Does Gluten Cause Leaky Gut?

When I asked people for topics they’d like me to research, gluten was by far the most popular. We’ve all heard so much about gluten lately! Many people assume it’s unhealthy, but have no idea what it is. Companies are labeling their water “gluten free”.  Let’s clear up the mess.

WHAT IS GLUTEN?

To simplify, gluten is a protein found in wheat, rye and barley. It helps these foods maintain their shape and makes them light, fluffy and elastic.

So, if gluten is just a fluffy delicious protein, why do so many people insist it will make you sick?

Well, because in some people, it can cause celiac disease or maybe even other autoimmune diseases. In celiac disease, an immune response is triggered when people eat gluten which causes damage to the lining of the small intestine, bloating, diarrhea, cramping, heartburn, skin rashes, and other health problems.

But wait a minute you say, I know people who insist gluten will make EVERYONE sick, not just people who have celiac disease.  I’ve heard gluten causes leaky gut and leaky gut can cause all kinds of problems from inflammation to cancer to autism. Let’s investigate.

1. The Claim

A large percentage of the population (generally somewhere between 10 and 100%) should not eat gluten because it can cause inflammation, leaky gut, digestive problems, learning disabilities, autoimmune diseases, cancer, autism, or other health problems.

2.  Results from Initial Search

Just like when I first started researching GMO’s, I found an overwhelming number of blogs and websites discussing the dangers of gluten. Most of what I found focused on celiac disease and “non-celiac gluten sensitivity” which was described as something that may or may not exist on popular sites such as WebMD. Some sites described FODMAPS (Fermentable Oligosaccharides, Disaccharides, Monosaccharides and Polyols.) which are present in many foods and can be difficult to digest. They suggested these could actually be what’s causing sensitivity rather than the gluten. Some naturopathic, functional medicine and holistic medicine practitioners linked gluten to SIBO (small intestine bacterial overgrowth), candida (yeast), fungal overgrowth, and parasitic infections, all via leaky gut.

Then, I arrived on something I had never heard of called: ZONULIN.  After digging in deeper, zonulin seemed to be the most promising explanation for the possibility of gluten sensitivity. Therefore, I narrowed my search to focus on how gluten triggers zonulin and zonulin triggers leaky gut. Keep in mind, other things besides gluten may cause leaky gut. Gluten may cause other problems besides leaky gut. AND other things besides gluten may trigger zonulin. But, to keep it manageable, I decided to focus only on how gluten triggers zonulin which then triggers leaky gut.

3. Follow-Up Questions

What is zonulin? Zonulin is a protein that modulates the permeability of tight junctions between cells of the wall of the digestive tract. In other words, it is a protein that opens and closes spaces between cells in the gut lining to let nutrients out into the bloodstream while keeping toxins in the intestine. It was discovered in 2000 by Alessio Fasano, M.D. Dr. Fasano found that when people eat gluten, one of the gluten proteins (gliadin) triggers the body to release large amounts of zonulin. This was especially true for celiac patients. The zonulin then opens the spaces in the gut lining. Then, gluten and other molecules are released out into the bloodstream. In people with celiac disease, the body sees the gliadin as an intruder and responds by creating antibodies which attack the intestine. This “attack” does not occur in all people. These processes have been widely researched and accepted by the scientific and medical communities as they relate to celiac disease.  Research is being conducted to determine who might be susceptible to gluten-related diseases in addition to those with celiac. The research is now focusing on how/whether zonulin (and gluten) may be linked to other autoimmune conditions such as insulin dependent diabetes, multiple sclerosis, and rheumatoid arthritis.

4. Reader Comments

I was provided with 2 peer-reviewed research articles describing how zonulin works by my CrossFit coach. These are discussed in the primary source review below.

5. Primary Source Review

(Note that these studies are out of chronological order. I have them listed in the order that I reviewed them which is completely random. I tried to rearrange them into chronological order, but found I would need to re-write definitions and explain ideas that I had already explained elsewhere. So I left them out of order. Some parts of the review would make more sense if they were described in chronological order. This blog is definitely a learning process.)

