Zonulin and Leaky Gut: What a High Result Means and How to Support Your Gut Barrier

Key takeaways

• Zonulin is the main protein your body uses to loosen the tight junctions between gut-lining cells. Researcher Alessio Fasano, who discovered it, describes it as the only physiological regulator of these junctions identified so far. [1]
• When zonulin rises, those junctions can loosen — one part of what people call “leaky gut”, the everyday term for increased intestinal permeability. [1][3]
• Gluten (specifically gliadin) and disturbed gut bacteria are the two best-studied triggers for zonulin release. [4][5] This does not mean it causes chronic “leaky gut” or damage in healthy people with normal gluten tolerance!
• The popular zonulin blood test has a known reliability problem — a 2018 study found the most widely used version doesn’t detect the protein it claims to. Read any single result with real caution. [6]
• Some nutrients — glutamine, zinc carnosine and vitamin D — have been studied for supporting the gut barrier, with evidence ranging from strong to preliminary. [7][9]

If you’ve been reading about gut health, you’ve probably met the word zonulin, usually next to the phrase leaky gut. It has become a popular marker of gut barrier health and is sometimes included in gut microbiome tests, like our Ultimate Gut Health Test — but there’s a lot of confusion about what it actually is, what a high result means, and what you can do about it. This article walks through the science in plain terms, including the parts still being debated.

What is zonulin?

Zonulin is a protein your body releases to loosen the tight junctions between the cells lining your gut, letting larger molecules pass briefly between cells rather than through them. [1] It was identified by the research group of Dr Alessio Fasano, who described it as pre-haptoglobin-2, a form of a common blood protein, and as the only physiological modulator of these junctions described so far. [1]

To picture what it acts on: your gut lining is only one cell thick. These cells sit side by side, held together by structures called tight junctions — think of them as the grouting between tiles, deciding what can slip between the cells and what cannot.

In a healthy gut, this loosening is normal and short-lived: the junctions open, then close again. The concern is when zonulin stays high and the junctions stay loose for longer than they should. [2]

What is “leaky gut”, and how does zonulin fit in?

“Leaky gut” is an everyday phrase for increased intestinal permeability — a gut barrier that lets through more than it normally would. It’s a real, measurable phenomenon, but it is not a formal medical diagnosis, and zonulin acts as one signal of it rather than proof of it. [3]

A 2019 review in the journal Gut set out what we do and don’t know. The author confirmed that increased permeability is real and measurable, but cautioned that many popular claims about leaky gut run well ahead of the evidence. [3]

Higher zonulin has been linked with increased permeability in several conditions, including coeliac disease and type 1 diabetes. [1] But a link is an association: zonulin travels alongside these conditions. It doesn’t prove that zonulin causes them, or the reverse. [1][3]

What are the symptoms of high zonulin or a weakened gut barrier?

There are no symptoms unique to high zonulin, and you cannot tell your zonulin level from how you feel. A stressed gut barrier tends to be discussed alongside non-specific digestive and whole-body symptoms, but these overlap heavily with many common conditions, and the science linking specific symptoms to permeability is still developing. [3]

Symptoms people commonly ask about in this context include:

• Bloating, wind, or abdominal discomfort
• Irregular bowel habits (loose stools, constipation, or both)
• Food reactions or new sensitivities
• Fatigue or low mood
• Skin flare-ups

The honest position is that these are non-specific. They can point to many things — including irritable bowel syndrome (IBS), coeliac disease, or simply an unbalanced diet — and none of them confirms “leaky gut” on its own. If symptoms are persistent, the useful next step is a proper assessment rather than self-diagnosis. See When should you see a GP? below for the warning signs that need medical review first.

What causes zonulin to rise?

