Intestinal permeability and "leaky gut": what is established, how it is measured, and what the supplements sold for it show

What it is

Intestinal permeability describes how easily substances cross the gut lining, which is made of surface mucus, an epithelial cell layer and immune defences. Increased permeability is documented in specific diseases: celiac disease has some of the best evidence, and it is clearly present in inflammatory bowel disease. "Leaky gut syndrome" as a stand-alone diagnosis is a different thing, and a major clinical review says public claims about it need confirmation before supplements are endorsed.

What the research says

Increased permeability is a measurable finding in celiac disease and inflammatory bowel disease, and in stress states such as NSAID use and endurance exercise. Whether restoring the barrier improves any disease is unproven. The popular blood test (zonulin ELISA) does not detect zonulin, according to two independent laboratory studies. For supplements: a 2024 meta-analysis found glutamine did not change permeability overall; one US-funded RCT found glutamine helped post-infectious IBS-D with measured hyperpermeability; zinc carnosine rests on a 10-person crossover trial partly funded by industry. We found no human trials of collagen or bone broth on permeability.

Evidence grade: Disputed.

What the evidence supports

Increased intestinal permeability is established in celiac disease and clearly present in inflammatory bowel disease, though in IBD it is unresolved whether it is a cause or a consequence of inflammation. (Source 1)

• Systematic review, Moderate certainty.
• Size: narrative review of human and experimental studies.
• Who: patients with celiac disease and IBD.
• How long: not applicable.
• Result: not a pooled estimate.
• Funding: not stated.

Increased permeability is clearly present in inflammatory bowel disease, but the question of whether this is a primary event or a consequence of inflammation remains unsolved.

In celiac disease, gluten ingestion is described as causally related to the impaired barrier. (Source 1)

• Systematic review, Moderate certainty.
• Size: narrative review.
• Who: people with celiac disease.
• How long: not applicable.
• Result: not a pooled estimate.
• Funding: not stated.

Gluten ingestion is causally related to the impaired intestinal barrier function in CeD.

In one RCT of post-infectious IBS-D with measured intestinal hyperpermeability, oral glutamine produced the primary response in 79.6% versus 5.8% on placebo. (Source 2)

• Randomized trial, Low certainty.
• Size: 106 completers (54 glutamine, 52 placebo)
• Who: adults with post-infectious IBS-D and hyperpermeability.
• How long: 8 weeks.
• Result: 43 (79.6%) vs 3 (5.8%) met primary endpoint.
• Funding: independent (NCCIH, NIDDK, US Department of Veterans Affairs)

Limit of this finding: This is one single-centre trial in a narrow group: adults whose diarrhoea-predominant IBS began after a gut infection and who had intestinal hyperpermeability measured beforehand. The 79.6% versus 5.8% gap is very large for a trial of 106 people, and the paper describes its own result as "dramatically" reducing symptoms, which is unusually strong wording for a single study. A reader should not read this as evidence that glutamine helps IBS in general; the pooled meta-analysis of glutamine and intestinal permeability found no overall effect.

The primary endpoint occurred in 43 (79.6%) in the glutamine group and 3 (5.8%) in the placebo group (a 14-fold difference).

Zinc carnosine prevented an indomethacin-induced rise in permeability in a 10-person crossover trial; the study was partly industry-funded. (Source 3)

• Randomized trial, Very low certainty.
• Size: 10 healthy volunteers.
• Who: healthy volunteers given indomethacin 50 mg three times a day.
• How long: 5 days.
• Result: L:R 0.35 to 0.88 on placebo (p<0.01); no significant rise with ZnC 37.5 mg twice daily.
• Funding: partly industry-funded (Lonza Nutrition, M&M Veterinary Health)

Limit of this finding: The paper’s own words overstate its own numbers. It calls the change a "threefold increase", but the ratios it prints in the same sentence rise from 0.35 to 0.88, which is about 2.5 times, not three. The direction of the finding is unaffected — permeability rose on the anti-inflammatory drug and did not rise significantly when zinc carnosine was given — but the word "threefold" should not be repeated as a fact. Note also that this was 10 healthy volunteers over 5 days, and the work was funded in part by Lonza Nutrition, a commercial supplier of zinc carnosine. A reader should not take it as evidence that zinc carnosine treats any condition.

In volunteers, indomethacin caused a threefold increase in gut permeability in the control arm; lactulose:rhamnose ratios were (mean (standard error of mean)) 0.35 (0.035) before indomethacin treatment and 0.88 (0.11) after 5 days of indomethacin treatment (p<0.01), whereas no significant increase in permeability was seen when ZnC was coadministered.

What the evidence does not support

A clinical review in Gut says restoring barrier function has not been shown to improve clinical outcomes in gastrointestinal or systemic diseases. (Source 4)

• Systematic review, Low certainty.
• Size: narrative review.
• Who: humans with GI and systemic diseases.
• How long: not applicable.
• Result: not applicable.
• Funding: not stated.

