Epigenetic regulation by gut microbiota-derived metabolites in celiac disease

Celiac disease (CeD) is a chronic autoimmune disorder triggered by gluten in genetically susceptible individuals carrying HLA-DQ2/DQ8 haplotypes. Although genetic predisposition and gluten exposure are necessary, they are insufficient in the development of the disease, pointing to critical roles for environmental factors—particularly gut microbiota dysbiosis and its metabolites—in disrupting immune tolerance through epigenetic mechanisms. This review collects current evidence on the microbiota–metabolite–epigenetic axis in CeD pathogenesis. Dysbiosis is characterized by reduced microbial diversity, depletion of protective taxa (e.g., Bacteroidetes), and enrichment of pro-inflammatory groups. Bacterial metabolites exert opposing effects: short-chain fatty acids (SCFAs), especially butyrate, act protectively by inhibiting histone deacetylases, promoting histone acetylation, stabilizing anti-inflammatory FOXP3 isoforms in regulatory T cells, and modulating alternative splicing and miRNA networks to reinforce barrier integrity and immune tolerance. Conversely, certain metabolites and microbial signals can drive pathogenic epigenetic changes, including altered DNA methylation, histone modifications, and miRNA dysregulation that amplify NF-κB, IL-17, and IFN-γ pathways. Emerging data from organoid models and multi-omics studies further highlight the therapeutic potential of microbial-derived postbiotics and cell-free supernatants (e.g., from Bacteroides vulgatus ) in restoring epithelial homeostasis and reprogramming detrimental miRNA profiles. Therefore, the microbiota–metabolite–epigenetic interplay emerges as a pivotal bridge between genetic risk and clinical disease, offering novel preventive and adjunctive therapeutic targets beyond strict gluten avoidance. • Gut dysbiosis precedes celiac disease and drives epigenetic loss of gluten tolerance. • Butyrate protects via histone deacetylases (HDACs) inhibition, FOXP3 splicing and Treg stabilization. • Postbiotics restore epigenetic balance and attenuate gluten-induced damage. • Microbiota-metabolite-epigenetic axis offers new therapeutic targets in celiac.