Two triggers stand out in the research: gluten (specifically a fragment called gliadin) and a disturbed balance of gut bacteria. [4][1]

Gluten (gliadin). Studies on human gut tissue show that gliadin prompts gut cells to release zonulin, which then loosens the junctions. [4] Later work found gliadin does this by binding to a specific receptor (CXCR3) on the gut cells. [5] The effect has been seen in people with and without coeliac disease, though it tends to be stronger and longer-lasting in those with coeliac disease. [4] Please note this does not mean we all need to avoid gluten.

Gut bacteria. When the balance of bacteria in the small intestine is disturbed, this can drive zonulin release too. [1] This is one reason gut barrier health is often discussed alongside SIBO (small intestinal bacterial overgrowth), where bacteria grow in the wrong place.

Other factors researchers connect to a weaker gut barrier include ongoing stress, heavy alcohol use, some medications, and a diet low in fibre and plant variety. [3][12]

What is a normal zonulin level, and what does a high result mean?

There is no universally agreed “normal” zonulin range you can rely on, largely because the most common commercial test doesn’t measure zonulin cleanly. A high result should be treated as a prompt to look at the wider picture, not as a diagnosis. [6]

Labs that offer zonulin testing publish their own reference ranges, but these vary between providers and assays, and — as the next section explains — the widely used blood test appears to pick up other proteins rather than zonulin itself. [6] That makes a single number hard to interpret in isolation. A result above a lab’s range is best read as one clue that your gut barrier may be worth investigating, alongside your symptoms, diet, and other markers — never as a standalone verdict.

Can you test zonulin — blood or stool — and can you trust the result?

You can complete both blood and stool (faecal) zonulin tests, but the most widely used blood commercial version has a known reliability problem, so a single zonulin result should be read with real caution rather than treated as a firm answer. [6]

Here’s the catch. In 2018, researchers examined the most widely used commercial zonulin blood test and found it did not actually detect pre-haptoglobin-2 — the protein it’s meant to measure. Instead, it appeared to pick up other, related proteins. [6] Faecal (stool) zonulin tests rely on similar antibody-based methods and carry comparable interpretation caveats, so the same “read with care” principle applies.

This doesn’t make zonulin meaningless. It means the number is one clue, not a verdict. [6]

A more useful approach is to look at the wider picture of your gut: the balance of your gut bacteria, signs of inflammation, and how you digest and absorb food, rather than relying on one isolated marker. A comprehensive gut microbiome test, such as the Ultimate Gut Health Test, is designed to do exactly this — and it’s reviewed by a practitioner who builds a personalised plan around your results and your symptoms, rather than leaving you to interpret a single figure alone.

As an example if you had a borderline zonulin result and you had low butyrate producing bacteria, low Akkermansia (a bacteria associated with the health of the mucosal layer lining the gut) perhaps elevated secretory IgA and a questionable calprotectin (indicating some inflammation in the gut)- we could form a strong argument for impaired gut barrier health compared to a slightly elevated zonulin with all these additional markers being comfortably in range.

If your symptoms point towards bacterial overgrowth in the small intestine, a breath test like the SIBO Breath Test can help work out whether that’s part of your picture, since this is one of the situations linked to a stressed gut barrier. [1]

How can you lower zonulin and support your gut barrier?

Because you can’t reliably measure zonulin, the practical goal isn’t to chase a lower number — it’s to support the gut barrier by removing what stresses it and supplying what strengthens it. In practice that means addressing known triggers (managing gluten if you react to it, and any bacterial imbalance), eating a varied, plant-rich diet, looking after stress and sleep, and considering specific nutrients studied for barrier support. [3][12]

A note if you have IBS or SIBO: high-fibre and prebiotic foods (for example inulin, found in onions, garlic, chicory and Jerusalem artichoke) support gut bacteria for many people, but they can worsen bloating and wind in some people with IBS or SIBO. If that’s you, increase fibre and plant variety gradually and consider doing so with practitioner support rather than all at once.

Which nutrients help support the gut barrier?

