Ciaccio EJ, Wolf RL, Ciacci C, Green PH, Acharya UR. Celiac disease onset and inflammatory milieu. World J Gastrointest Endosc 2026; 18(8): 118718 [DOI: 10.4253/wjge.118718]
Corresponding Author of This Article
Edward J Ciaccio, PhD, Senior Scientist, Department of Medicine, Celiac Disease Center, Columbia University College of Physicians and Surgeons, HP 9-943, 180 Fort Washington Avenue, New York, NY 10032, United States. ciaccio@columbia.edu
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Gastroenterology & Hepatology
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review-article
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Ciaccio EJ, Wolf RL, Ciacci C, Green PH, Acharya UR. Celiac disease onset and inflammatory milieu. World J Gastrointest Endosc 2026; 18(8): 118718 [DOI: 10.4253/wjge.118718]
World J Gastrointest Endosc. Aug 16, 2026; 18(8): 118718 Published online Aug 16, 2026. doi: 10.4253/wjge.118718
Celiac disease onset and inflammatory milieu
Edward J Ciaccio, Randi L Wolf, Carolina Ciacci, Peter H Green, U Rajendra Acharya
Edward J Ciaccio, Peter H Green, Department of Medicine, Celiac Disease Center, Columbia University College of Physicians and Surgeons, New York, NY 10032, United States
Randi L Wolf, Department of Health Studies and Applied Educational Psychology, Columbia University, Teachers College, New York, NY 10027, United States
Carolina Ciacci, Department of Medicine, Surgery, Dentistry, Scuola Medica Salernitana, University of Salerno, Salerno 84081, Italy
U Rajendra Acharya, Department of Mathematics, Physics, and Computing, University of Southern Queensland, Toowoomba QLD 4300, Australia
Author contributions: Ciaccio EJ conceived the review framework, developed the scientific reasoning, and drafted the manuscript; Wolf RL contributed to epidemiologic and environmental interpretation; Ciacci C and Green PH provided clinical and translational expertise; Acharya UR contributed to systems modeling and analytical structure. All authors reviewed, edited, and approved the final manuscript.
AI contribution statement: The authors acknowledge the assistance of OpenAI’s ChatGPT (GPT-5) and Google AI in editorial review and icon generation.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Edward J Ciaccio, PhD, Senior Scientist, Department of Medicine, Celiac Disease Center, Columbia University College of Physicians and Surgeons, HP 9-943, 180 Fort Washington Avenue, New York, NY 10032, United States. ciaccio@columbia.edu
Received: January 12, 2026 Revised: February 3, 2026 Accepted: July 29, 2026 Published online: August 16, 2026 Processing time: 213 Days and 11.3 Hours
Abstract
No one is born with celiac disease, yet some individuals are predisposed to its development, based on two main factors. The transition from gluten tolerance to onset occurs in a subset of individuals who both carry the human leukocyte antigen (HLA)-DQ2 or HLA-DQ8 alleles in their genetic makeup (30%-40%) and consume gluten. What transpires to foment evolution in approximately 3% of these individuals, and why it happens, is of interest to benefit public health. At issue is the tipping point, where deamidated gluten peptides acquire increased affinity and binding to specific HLA-DQ2/DQ8 molecules on the surface of antigen-presenting cells (APCs), thereby alerting CD4+ T-cells to inflict damage on small intestinal mucosa. Is the transition to celiac disease caused by an alteration in the special manner that gluten peptides, deamidated by transglutaminase, are bound, and how strongly they are bound on the APCs, to render them recognizable as antigen by CD4+ T-cells? Or does the transformation occur when the CD4+ T-cells are rendered immunogenic to the tightly bound and deamidated gluten peptides on the APCs? Are supplementary conditions crucial? Might the modification be reversible under certain circumstances? It is suggested that onset may be triggered by the cumulative burden of extrinsic inflammatory factors vs anti-inflammatory factors acting on a genetically susceptible host consuming gluten, rather than arising from a sole insult. A paradigm to possibly reduce the odds of developing the disease, and to reduce the time needed for recovery after diagnosis, is presented. Implications for incorporating modern gastrointestinal endoscopic techniques are discussed.
Core Tip: In this article, the relationship between celiac disease and the inflammatory milieu is discussed and contrasted. The effects of inflammation on disease onset and recovery on a gluten-free diet are described in detail. After thoroughly covering the published literature, we suggest a hypothesis-generating paradigm that may possibly reduce the odds of a susceptible person developing the disease, and reduce the time needed for recovery after diagnosis. The paradigm reflects biologic plausibility and emerging mechanistic evidence, rather than clinical endorsement. The growing relevance of these concepts to modern gastrointestinal endoscopic technique is then highlighted.