• https://www.ncbi.nlm.nih.gov/pubmed/22731712 Zonulin, regulation of tight junctions, and autoimmune disease (2102)
  • This article claims that the “upregulation” of zonulin in genetically susceptible people leads to a variety of autoimmune diseases. Zonulin upregulation is most commonly caused by ingesting gluten (gliadin) or by bacteria in the small intestine. When the opening of the gut lining is triggered by the bacteria, it is thought to be a defense mechanism to flush out unwanted microorganisms.
  • Celiac disease: This is fairly well understood. Gliadin triggers zonulin. Zonulin opens tight junctions between cells. Harmful proteins, bacteria, toxins, etc. escape. An immune response attacks both the escaped toxins AND the intestine. It is important to note that celiac patients have much higher zonulin levels than controls EVEN when on a gluten free diet.
  • Type 1 diabetes: I have to admit this portion was difficult to understand. The best way I can explain it is that the study found that increased intestinal permeability occurred 2-3 weeks before the onset of type 1 diabetes in mice. Similar findings occurred in studies with children. This suggests that the intestinal permeability is triggering islet autoimmunity (type 1 diabetes).
  • Treatment: Zonulin inhibitor AT 1001 is a drug that inhibits the release of zonulin. It has been shown to be very effective in human trials at preventing loss of tight junctions in the intestine. It prevented or lessened gastrointestinal symptoms of 2/3 of the participants. In rat studies, it prevented the “insult of pancreatic islets”, therefore preventing the onset of type 1 diabetes.
  • Conclusion of review:  Genetic predisposition, mis-communication 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. In other words, you need certain genes, plus exposure to gluten, plus leaky gut in order to develop inflammation, autoimmunity and certain cancers.
  • Note: cancer, Crohn’s disease, schizophrenia, and chronic kidney disease were briefly discussed in association with the HP2 gene (described as alias zonulin) in this report. I was unable to interpret the content. If anyone wants to take a stab at it, feel free to help me understand.
• https://www.ncbi.nlm.nih.gov/pubmed/19538307 Tight junctions, intestinal permeability, and autoimmunity: celiac disease and type 1 diabetes paradigms (2009)
  • This article is very similar to the one above.
  • It supports the hypothesis that a combination of genetic factors, environmental factors AND loss of intestinal barrier function are all necessary in order to develop an autoimmune condition, especially celiac disease and type 1 diabetes.
  • Conclusion of review: Loss of intestinal barrier function is needed in order to develop autoimmunity. Reestablishing the intestinal barrier function could then treat the autoimmunity.
• https://www.ncbi.nlm.nih.gov/pubmed/16635908 Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines (2006)
  • Celiac and non-celiac ex vivo (outside of the body) human small intestines were exposed to gliadin. The intestines of celiac patients had sustained zonulin release whereas non-celiac intestines had a limited transient zonulin release.
  • The non-celiac intestines still experienced an increase in intestinal permeability, but it never reached the level of permeability of the celiac intestines.
  • Conclusion of study: gliadin activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules. This means that in test tubes, gluten caused some degree of “leaky gut” in all types of people. However, it was much more severe in celiac tissue.
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3705319/ Dietary intake of wheat and other cereal grains and their role in inflammation (2013)
  • Conclusions: The effects of gliadin on intestinal permeability and the immune system have been confirmed in humans. In celiac disease and gluten-sensitive individuals, adverse reactions are apparent. They recommend highly controlled clinical studies involving patients suffering from other “inflammation-related diseases” and healthy people.  They state that most studies we have are confounded by other variables in people’s diets.