Several nutrients have been studied for supporting the cells and junctions of the gut lining. The evidence varies, so it’s worth being clear about what each has and hasn’t shown. None is a quick fix, and they work best as part of a wider, personalised plan.

Glutamine

Glutamine is an amino acid that gut cells use as a main fuel source, and it appears to help maintain tight junctions — though the clinical trial evidence is mixed. When the body is under stress, demand rises and levels can fall. [7] A 2024 systematic review and meta-analysis pooled ten clinical trials: across all trials combined, glutamine did not produce a clear reduction in gut permeability. In subgroup analyses, however, higher doses taken over a short period (under two weeks), and trials using the lactulose/mannitol test, did show a statistically significant reduction — although the effects were small and their clinical relevance is uncertain. [8] In clinic, and personally, I have found glutamine to be an excellent option with noticeable improvement in symptoms such as skin health, histamine issues and bowel movements.

Recommended Product: Rezcue

Zinc carnosine

In a small trial, zinc carnosine prevented a drug-induced rise in gut permeability in healthy volunteers. Participants took indomethacin — an anti-inflammatory painkiller (NSAID) known to increase permeability — which caused a roughly threefold rise in gut leakiness. When zinc carnosine was taken at the same time, that expected rise did not occur. [9] The same work reported that zinc carnosine supported repair processes in the gut lining in laboratory and animal studies. [9] The human trial was small, so more research is warranted, but the findings are encouraging.

Recommended Product: Rezcue

Zinc

Zinc more broadly is essential for a healthy gut lining, and low zinc is linked with a weaker barrier. [12] A 2025 patient-based study in otherwise-healthy people found that oral zinc reduced a marker of leakiness across the gut barrier and shifted tight-junction proteins in a protective direction, adding human evidence to earlier laboratory work. [10]

Recommended Producy (not needed if using Rezcue): Zinc 15

Vitamin D

Vitamin D helps regulate the proteins that build tight junctions, and in laboratory and animal studies it reduced gliadin-driven barrier damage and lowered zonulin release. [11] Human evidence here is still developing, so this is best seen as promising rather than settled.

Recommended Product: Vitamin D3 & K2

Polyphenols and other plant compounds

Polyphenols — colourful compounds in fruit, vegetables, herbs, tea and extra virgin olive oil — are highlighted in reviews as supportive of the gut lining, partly through their effect on your gut bacteria. [12] A diverse plate is one of the simplest daily ways to support your gut (bearing in mind the IBS/SIBO caveat above).

Recommended Product: Poly-ProFlora Powder

What lifestyle habits help?

Day-to-day habits matter as much as any supplement — often more. Eating a wide range of plants gives your gut bacteria the fibre and polyphenols they thrive on; managing stress, protecting your sleep, moving your body, and being mindful with alcohol all support the barrier too. [12][3] These changes aren’t glamorous, but they’re the foundation everything else builds on.

If gut symptoms have been part of your life for a long time, you don’t have to work it out alone. A practitioner-led review can help you see the whole picture and focus your energy where it will count.

When should you see a GP?

Some symptoms should always be checked by a GP before you explore gut testing or supplements, because they can signal conditions that need prompt medical attention. See your GP (or NHS 111) if you have any of the following:

• Blood in your stool, or black, tarry stools
• Unexplained weight loss
• A persistent change in bowel habit lasting three weeks or more
• Difficulty swallowing, or persistent vomiting
• A lump or swelling in your tummy
• Persistent abdominal pain, or symptoms that wake you at night
• Unexplained fatigue, or signs of anaemia (such as breathlessness or pallor)

These are general warning signs, not a complete list. If you’re worried about any symptom, it’s always reasonable to speak to your GP.

