any of this information as I don’t want to put Brand names here. All the very best with your health Lynda

      • suz-q

        Can you send me the brands ypu are using? Thanks

  • Adam

    It’s very common, in the research I’ve been doing lately, to observe many people affected by gut flora issues and disbiosis. Whether diagnosed with an autoimmune disease or allergies, it all starts with a leaky gut, which leads to all sorts of other allergies and autoimmune issues (immunomodulatory problems). A vicious cycle.

    I couldn’t state this strongly enough, but if you know your gut is leaky then you are likely to develop allergies to the foods you eat the most. My wife is coeliac and I am IBS with other seemingly unrelated health issues. Ultimately these problems lead to skin problems for most people, and even behavioral changes. Even schizophrenia seems to have a strong connection and perhaps inception in the gut as well. I hope more research is done to show how disbiosis or flora that’s even just a little out of whack impedes proteins like cytokines and hormones ability to reach and/or function in the brain.

  • ease

    I have learned the importance of making sure my clients stop up the gut BEFORE taking in any other protocols; the nutrients in other supplements can be damaging to your system if they get out of the gut, too…..especially probiotics! First, fix the holes; then find out the damages elsewhere and work on that. And, yes, do get professional help — very important.

  • Jennifer Miller

    How do I test for this problem?

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