# Elevated serum zonulin is associated with high attack frequency in hereditary angioedema: providing insight into the gut–angioedema axis

## TL;DR

High levels of a protein called zonulin in the blood are linked to more frequent attacks in a rare genetic disorder called hereditary angioedema.

## Contribution

This study is the first to show that elevated zonulin levels correlate with higher attack frequency in hereditary angioedema patients.

## Key findings

- Patients with high attack frequency had significantly higher serum zonulin levels compared to low-frequency patients and healthy controls.
- Zonulin levels remained independently associated with attack frequency after adjusting for body mass index.
- Zonulin elevation appears to reflect inflammatory activity rather than psychiatric symptoms in hereditary angioedema.

## Abstract

Zonulin is a key regulator of epithelial barrier permeability and has been implicated in barrier dysfunction across various inflammatory conditions. To elucidate the potential role of intestinal permeability in HAE, this study investigated serum zonulin levels and evaluated their association with disease activity and psychiatric status.

The study included 28 patients with HAE type 1 (HAE-C1INH) and 30 age- and sex-matched healthy controls. Serum zonulin levels were measured by ELISA. Patients were stratified according to attack frequency (high: ≥2 vs. low: <2 attacks/month). Psychiatric status was assessed using the Hospital Anxiety and Depression Scale (HADS). Multivariable linear regression analysis was performed to evaluate the association between zonulin levels and attack frequency after adjustment for body mass index (BMI).

Overall serum zonulin levels did not differ significantly between patients with HAE and healthy controls (p = 0.06). However, stratified analyses revealed that patients with high attack frequency exhibited significantly higher zonulin levels compared with both low-attack-frequency patients and controls (p < 0.01), whereas zonulin levels in the low-attack-frequency group were comparable to controls. In multivariable analysis, attack frequency remained independently associated with serum zonulin levels after adjustment for BMI. Although zonulin levels were higher among patients with clinically significant anxiety and/or depressive symptoms based on HADS, this association was weaker than that observed for attack frequency.

This pilot study provides preliminary evidence that elevated serum zonulin levels in HAE are associated with higher attack burden, rather than representing a uniform feature of the disease. These findings suggest that zonulin elevation reflects inflammatory activity independent of psychiatric symptom burden and position intestinal barrier integrity as a relevant mechanistic component within the proposed Gut–Angioedema Axis. Future prospective studies are warranted to validate these findings.

Not applicable.