It is still unproven that restoring barrier function can ameliorate clinical manifestations in GI or systemic diseases.

The same review says public-domain claims about 'leaky gut' need confirmation before supplements to repair it are endorsed. (Source 4)

• Systematic review, Low certainty.
• Size: narrative review.
• Who: general public claims.
• How long: not applicable.
• Result: not applicable.
• Funding: not stated.

Information on 'healthy' or 'leaky' gut in the public domain requires confirmation before endorsing dietary exclusions, replacement with non-irritating foods (such as fermented foods) or use of supplements to repair the damage.

A widely used commercial zonulin ELISA did not recognise pre-haptoglobin2 (zonulin) and appears to detect related proteins such as properdin. (Source 5)

• Lab study in cells, Moderate certainty.
• Size: 376 subjects.
• Who: Sorb cohort, Germany.
• How long: cross-sectional.
• Result: ELISA did not detect pre-haptoglobin2.
• Funding: not stated.

Our study suggests that the zonulin ELISA does not recognize pre-haptoglobin2, rather structural (and possibly functional) analog proteins belonging to the mannose-associated serine protease family, with properdin being the most likely possible candidate.

A second independent group found two commercial zonulin assays (CUSABIO and Immundiagnostik) do not detect the actual protein and advised caution in using serum zonulin as a barrier marker. (Source 6)

• Lab study in cells, Moderate certainty.
• Size: patient and healthy control sera.
• Who: people with GI dysfunction and healthy controls.
• How long: not applicable.
• Result: top matches were haptoglobin and complement C3.
• Funding: not stated.

These findings confirm that current commercial zonulin assays are not detecting the actual protein as prehaptoglobin-2.

A 2024 meta-analysis of 10 randomised trials found glutamine did not significantly change intestinal permeability overall; the paper also reports a higher-dose subgroup result, but its own participant totals, confidence interval and dose figures contradict each other, so that subgroup result cannot be relied on. (Source 7)

• Meta-analysis, Low certainty.
• Size: 10 trials (1998-2014); the paper gives the total as 352 participants in one sentence and as 216 plus 212 in the next.
• Who: adults with various diseases.
• How long: varied across the included trials.
• Result: Overall WMD -0.00 (95% CI -0.04, 0.03), i.e. no significant effect.
• Funding: not stated.

Limit of this finding: Treat the numbers in this paper with care: it contradicts itself in three places. (1) It says 352 people took part, then says 216 were in the glutamine group and 212 in the control group, which adds up to 428 — the two totals cannot both be right. (2) For the higher-dose subgroup it prints an average difference of −0.01 alongside a confidence interval of −0.10 to −0.08; the −0.01 falls outside its own interval, which is arithmetically impossible and is almost certainly a typesetting error. (3) The dose threshold is given as "over 30g/day" in one sentence and "exceeding 30 mg/day" in another — a thousand-fold difference the paper never resolves. What a reader can take from it: across these ten trials, glutamine showed no overall effect on intestinal permeability. What a reader should not take from it: that any particular dose of glutamine reduces intestinal permeability, or what that dose would be.

Overall, glutamine supplementation did not significantly affect intestinal permeability (WMD: −0.00, 95% CI −0.04, 0.03).

Where the evidence is mixed

The lactulose-mannitol urine sugar test is the most common in vivo test, but its validity and interpretation are disputed. (Source 1)

• Systematic review, Low certainty.
• Size: narrative review.
• Who: not applicable.
• How long: not applicable.
• Result: not applicable.
• Funding: not stated.

However, the evidence supporting this hypothesis is scarce, leading to controversy on the validity and especially the interpretation of the lactulose-mannitol test.

Laboratory analysis of bone broths found lead and cadmium at a few micrograms per serving, judged minimal risk, and calcium and magnesium below 5% of daily recommended levels. (Source 8)

• Lab study in cells, Low certainty.
• Size: laboratory broth samples.
• Who: home-made and commercial broths.
• How long: not applicable.
• Result: Pb and Cd a few μg per serving.
• Funding: not stated.

The risks that are associated with the ingestion of heavy metals such as Pb and Cd in broth are minimal because the levels were in the ranges of a few μg per serving.

Where the research disagrees

Whether serum zonulin is a valid marker of intestinal permeability

• Vanuytsel, Tack and Farre (2021 review), narrative review: Celiac disease is one of the conditions with the best evidence for impaired barrier function playing a crucial role with zonulin as its proposed regulator. (Source 1)
• Ajamian et al. (2019), laboratory assay validation: Until assay methodology is improved, we advise the greater scientific and medical community to exercise caution in considering the measurement of serum zonulin as a marker of mucosal barrier integrity. (Source 6)

A common belief, and what the research shows

The belief: A zonulin blood or stool test can diagnose leaky gut, and supplements such as glutamine repair it.

What the research shows: Two laboratory studies found commercial zonulin kits do not detect zonulin ("These findings confirm that current commercial zonulin assays are not detecting the actual protein as prehaptoglobin-2."), and a meta-analysis found "Overall, glutamine supplementation did not significantly affect intestinal permeability (WMD: −0.00, 95% CI −0.04, 0.03)."