Frequently asked questions

Is leaky gut a real diagnosis? Increased intestinal permeability is real and measurable. “Leaky gut syndrome” as a standalone diagnosis is not formally recognised, and popular claims about it should be read carefully. [3]

Does high zonulin mean I definitely have leaky gut? Not on its own. Zonulin has been associated with increased permeability, but the common blood test has known reliability issues, so results are best interpreted in context rather than treated as proof. [1][6]

Will cutting out gluten lower my zonulin? Gliadin, a part of gluten, has been shown to trigger zonulin release in gut tissue. [4] Whether removing it helps you personally depends on your own situation, and it’s worth discussing with a qualified practitioner before cutting out food groups.

How can I lower zonulin naturally? Because zonulin can’t be measured reliably, the practical aim is to support the gut barrier — addressing triggers like gluten (if you react to it) and bacterial imbalance, eating a varied plant-rich diet, managing stress and sleep, and considering studied nutrients such as glutamine, zinc and zinc carnosine. [3][9]

How long does it take to support the gut barrier? There’s no fixed timeline, and it varies from person to person. A steady, consistent approach to diet and lifestyle tends to serve people better than any short-term plan.

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The information in this article is for educational purposes only. It is not intended to diagnose, treat, cure or prevent any disease, and it is not a substitute for personalised advice from a qualified healthcare professional.

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Scientific references

1. 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. https://pubmed.ncbi.nlm.nih.gov/21248165/
2. Sturgeon C, Fasano A. Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases. Tissue Barriers. 2016;4(4):e1251384. https://www.tandfonline.com/doi/full/10.1080/21688370.2016.1251384
3. Camilleri M. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut. 2019;68(8):1516–1526. https://pubmed.ncbi.nlm.nih.gov/31076401/
4. Drago S, El Asmar R, Di Pierro M, et al. Gliadin, zonulin and gut permeability: effects on coeliac and non-coeliac intestinal mucosa and intestinal cell lines. Scand J Gastroenterol. 2006;41(4):408–419. https://pubmed.ncbi.nlm.nih.gov/16635908/
5. Lammers KM, Lu R, Brownley J, et al. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology. 2008;135(1):194–204. https://pubmed.ncbi.nlm.nih.gov/18485912/
6. Scheffler L, Crane A, Heyne H, et al. Widely used commercial ELISA does not detect precursor of haptoglobin-2, but recognizes properdin as a potential second member of the zonulin family. Front Endocrinol. 2018;9:22. https://pubmed.ncbi.nlm.nih.gov/29459849/
7. Rao R, Samak G. Role of glutamine in protection of intestinal epithelial tight junctions. J Epithel Biol Pharmacol. 2012;5(Suppl 1-M7):47–54. https://pubmed.ncbi.nlm.nih.gov/25810794/
8. Abbasi F, Haghighat Lari MM, Khosravi GR, et al. A systematic review and meta-analysis of clinical trials on the effects of glutamine supplementation on gut permeability in adults. Amino Acids. 2024;56(1):60. https://doi.org/10.1007/s00726-024-03420-7
9. Mahmood A, FitzGerald AJ, Marchbank T, et al. Zinc carnosine, a health food supplement that stabilises small bowel integrity and stimulates gut repair processes. Gut. 2007;56(2):168–175. https://pubmed.ncbi.nlm.nih.gov/16777920/
10. Del Rio EA, Valenzano MC, DiGuilio KM, et al. Orally administered zinc gluconate induces tight junctional remodeling and reduces passive transmucosal permeability across human intestine in a patient-based study. Int J Mol Sci. 2025;26(17):8540. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12429388/
11. Dong S, Singh TP, Wei X, et al. Protective effect of 1,25-dihydroxy vitamin D3 on pepsin–trypsin-resistant gliadin-induced tight junction injuries. Dig Dis Sci. 2018;63(1):92–104. https://link.springer.com/article/10.1007/s10620-017-4738-0
12. Aleman RS, Moncada M, Aryana KJ. Leaky gut and the ingredients that help treat it: a review. Molecules. 2023;28(2):619. https://pubmed.ncbi.nlm.nih.gov/36677677/