• http://physrev.physiology.org/content/91/1/151.long Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. (2011)
  • This article goes into great detail about how zonulin works. It’s way over my head.
  • It describes how zonulin has been proven to be involved in the development of: celiac disease and type 1 diabetes.
  • The authors hypothesize about how zonulin is playing a role in: asthma, multiple sclerosis, glioma, and inflammatory bowel disease.
  • They described how zonulin is a biomarker in autoimmune diseases, diseases of the nervous system, and neoplastic conditions.
  • Conclusions: Exactly the same as the first two articles. Increased permeability occurs before disease. Therefore, disease might be prevented or treated by decreasing permeability.
• https://www.ncbi.nlm.nih.gov/pubmed/18485912/ Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. (2008)
  • Researchers studied ex-vivo small intestines from mice. They found that gliadin binds to CXCR3 (a receptor protein) and leads to MyD88-dependent zonulin release and increased intestinal permeability.
  • This means, they figured out a little more about how zonulin causes the spaces between cells in the gut lining to open. Keep in mind, they used mouse intestines in test tubes.
• https://www.ncbi.nlm.nih.gov/pubmed/25734566 Effect of gliadin on permeability of intestinal biopsy explants from celiac disease patients and patients with non-celiac gluten sensitivity. (2015)
  • 23 patients total were studied. They were split into 4 groups: celiac patients with active disease, celiac patients in remission, non-celiac patients with gluten sensitivity, and non-celiac controls.
  • Ex-vivo human duodenal biopsies were incubated with either gliadin or media alone (control)
  • Conclusion: All groups showed a greater increase in permeability when incubated with gliadin vs. media alone. The highest rates of increased permeability were in the patients with active celiac disease and the patients who reported to be gluten sensitive.
• https://www.ncbi.nlm.nih.gov/pubmed/23357715 A controlled trial of gluten-free diet in patients with irritable bowel syndrome-diarrhea: effects on bowel frequency and intestinal function. (2013)
  • A 4 week randomized control trial involving people with diarrhea-predominant irritable bowel syndrome (IBS-D) found that gluten alters bowel barrier functions, especially in genetically susceptible patients.
• https://www.ncbi.nlm.nih.gov/pubmed/21224837 (2011)Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial.
  • 34 patients with IBS, but not celiac disease, participated in a trial. They found that the group that received gluten rather than the placebo did experience more severe gastrointestinal symptoms.
  • However, they could not determine why. The groups showed no difference in intestinal permeability or other celiac markers.
• http://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-9-23 (2011) Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity
  • This study had 3 groups: celiac disease, gluten sensitive, and gluten tolerant controls. They evaluated intestinal permeability using a “lactulose and mannitol probe”. This is a test to determine whether someone has increased intestinal permeability and is reported to have high sensitivity and specificity (it is good at identifying the people with leaky gut and the people without leaky gut).
  • They found that gluten sensitivity was not associated with increased intestinal permeability. In fact, the people with gluten sensitivity had LESS intestinal permeability than the CONTROL group.
• https://www.ncbi.nlm.nih.gov/pubmed/28123927 (2016) Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases.
  • I did not have access to this article, but the abstract states, “This review focuses on the recent research implicating zonulin as a master regulator of intestinal permeability linked to the development of several chronic inflammatory disorders”.