Questions and answers

Intestinal permeability is how easily material passes through the gut lining. The lining is a barrier of mucus, a single layer of cells and immune defences. 'Leaky gut' is shorthand for increased permeability; 'leaky gut syndrome' as a diagnosis is not an established disease. (Source 4)

A tight barrier limits what crosses from the gut into the body. Increased permeability is documented in celiac disease and inflammatory bowel disease and in stress states such as NSAID use, endurance exercise and pregnancy. Whether fixing it improves disease is unproven. (Source 4)

Increased permeability is a real, measurable feature of some diseases, but in inflammatory bowel disease it is not settled whether it is a cause or a result of inflammation. Restoring the barrier has not been shown to cure any disease. (Source 4)

Does not apply in the usual sense: the question is what tightens the barrier. The Gut review reports dietary factors reversed leakiness in stress states, but says public 'leaky gut' supplement claims need confirmation. (Source 4)

What reduces permeability depends on the cause. In celiac disease gluten is causally linked to the barrier defect. For supplements, glutamine did not change permeability overall in a meta-analysis of 10 trials; zinc carnosine has one 10-person trial. (Source 1)

Reasons documented for a leakier barrier include celiac disease, inflammatory bowel disease, NSAID use, endurance exercise, pregnancy and bile acids or emulsifiers. (Source 4)

We found no human trial showing that bone broth or collagen reduces intestinal permeability. A laboratory study of bone broths found low calcium and magnesium and a few micrograms of lead and cadmium per serving. (Source 8)

Reframed for a barrier: what happens if permeability is increased. It accompanies disease in celiac disease and IBD, but restoring it has not been shown to improve clinical outcomes. (Source 4)

Research tests include urine sugar probes (lactulose-mannitol) and biopsies in Ussing chambers, the gold standard. The sugar test's interpretation is disputed. Commercial zonulin blood tests do not detect zonulin, according to two independent labs. (Source 1)

Is 'leaky gut' real?

Increased intestinal permeability is real and documented in celiac disease and inflammatory bowel disease, and after NSAIDs or endurance exercise. 'Leaky gut syndrome' as a diagnosis that explains many symptoms and is treated with supplements is not established; a Gut review says those public claims need confirmation.

How is intestinal permeability measured, and is the zonulin test reliable?

Research methods are urine sugar tests (lactulose-mannitol) and biopsies tested in Ussing chambers. Two independent laboratory studies found commercial zonulin ELISA kits do not measure zonulin, and a review says zonulin literature should be read with extreme caution.

What do studies show for glutamine, zinc carnosine, collagen and bone broth?

Glutamine: no overall effect on permeability across 10 RCTs (low certainty), though one RCT found benefit in post-infectious IBS-D with measured hyperpermeability. Zinc carnosine: one 10-person, partly industry-funded crossover trial against NSAID-induced permeability. Collagen and bone broth: we found no human trials on permeability; one lab study measured metals in broth.

What is needed after being told you have leaky gut?

The literature does not support a single supplement protocol for 'leaky gut'. The evidence points to identifying a cause (for example celiac disease or IBD), since restoring barrier function alone has not been shown to improve disease.

References

1. Frontiers in Nutrition. The Role of Intestinal Permeability in Gastrointestinal Disorders and Current Methods of Evaluation. 2021. PMID 34513903, DOI 10.3389/fnut.2021.717925. Read the source
2. Gut. Randomised placebo-controlled trial of dietary glutamine supplements for postinfectious irritable bowel syndrome. 2019. PMID 30108163, DOI 10.1136/gutjnl-2017-315136. Read the source
3. Gut. Zinc carnosine, a health food supplement that stabilises small bowel integrity and stimulates gut repair processes. 2007. PMID 16777920, DOI 10.1136/gut.2006.099929. Read the source
4. Gut. Leaky gut: mechanisms, measurement and clinical implications in humans. 2019. PMID 31076401, DOI 10.1136/gutjnl-2019-318427. Read the source
5. Frontiers in Endocrinology. Widely Used Commercial ELISA Does Not Detect Precursor of Haptoglobin2, but Recognizes Properdin as a Potential Second Member of the Zonulin Family. 2018. PMID 29459849, DOI 10.3389/fendo.2018.00022. Read the source
6. PLOS ONE. Serum zonulin as a marker of intestinal mucosal barrier function: May not be what it seems. 2019. PMID 30640940, DOI 10.1371/journal.pone.0210728. Read the source
7. Amino Acids. A systematic review and meta-analysis of clinical trials on the effects of glutamine supplementation on gut permeability in adults. 2024. PMID 39397201, DOI 10.1007/s00726-024-03420-7. Read the source
8. Food & Nutrition Research. Essential and toxic metals in animal bone broths. 2017. DOI 10.1080/16546628.2017.1347478. Read the source