Airway inflammationBiomarkerBronchial epitheliumCOREA cohortEpithelial barrier

Serum Zonulin Is a Biomarker for Severe Asthma

  • 2023
  • Na Young Kim, Eun Shin, Sun-Ju Byeon, et al.
Why this matters for your gut health

Asthma affects over 300 million people worldwide, and severe asthma is the hardest form to manage. A weakened airway lining (epithelial barrier) is a hallmark of asthma, especially severe asthma. Zonulin is a protein that loosens the tight junctions between cells and was first known as a regulator of gut permeability. This study suggests a simple blood test for zonulin could help identify severe asthma. It also points to the zonulin pathway as a possible target for treatments that protect the airway barrier rather than only controlling inflammation.

Summary

This brief communication analyzed data from the Korean COREA asthma cohort and the Soonchunhyang University Bucheon Hospital Biobank. It compared 29 patients with severe asthma, 27 with mild-to-moderate asthma and 33 healthy non-atopic controls. Serum zonulin was measured by ELISA, and zonulin expression in bronchial tissue was examined by immunohistochemical staining on a few biobank samples. Zonulin was highest in severe asthma, intermediate in mild-to-moderate asthma and lowest in controls. It correlated inversely with lung function (%FEV1) but not with IgE or blood eosinophils. A cutoff of 38.83 ng/mL separated severe from mild-to-moderate asthma with good accuracy. Bronchial zonulin staining was strongest in severe asthma and undetectable in controls. The authors conclude that zonulin may play a role in severe asthma and could serve as a biomarker, but note small numbers and several limitations.

Key findings

  • Serum zonulin was significantly higher in severe asthma (51.98 ± 19.66 ng/mL) than in mild-to-moderate asthma (26.35 ± 13.70 ng/mL) and normal controls (17.26 ± 10.29 ng/mL) (both P < 0.001).
  • Zonulin was also higher in mild-to-moderate asthma than in controls (P = 0.017).
  • These differences remained significant after adjusting for age, sex and atopic status.
  • Serum zonulin correlated negatively with %FEV1 (Spearman r = −0.35, P = 0.009). This held after adjusting for age and sex (P = 0.011).
  • Zonulin did not significantly correlate with total IgE or blood eosinophil counts (P > 0.05).
  • ROC analysis gave an AUC of 0.883 (95% CI 0.795–0.970; P = 0.008). The optimal cutoff of 38.83 ng/mL separated severe from mild-to-moderate asthma with 88.9% sensitivity and 72.4% specificity.
  • Bronchial epithelial zonulin expression was strong in severe asthma, weak in mild-to-moderate asthma and undetectable in controls. This is described as the first report of increased zonulin expression in the bronchial epithelium in asthma.
  • The severe group had much lower lung function (median %FEV1 63.0% vs 90.0%, P < 0.001) and more males (51.7% vs 25.9%, P = 0.048). Age, BMI, smoking, atopy, IgE and eosinophil counts did not differ significantly.
  • The authors’ cutoff differs greatly from the 198 ng/mL reported in an earlier house-dust-mite asthma study. They attribute this to different ELISA kits and call for validation and standardization.
  • Limitations: small sample size, no adjustment for other allergic or autoimmune diseases, unquantified staining intensity, and no assessment of intestinal barrier function. The immunohistochemistry used only 7 tissue samples (2 severe, 2 mild-to-moderate, 3 controls).
  • The staining used an anti-haptoglobin antibody, since zonulin is a form of prehaptoglobin-2. Treat the tissue findings as preliminary.

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Citation

Kim NY, Shin E, Byeon SJ, Hong SJ, Kang SH, Lee T, Kim TB, Choi JH. Serum Zonulin Is a Biomarker for Severe Asthma. Allergy Asthma Immunol Res. 2023 Jul;15(4):526-535. doi:10.4168/aair.2023.15.4.526

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