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Unlike other autoimmune diseases, CeD offers an exceptional degree of mechanistic clarity, stemming from the identification of the main environmental driver, gluten, and its link with genetic susceptibility. Summary: While gluten and HLA genotype are necessary for developing CeD, they are not sufficient. Emerging research highlights that environmental and lifestyle factors, including early-life ecosystem, infections, and gut microbiota, critically modulate CeD risk and severity. This review synthesizes emerging insights and focuses on the role of the intestinal epithelium not just as target of immune-mediated injury but as an active interface integrating genetic susceptibility with environmental cues. Recent data reveal that intestinal epithelial cells can release tissue transglutaminase 2 that modifies gluten peptide antigenicity, participate in antigen presentation and immune signaling, and respond to microbial and dietary factors, positioning them as contributors to CeD initiation and progression. The review also highlights knowledge gaps and areas of active debate in CeD. Key Messages: CeD has a main environmental driver (gluten) and a defined genetic susceptibility, linked to major histocompatibility complex class II DQ2 and DQ8. Activation of the CD4+ T-cell response by gluten and cytotoxic transformation of intraepithelial lymphocytes culminate in villus atrophy of the proximal small intestine. In this opinion-based perspective, we integrate and review recent evidence suggesting the intestinal epithelium plays an active role in CeD initiation and\/or progression, which could lead to strategies to prevent or better treat this condition.<\/jats:p>","DOI":"10.1159\/000551888","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T16:00:55Z","timestamp":1776182455000},"page":"101-115","source":"Crossref","is-referenced-by-count":0,"title":["Gene-Environment Interactions in Celiac Disease: The Role of the Intestinal Epithelium"],"prefix":"10.1159","volume":"19","author":[{"given":"Sara","family":"Rahmani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xavier","family":"Mas-Orea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando 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