By Lucy Piper, medwireNews Reporter
medwireNews: Serum levels of the protein zonulin, high levels of which are associated with increased intestinal permeability, may be a useful biomarker for the development of celiac disease autoimmunity (CDA) in children at genetic risk of the condition, suggest findings from the CD-GEMMA study.
The results, published in Pediatrics, also indicate that multiple courses of antibiotics, “as a proxy of infections or as a direct effect on the gut”, may increase a child’s risk of CDA by increasing zonulin and intestinal permeability, note Maureen Leonard (Massachusetts General Hospital, Boston, USA) and colleagues.
“Clinically, this novel information may be used by physicians and families to help determine if a child with a strong family history of [celiac disease] or other autoimmune diseases should more carefully avoid unnecessary antibiotics or if they should consider future therapeutics that alter disease trajectory.”
The nested case-control study involved 102 children from the USA and Italy with a first-degree relative with celiac disease who were enrolled in the CD-GEMM study between 2014 and 2022. They had gluten introduced before 12 months of age and blood samples drawn from birth through 10 years of age, which were assessed for celiac autoantibodies and human leukocyte antigen (HLA) genotype.
Among the 102 children, 51 had developed CDA, as determined by elevated celiac autoantibodies on at least two occasions or biopsy-confirmed duodenal villous atrophy. These children were matched to the 51 children who did not develop CDA according to mode of delivery at birth, sex, country and HLA genetic risk.
Zonulin levels were tested using the serum Zonulin ELISA kit (Immundiagnostik AG, Bensheim, Germany) from 12 months of age to the time of CDA diagnosis. When included as an independent variable in a mixed effects longitudinal model, zonulin levels increased significantly more steeply in the 6 to 78 months before CDA onset in the affected children than in the controls, with a slope differential of 0.1277.
This was more evident among children from Italy than the USA, who had a higher zonulin mean across time as a whole, at 30.24 ng/mL versus 25.43 ng/mL.
Neither the age at which gluten was introduced, nor the number of servings of gluten per month had a significant effect on zonulin levels, however.
The researchers highlight that in further analysis the increase in zonulin was positively associated with a greater number of antibiotic courses, significantly steepening the rise in zonulin levels “almost exclusively” in the children who went on to develop CDA. But there was no effect of respiratory or gastrointestinal infections on zonulin levels.
Leonard et al comment that they “did not identify a threshold of zonulin that was significant in predicting CDA, rather we found a greater rate of rise of zonulin was predictive of CDA onset.”
They say: “These findings of increased intestinal permeability may result in expanded antigen trafficking of gliadin”, the inciting factor of celiac disease, “which could contribute to loss of tolerance to gluten in genetically susceptible individuals.”
And the researchers point out that “[e]xamining the physiologic alterations in the predisease state is crucial to early intervention and disease prevention.”
The team concludes that zonulin is a “practical biomarker of intestinal permeability,” but acknowledges that its use is limited by the fact that “commercially available assays do not currently measure all known proteins in this family.”
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Pediatrics 2023; doi:10.1542/peds.2023-063050