--- title: "What Causes Leaky Gut and Why Zonulin Tests Mislead" entity: "blog" canonical_url: "https://www.drdanwool.com/blog/leaky-gut-causes-testing-repair" markdown_url: "https://www.drdanwool.com/llms/blog/leaky-gut-causes-testing-repair" lastmod: "2026-10-27T10:00:00.000Z" --- Written and Medically Reviewed by [Dr. Dan Wool, NMD](/about) Arizona-Licensed Naturopathic Physician and Gastroenterology Specialist Updated: October 27, 2026 ## Quick Summary - Leaky gut is the common name for increased intestinal permeability. The seals between the cells lining your intestine loosen, and more bacterial fragments and food proteins reach the immune system in the gut wall. - Permeability is real and measurable. It shows up in celiac disease, inflammatory bowel disease, and a large share of people with IBS, especially IBS that started after a gut infection. - The most popular blood test for leaky gut has a reliability problem. Research found that common zonulin kits were picking up other proteins, so a single zonulin result should never drive a treatment plan. - Lasting repair starts with finding what loosened the barrier. NSAIDs, gluten, stress, infection, alcohol, and microbial imbalance are the drivers I look for first. Supporting the lining comes after that. Jen (pseudonym) was 44 and managed a busy dental office in Mesa. For two years she was bloated after almost every meal. A rash came and went on her forearms, and her knees and fingers were stiff most mornings. She took ibuprofen most days to get through work. Her colonoscopy was clean, her blood work was normal, and the last specialist she saw told her leaky gut was something people read about on the internet. I hear some version of that story every week in my Scottsdale practice. I lived a version of it too. Before I became a physician, I spent three years with a burning gut while my labs kept coming back normal. The answer turned out to be celiac disease. Celiac disease happens to be one of the clearest examples of a leaky gut in all of medicine. The term gets oversold online and brushed off in the exam room. The useful answer sits in the evidence between those two camps. ## What Leaky Gut Means Leaky gut is the everyday name for increased intestinal permeability. Your intestine has to do two jobs at once. It has to absorb water and nutrients, and it has to keep bacteria, bacterial fragments, and undigested food proteins out of your bloodstream. The structure that manages both jobs is called the intestinal barrier. Researchers describe it in three layers [1]. ### The mucus layer A coating of mucus sits on top of the lining. It keeps most bacteria at a distance from the cells underneath. ### The cell layer and its seals The lining itself is a single layer of cells. Neighboring cells are joined by protein seals called tight junctions. These seals open and close to control what passes between cells. ### The immune layer Just beneath the lining sits one of the largest collections of immune cells in your body. When more material slips through, these cells respond with inflammation. When any of these layers weakens, more material crosses than should. That increase is what researchers mean by intestinal permeability. They measure it with a urine sugar test. You drink two sugars of different sizes. A higher share of the larger sugar showing up in your urine signals a more permeable gut [1]. ## Is Leaky Gut Real? I get asked this a lot. And the answer is yes, but with an important qualification. Increased permeability is well documented in [celiac disease](/celiac-disease-treatment) and [inflammatory bowel disease](/crohns-disease-treatment), and it appears in many people with [IBS](/blog/what-ibs-actually-is-and-why-standard-treatment-fails) [1,2]. What remains unproven is that repairing the barrier by itself cures any of those conditions [1]. So mainstream medicine treats leaky gut as a finding, and it does not recognize it as a standalone diagnosis. I agree with that, actually. I think of permeability as a mechanism that sits downstream of something else: whatever loosened the barrier is what needs attention. ## How Leaky Gut Shows Up In my practice, the gut symptoms are the familiar ones: [bloating](/bloating-treatment-scottsdale), gas, loose stools, cramping, and new reactions to foods that used to be fine. Outside the gut, patients often describe skin flares, joint stiffness, fatigue, and brain fog. None of these symptoms is specific to leaky gut. They overlap with [IBS](/ibs-treatment), [SIBO](/sibo), [celiac disease](/celiac-disease-treatment), and [inflammatory bowel disease](/ulcerative-colitis-treatment), which is why history and testing matter more than a symptom checklist. IBS research shows how common barrier problems are. A 2021 systematic review found barrier dysfunction in 37-62 percent of people with diarrhea-predominant IBS. It also found it in 17-50 percent of people whose [IBS started after a gut infection](/blog/post-antibiotic-dysbiosis-diarrhea) [2]. Most studies in that review