Glossary · Markers and tests
Zonulin
In one sentence
Zonulin is a human protein, identified as prehaptoglobin-2, that reversibly regulates tight junctions in the intestinal lining. It has been proposed as a marker of intestinal permeability.
Also known as: prehaptoglobin-2 · pre-haptoglobin 2 · pre-HP2
What is zonulin?
Zonulin is a protein involved in regulating the tight junctions between the cells of the intestinal lining. When these junctions open, more material passes between cells (paracellular transport), which increases intestinal permeability.
It was described by Alessio Fasano’s group in The Lancet in 2000, as a human analogue of the Zot toxin produced by Vibrio cholerae. That paper reported raised expression in intestinal tissue during the acute phase of coeliac disease. In 2009, the same group (Tripathi et al., PNAS) identified zonulin as prehaptoglobin-2, the uncleaved precursor of haptoglobin-2.
How it is measured
Zonulin is measured by immunoassay (ELISA) in serum or stool. Each kit has its own reference values, which cannot be compared across manufacturers or sample types.
Why it is debated
Zonulin is a good example of a biomarker whose analytical validity is unresolved:
- Scheffler and colleagues (Frontiers in Endocrinology, 2018) found that a widely used commercial ELISA did not detect recombinant prehaptoglobin-2 and probably recognised other proteins, with properdin the most likely candidate.
- Ajamian and colleagues (PLoS One, 2019) analysed two commercial kits with mass spectrometry and concluded that they were not detecting the protein they claim to measure, advising caution in using serum zonulin as a barrier marker.
This does not mean zonulin lacks biological interest. It means results from commercial kits should be read cautiously and never as definitive proof of “leaky gut”.
Example
A gastroenterologist receives a report showing a raised zonulin in a patient with non-specific digestive symptoms. Faecal calprotectin is normal and there are no other signs of inflammation. He treats the zonulin value as a low-specificity, supportive finding and, if clinical suspicion of barrier dysfunction persists, considers a dual-sugar permeability test rather than acting on that figure alone.
Zonulin at Xenogene
Xenogene measures zonulin by ELISA, on stool or serum depending on the assay, and reports it as accessory data within the gut axis, never as an isolated diagnosis. The value always comes with the relevant interpretive caveats, in line with the scientific debate over these immunoassays. Within the integrated profiles, the Sophia assistant places it in context alongside faecal calprotectin and, where appropriate, dual-sugar tests. Interpretation rests with the licensed healthcare professional who requests it.
Frequently asked questions
What does a high zonulin level mean?
It may suggest a change in gut barrier function, but it cannot show this on its own. Commercial immunoassays have specificity problems, so the value should be interpreted alongside the clinical picture and other markers by the professional who requested the test.
Is a stool or blood zonulin test better?
Both sample types are used, and each assay has its own reference values, so results are not interchangeable. Doubts about which protein the kits actually detect apply to both.
Can zonulin diagnose leaky gut?
Not as a single test. The reference tests for intestinal permeability are sugar absorption tests such as lactulose/mannitol. Zonulin is, at most, complementary information.
Related terms
- Intestinal permeability
Intestinal permeability is how easily substances in the gut lumen cross the intestinal lining into the bloodstream. It is a normal, regulated property; increased permeability is associated with several diseases.
- Faecal calprotectin
Faecal calprotectin is a neutrophil protein measured in stool as a marker of inflammation of the intestinal lining. It helps distinguish inflammatory bowel disease from functional disorders such as irritable bowel syndrome.
- Dysbiosis
Dysbiosis is a change in the composition or function of the microbiota away from what is considered compatible with health: loss of diversity, loss of beneficial microbes or overgrowth of others.
- Biomarker
A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, disease processes or responses to a therapeutic intervention. It may be a molecule, a genetic variant or an imaging finding.
Educational content for healthcare professionals and the general public. It does not replace assessment by a healthcare professional: ordering and interpreting any test is the responsibility of the requesting clinician.
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