Leaky gut: what the evidence says and what zonulin measures

Increased intestinal permeability exists and can be measured in laboratories. The jump that follows, from a measured phenomenon to leaky gut as a standalone diagnosis with its own home test, is where the evidence thins. And the most popular test attached to it, zonulin, has a problem few sellers mention.

This is a subject where two camps shout past each other. I think both are half right, and the difference sits in the details.

Is leaky gut real?

The underlying mechanism is real. Your gut wall normally lets substances through selectively, regulated by protein connections between cells called tight junctions. With inflammation, certain medicines, alcohol and hard exercise, that permeability can rise temporarily.

So this is not an alternative theory. It sits in the mainstream gastroenterology literature.

Where it goes wrong is the next step. A broad review in Gut concludes that raised permeability is seen across many conditions, but is usually a consequence rather than a demonstrated cause, and that public-domain information on it needs confirmation (PMID 31076401).

Put briefly: the phenomenon is real, the disease built around it much less so.

What is zonulin, and does the test measure it?

Zonulin is a protein thought to be involved in opening the tight junctions, and it is sold as a measure of gut permeability in blood or stool. The problem sits in the assay itself. Researchers showed that the widely used commercial ELISA does not recognise the intended protein, and picks up properdin among others (PMID 29459849).

That is fairly fundamental. A test measuring something other than what the box says cannot support a reliable conclusion.

The first row is what researchers use when they want to measure permeability seriously. The second row is what you meet online.

When does gut permeability rise?

During hard exercise, in heat, and under acute stress, and in all three cases usually temporarily. During intense training blood flow shifts away from your gut towards your muscles, which briefly strains the barrier function. A systematic review describes this whole pattern as exercise-induced gastrointestinal syndrome (PMID 28589631).

Stress does something comparable. In healthy volunteers, acute psychological stress raised small intestinal permeability through a mast cell dependent mechanism (PMID 24153250).

Picture a triathlete running a half in July at 28 degrees. Around kilometre 15 the nausea arrives, he misses two water cups, and the rest of the race is survival. That is load plus heat, not a chronic condition.

The distinction between temporary and lasting is exactly what the home-test market leaves out.

What does this mean for your training?

Mainly that you can treat gastrointestinal symptoms during exercise as a training variable. You can accustom your gut to fuelling during exercise by practising it in training rather than only on race days. Heat, dehydration and a high sugar intake per hour measurably worsen symptoms.

Not exciting, but it is the part you control.

What I would skip: expensive gut repair protocols based on a zonulin result. If the measurement itself is unreliable, so is the plan built on it.

For the broader question of which gut tests are worth anything, see food intolerance: which tests work. For the role your head plays, see gut symptoms and stress.

Which blood values say something here?

No blood value demonstrates a leaky gut, but several give context to persistent symptoms. An inflammation marker shows whether something is going on, and values around iron and vitamins show whether absorption or diet has left traces. Those are data a doctor can work with.

In practice that means CRP, ferritin, vitamin B12 and haemoglobin. A panel such as 360 Health includes these values, with a doctor's assessment.

If fatigue is a large part of the picture, also read hs-CRP and fatigue.

A varied diet with enough fibre remains the foundation, and that needs no measurement at all. The Dutch Nutrition Centre works with roughly 30 to 40 grams of fibre a day for adults.

What I would do

Treat symptoms during exercise as a training and fuelling problem, and rehearse your race nutrition beforehand. If symptoms persist at rest too, or you see blood in your stool or unintended weight loss, discuss that with your GP rather than a test vendor.

Every blood test result includes a professional assessment from a BIG-registered doctor. For treatment decisions, discuss your results with your GP.

References

• Camilleri M. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut. 2019;68(8):1516-1526. PMID 31076401.
• Scheffler L, Crane A, Heyne H, et al. Widely Used Commercial ELISA Does Not Detect Precursor of Haptoglobin2, but Recognizes Properdin as a Potential Second Member of the Zonulin Family. Front Endocrinol. 2018. PMID 29459849.
• Costa RJS, Snipe RMJ, Kitic CM, Gibson PR. Systematic review: exercise-induced gastrointestinal syndrome. Aliment Pharmacol Ther. 2017. PMID 28589631.
• Vanuytsel T, van Wanrooy S, Vanheel H, et al. Psychological stress and corticotropin-releasing hormone increase intestinal permeability in humans by a mast cell-dependent mechanism. Gut. 2014;63(8):1293-1299. PMID 24153250.