linked a weaker barrier to more abdominal pain and more disturbed bowel habits [2]. ## Warning Signs That Need a Conventional Workup First Some symptoms point away from a functional problem and toward disease that needs a scope, imaging, or urgent care. See your primary care doctor or a gastroenterologist promptly if you have any of these: - Blood in your stool, or black, tarry stools - Unintentional weight loss - Iron deficiency anemia - Symptoms that wake you from sleep - Fever with ongoing diarrhea - Trouble swallowing or persistent vomiting - A family history of colon cancer, inflammatory bowel disease, or celiac disease - New bowel changes that start after age 50 Conventional gastroenterology is very good at this part. I want it done before I treat anyone for a barrier problem. ## What a Normal Scope and Normal Labs Don't Measure A [colonoscopy](/blog/when-should-you-get-a-colonoscopy) looks for polyps, cancer, other abnormal tissue changes and visible inflammation. Routine blood work screens for anemia, infection, and organ function. All of that is essential. None of it measures how permeable your gut lining is or what is driving a change in it. A normal result rules out serious structural disease. But, it leaves the functional question open. ## How I Test for Leaky Gut The research standard for measuring permeability is the lactulose-mannitol urine test described above [1]. I order it when a direct measure would change the plan. That's less often than you might expect. Most of the time I test for the drivers instead. Depending on your history, that can include celiac blood screening, a comprehensive stool analysis for infections, inflammation, and microbial imbalance, [SIBO breath testing](/blog/siboguide), or [organic acids testing](/blog/organic-acids-testing). Finding the driver tells me what to treat. A permeability number on its own does not. ## 7 Drivers Behind Leaky Gut The barrier usually loosens in response to something else. These are the seven drivers I look for. ### 1. NSAIDs [Chronic use of anti-inflammatory pain relievers](/blog/nsaids-gut-health) are the best-documented cause of a leakier gut. In healthy volunteers, five days of indomethacin tripled small intestinal permeability [3]. Ibuprofen and naproxen belong to the same drug class. Daily use for back pain or workouts is common in my patients, and Jen was one of them. If you rely on these medications, talk with your prescriber before changing anything. ### 2. Gluten and celiac disease Gliadin is a protein in wheat. In a study of intestinal biopsy tissue, gliadin increased permeability in every group tested. The largest increases came from people with active [celiac disease](/celiac-disease-treatment), and tissue from people with [gluten sensitivity](/blog/non-celiac-gluten-sensitivity) also reacted more than tissue from celiac patients in remission [4]. I was that patient. Every person I evaluate for leaky gut gets screened for celiac disease. ## 3. Psychological stress [Stress changes the gut](/blog/stress-gut-motility-bloating) in measurable ways. In a human study, preparing and giving a public speech increased small intestinal permeability. The effect appeared only in people whose cortisol rose with the stress [5]. Stress hormones act on immune cells in the gut wall, which then loosen the seals between cells [5]. ### 4. Gut infections Food poisoning and traveler's diarrhea can leave the barrier weakened well after the infection clears. [Post-infectious IBS](/blog/post-antibiotic-dysbiosis-diarrhea) carries one of the highest rates of barrier dysfunction in the research [2]. When a patient's symptoms started with a bad stomach bug, I take that history seriously. ### 5. Dysbiosis The microbes in your gut help maintain the mucus layer and feed the cells of the lining. When that community shifts, I often find the barrier has shifted with it. [Bacterial fragments called lipopolysaccharides (LPS)](/blog/lipopolysaccharides-lps-gut-health)are part of what crosses a leaky barrier. Researchers have linked barrier dysfunction with body-wide inflammation, oxidative stress, and reduced insulin sensitivity [6]. My dysbiosis guide covers the microbial side in depth ([https://drdanwool.com/blog/gut-dysbiosis-what-it-means-how-to-test](https://drdanwool.com/blog/gut-dysbiosis-what-it-means-how-to-test)). ### 6. Alcohol [Heavy drinking stresses the barrier directly](/blog/alcohol-and-gut-health). In a study of people with alcohol dependence, some developed a leaky gut and others did not. Those with a leaky gut also had altered gut bacteria, and after three weeks without alcohol they reported more depression, anxiety, and craving [7]. In my practice, cutting back is one of the fastest changes patients notice. ### 7. A low-fiber diet Gut bacteria ferment fiber into butyrate. [Butyrate is a short-chain fatty acid](/blog/butyrate)that feeds the cells lining your colon. In my experience, a diet built on refined, low-fiber foods leaves less fuel for the lining and fewer of the bacteria that make