6. What we know and don’t know

• We know…

• • Based on the research, I can say with certainty that intestinal permeability or “leaky gut” is a REAL thing. It’s not made up. Not pseudoscience. Many well-respected researchers have published studies proving that the spaces between the cells in the gut can be opened.
  • Zonulin is the only protein we know of right now that can cause the spaces to open.
  • People with celiac disease have higher levels of zonulin in their blood than other people, even when they have been on a gluten-free diet for years.
  • Gliadin (from gluten) causes increased production of zonulin in ALL people, but it causes a much greater increase in people with celiac disease.
• We don’t really know…
  • If gliadin causes an increase in zonulin production in all people, and zonulin binds to receptors in the gut lining in all people to open the spaces, why doesn’t everyone test positive for leaky gut after eating gluten? According to test-tube studies, it seems like all people should be experiencing leaky gut in response to gluten. However, only people with celiac disease test positive for leaky gut given the lactulose-mannitol probe. Is there a problem with the test? Is something in the living body somehow preventing or quickly “cleaning up” the damage in healthy people? Were the test tube studies flawed?
  • If only people with celiac disease test positive for leaky gut after eating gluten, why does a gluten-free diet seem to help many people with IBS-D or self-reported gluten sensitivity?
  • If people with celiac disease continue to have much higher serum zonulin than controls years after starting a gluten-free diet, why don’t they continue to have symptoms?
  • Are there more independent studies to prove that a leaky gut is one of the key components in type 1 diabetes and other autoimmune disorders? Dr. Alessio Fasano is the lead author in the majority of these studies and reviews. Every study I’ve found related to leaky gut or intestinal permeability over the past 20 years references his work. He has created a medication to help prevent leaky gut. Is there a conflict of interest? Could he be exaggerating his claims?
    • Note: Dr. Fasano DOES NOT recommend a gluten free diet for everyone. He states that about 1 in 100 people has celiac disease, many more have an autoimmune disorder or gluten sensitivity, and these numbers are rising. He suggests a gluten free diet is only necessary for these populations. He also wants his treatment to be approved only as a backup for when these people may unknowingly encounter gluten (like when they eat at a restaurant). He also feels that gluten has been “sensationalized” as causing a number of unrelated conditions. As far as I can tell, he is widely respected among both the scientific/medical and naturopathic/functional medicine communities. Please let me know if you have any more information on how he’s received in the medical community.
  • We know that gut bacteria play a role in zonulin upregulation. Are there any other conditions or factors that may cause zonulin upregulation or leaky gut in some other way? Lifestyle factors have been proposed such as diets high in sugar and alcohol or obesity.
  • What is the current research on how zonulin or leaky gut might be associated with other conditions?

7. Conclusions and applications

• • Wow, what do we do with all this knowledge and all this uncertainty? Here’s what I think. There is a LOT of well-respected, published research to show that gluten may be linked to autoimmune diseases for genetically susceptible people. There is also a lot of published research that shows that a gluten free diet can help people with IBS-D. And obviously, if you have celiac disease, you should not eat gluten.
  • I’d say it’s a good idea for people with a family history of celiac, IBS-D, type 1 diabetes, or even other autoimmune diseases to give the gluten-free thing a shot, if they think it might help. I would even say that ANYONE who wanted to give it a shot should go ahead and do so. There’s really no harm in replacing gluten containing foods with rice, oats, potatoes, or gluten free alternatives. See how you feel. If you like it, great. If it makes no difference to you, great. If it keeps you from eating junk food, great. Go FOR IT!
  • If you feel fine when you eat gluten (or drink beer), you’re probably really fine. Keep consuming gluten without guilt or worry. The evidence that gluten causes leaky gut in all people is limited to test tube studies only. In living healthy people, the testing shows gluten does not cause leaky gut, even in people who claim to feel much better when they don’t eat gluten. The lactulose/mannitol test is reported to have high sensitivity and specificity. This means it is good at telling who has a leaky gut and who doesn’t have a leaky gut. Researchers don’t have any clue why some people feel better when they go gluten free, but they acknowledge that these people aren’t making it up. It’s not in their heads.
  • There’s one guy, Dr. Alessio Fasano, who is really a leader in all this research. Some of his peers disagree with him and think he’s gone a bit too far in suggesting there could be links between gluten and say, cancer or asthma. Even he says he would not recommend a gluten-free diet to the majority of the population. THIS GUY EATS BURGERS…with the bun. And he thinks most people can do so with no problem.
  • Don’t waste your money. If you’re spending extra money to buy gluten-free alternatives and you can’t really tell a difference in the way you feel, you’re not doing yourself any favors.
  • So, what will I do with this information? I have chronic digestive problems, but I’ve already gone long periods of time without eating gluten (like 3 months at a time). I never noticed an improvement in my digestion. In fact, it got worse. I might try it again at some point if more convincing research comes out pertaining to my specific symptoms. Otherwise, I’ll rest assured that the alcohol in my beer and the sugar in my cupcake are definitely doing more harm than the gluten. That’s probably the simple truth for most of us. At the same time, your friend that swears she doesn’t feel good when she eats gluten probably isn’t a nut case. Respect that science doesn’t have all the answers to why gluten makes some people feel some kinda way.

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