Pediatrics. 2024 Jan 1;153(1):e2023063050. doi: 10.1542/peds.2023-063050.

Tracey M DaFonte ^1 2 3, Francesco Valitutti ⁴, Victoria Kenyon ^2 3, Joseph J Locascio ^5 6, Monica Montuori ⁷, Ruggiero Francavilla ⁸, Tiziana Passaro ⁹, Marco Crocco ¹⁰, Lorenzo Norsa ¹¹, Pasqua Piemontese ¹², Mariella Baldassarre ¹³, Alessio Fasano ^1 2 3 4, Maureen M Leonard ^1 2 3; CD-GEMM Study Group

Author information

¹Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, MassGeneral Hospital for Children, Harvard Medical School, Boston, Massachusetts.

²Mucosal Immunology and Biology Research Center.

³Center for Celiac Research and Treatment.

⁴European Biomedical Research Institute of Salerno (EBRIS), Salerno, Italy.

⁵Departments of Biostatistics, Harvard Catalyst Biostatistical Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

⁶Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

⁷Pediatric Gastroenterology Unit, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.

⁸Pediatric Unit "Bruno Trambusti," Osp Pediatrico Giovanni XXIII, University of Bari, Bari, Italy.

⁹Celiac Disease Referral Center, "San Giovanni di Dio e Ruggi d'Aragona" University Hospital, Pole of Cava de' Tirreni, Salerno, Italy.

¹⁰Pediatrics, IRCCS Ospedale Giannina Gaslini, Genova, Italy.

¹¹Pediatric Hepatology, Gastroenterology, and Transplant Unit, Ospedale Papa Giovanni XXIII, Bergamo, Italy.

¹²Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.

¹³NICU, University of Bari, Bari, Italy.

Abstract

Objectives: Increased intestinal permeability seems to be a key factor in the pathogenesis of autoimmune diseases, including celiac disease (CeD). However, it is unknown whether increased permeability precedes CeD onset. This study's objective was to determine whether intestinal permeability is altered before celiac disease autoimmunity (CDA) in at-risk children. We also examined whether environmental factors impacted zonulin, a widely used marker of gut permeability.

Methods: We evaluated 102 children in the CDGEMM study from 2014-2022. We included 51 CDA cases and matched controls, who were enrolled for 12 months or more and consumed gluten. We measured serum zonulin from age 12 months to time of CDA onset, and the corresponding time point in controls, and examined clinical factors of interest. We ran a mixed-effects longitudinal model with dependent variable zonulin.

Results: Children who developed CDA had a significant increase in zonulin in the 18.3 months (range 6-78) preceding CDA compared to those without CDA (slope differential = β = 0.1277, 95% CI: 0.001, 0.255). Among metadata considered, zonulin trajectory was only influenced by increasing number of antibiotic courses, which increased the slope of trajectory of zonulin over time in CDA subjects (P = .04).

Conclusions: Zonulin levels significantly rise in the months that precede CDA diagnosis. Exposure to a greater number of antibiotic courses was associated with an increase in zonulin levels in CDA subjects. This suggests zonulin may be used as a biomarker for preclinical CeD screening in at-risk children, and multiple antibiotic courses may increase their risk of CDA by increasing zonulin levels.