it. ## The Hormone Connection A leaky gut doesn't stay in the gut. The stress driver above runs in both directions: stress hormones loosen the barrier, and the inflammation that follows keeps the stress response engaged [5]. [Men's health](/mens-health)offers a newer example. In a pilot study of 50 men, higher levels of a blood marker for [bacterial endotoxin](/blog/lipopolysaccharides-lps-gut-health) were associated with lower testosterone, and an inflammatory signal called IL-6 tracked closely with lower testosterone too [8]. The study was small and observational, so it can't prove cause and effect. However, it fits what I see clinically. When I look at a low testosterone result, I ask about the gut. My master [gut health guide covers the gut-hormone axis in more detail](/blog/gut-health-what-it-is-and-how-it-breaks-down). ## Why I Don't Trust a Zonulin Result Serum zonulin is the most heavily marketed blood test for leaky gut. And I'm a little leery of it. Zonulin is a real protein that helps open the seals between intestinal cells. The problem is the test. A 2019 study examined two widely used commercial zonulin kits. The kits were detecting other proteins, including complement C3 and haptoglobin [9]. The researchers advised caution about using serum zonulin as a barrier marker until the assays improve [9]. A later review from the Mayo Clinic called for human studies showing that a specific nutrient or supplement actually causes barrier repair before it gets marketed for that purpose [6]. I agree with both. A zonulin number gets used to diagnose leaky gut and then to sell a supplement protocol to fix it. Neither step holds up. I would rather find the driver and track how you feel. ## My Five-Step Approach to Leaky Gut ### Step 1. Rule out what has to be ruled out Alarm features, [celiac disease](/celiac-disease-treatment), and [inflammatory bowel disease](/crohns-disease-treatment) come first. If something points that way, I coordinate with your gastroenterologist. ### Step 2. Test for the driver I choose testing based on your history. For most patients that means celiac screening and a stool PCR panel. Some also need breath testing or a direct permeability test. ### Step 3. Remove the driver This is where most of the improvement happens. That might mean a conversation with your prescriber about[daily NSAIDs](/blog/nsaids-gut-health), a structured elimination diet/trial, treating an infection, pulling back on [alcohol](/blog/alcohol-and-gut-health), or building real recovery into a [high-stress](/blog/stress-gut-motility-bloating) schedule. ### Step 4. Support the lining [L-glutamine](/blog/lglutamine) is an amino acid that the cells lining your intestine burn for fuel. A 2019 randomized trial enrolled people whose IBS-D began after a gut infection and who had increased permeability. After eight weeks, about 80 percent of the glutamine group met the main symptom goal, compared with about 6 percent on placebo, and their permeability returned to normal [10]. It was one trial in a narrow group, and it needs to be repeated but interesting, right? In my practice I often recommend L-glutamine for patients with this presentation. The trial used 5 grams three times daily, and research supports doses in this range that are worth discussing with your practitioner. For patients whose barrier problems trace back to [NSAIDs](/blog/nsaids-gut-health), I often consider [zinc carnosine](/blog/zinc-carnosine). In the same volunteer study that showed indomethacin tripling permeability, adding zinc carnosine prevented that rise [3]. ### Step 5. Rebuild and re-feed Food comes first: a wide variety of plants, [fermented foods](/blog/are-fermented-foods-good-for-the-gut) as tolerated, and enough fiber to feed your [butyrate producers](/blog/akkermansia-muciniphila). Increase fiber slowly if it has caused bloating in the past. Timelines vary. A patient whose problem traces to [daily NSAIDs](/blog/nsaids-gut-health) may improve faster than someone with untreated celiac disease or ongoing high stress. I plan in months. I tell patients that on day one. We generally have monthly follow-ups and I begin reassessing at 3-4 months. ## Leaky Gut and Intestinal Permeability Hub Directory Every article in this hub, grouped by what you're trying to figure out. ### Start here - Leaky gut overview: [https://drdanwool.com/blog/leaky-gut](https://drdanwool.com/blog/leaky-gut) ### What crosses a leaky barrier - Lipopolysaccharides (LPS) and gut health: [https://drdanwool.com/blog/lipopolysaccharides-lps-gut-health](https://drdanwool.com/blog/lipopolysaccharides-lps-gut-health) ### Supporting the gut lining - L-glutamine: [https://drdanwool.com/blog/lglutamine](https://drdanwool.com/blog/lglutamine) - Zinc carnosine: [https://drdanwool.com/blog/zinc-carnosine](https://drdanwool.com/blog/zinc-carnosine) - N-acetyl glucosamine (NAG): [https://drdanwool.com/blog/nag-n-acetyl-glucosamine-gut-health](https://drdanwool.com/blog/nag-n-acetyl-glucosamine-gut-health) - Type II collagen: [https://drdanwool.com/blog/type-ii-collagen-gut-health](https://drdanwool.com/blog/type-ii-collagen-gut-health) - Bovine colostrum: [https://drdanwool.com/blog/bovine-colostrum-gut-health](https://drdanwool.com/blog/bovine-colostrum-gut-health) ### Where the research is headed - BPC-157: [https://www.drdanwool.com/blog/bpc157](https://www.drdanwool.com/blog/bpc157) - KPV: [https://www.drdanwool.com/blog/kpv](https://www.drdanwool.com/blog/kpv) - Larazotide: [https://drdanwool.com/blog/larazotide](https://drdanwool.com/blog/larazotide) ## The Bottom Line on Leaky Gut Leaky gut describes a measurable change in how your intestinal lining controls what gets through. It shows up in celiac disease, inflammatory bowel disease, and a large share of [IBS](/blog/ibs-d-guide). [NSAIDs](/blog/nsaids-gut-health), [gluten](/blog/non-celiac-gluten-sensitivity), [stress](/blog/stress-gut-motility-bloating), [infection](/blog/post-antibiotic-dysbiosis-diarrhea), dysbiosis, [alcohol](/blog/alcohol-and-gut-health), and [low-fiber eating](/blog/fiber) can all push it along. Skip the zonulin test, find the driver, remove it, and then support the lining. If Jen's story sounds like yours, it's worth getting properly evaluated. ## Related Reading - Gut Health: What It Is and How It Breaks Down [https://drdanwool.com/blog/gut-health-what-it-is-and-how-it-breaks-down](https://drdanwool.com/blog/gut-health-what-it-is-and-how-it-breaks-down) - What Gut Dysbiosis Means and How to Test for It [https://drdanwool.com/blog/gut-dysbiosis-what-it-means-how-to-test](https://drdanwool.com/blog/gut-dysbiosis-what-it-means-how-to-test) - What IBS Actually Is and Why Standard Treatment Fails [https://drdanwool.com/blog/what-is-ibs-why-standard-treatment-fails](https://drdanwool.com/blog/what-is-ibs-why-standard-treatment-fails) - Celiac Disease [https://drdanwool.com/blog/celiac-disease](https://drdanwool.com/blog/celiac-disease) - NSAIDs and Gut Health [https://drdanwool.com/blog/nsaids-gut-health](https://drdanwool.com/blog/nsaids-gut-health) - Alcohol and Gut Health [https://drdanwool.com/blog/alcohol-and-gut-health](https://drdanwool.com/blog/alcohol-and-gut-health) ## Frequently Asked Questions about Leaky Gut ### What are the symptoms of leaky gut? Quick Answer: [Bloating](/bloating-treatment-scottsdale), gas, loose stools, and abdominal pain are the most common. None of them is specific to leaky gut. Full Answer: In my practice, patients also describe new food reactions, skin flares, joint stiffness, and fatigue. Those symptoms overlap with [IBS](/blog/what-ibs-actually-is-and-why-standard-treatment-fails), [celiac disease](/celiac-disease-treatment), [SIBO](/sibo), and [inflammatory bowel disease.](/crohns-disease-treatment) That overlap is why symptoms alone can't confirm increased permeability, and why I look for the driver with targeted testing. ### Is leaky gut a real medical condition? Quick Answer: Increased intestinal permeability is real and measurable. Leaky gut is not recognized as a standalone diagnosis. Full Answer: Permeability changes are well documented in [celiac disease](/celiac-disease-treatment), i[nflammatory bowel disease,](/ulcerative-colitis-treatment) and many people with [IBS](/blog/what-ibs-actually-is-and-why-standard-treatment-fails) [1,2]. What remains unproven is that repairing the barrier alone cures a disease [1]. I treat permeability as a sign that something upstream needs attention. ### What causes leaky gut? Quick Answer: The best-documented causes are [NSAIDs](/blog/nsaids-gut-health), gluten in people with celiac disease or [gluten sensitivity,](/blog/non-celiac-gluten-sensitivity) and psychological [stress](/blog/stress-gut-motility-bloating). Full Answer: [Gut infections](/blog/post-antibiotic-dysbiosis-diarrhea), [alcohol](/blog/alcohol-and-gut-health), microbial imbalance, and a [low-fiber diet](/blog/fiber) also contribute. Indomethacin tripled permeability in healthy volunteers [3], and a public speech raised it in people whose cortisol rose [5]. Most patients I see have more than one driver. ### How do you test for leaky gut? Quick Answer: The research standard is a urine test that measures how two sugars of different sizes cross the gut lining. Full Answer: The lactulose-mannitol test gives a direct measure of small intestinal permeability [1]. I order it when the result would change the plan. More often I test for the drivers instead, using celiac screening, a comprehensive stool analysis, or [SIBO](/blog/siboguide) breath testing. ### Is a zonulin blood test accurate for leaky gut? Quick Answer: Current commercial serum zonulin tests are unreliable. One study found they were detecting other proteins. Full Answer: A 2019 study found that two widely used commercial kits were picking up proteins such as complement C3 and haptoglobin instead of zonulin [9]. The researchers advised caution until the assays improve. I don't base treatment decisions on a zonulin result. ### Does L-glutamine help leaky gut? Quick Answer: It can in the right patient. …