{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T11:05:25Z","timestamp":1784027125196,"version":"3.55.0"},"reference-count":119,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>DNA methylation plays a fundamental role in maintaining intestinal homeostasis, immune tolerance, and inflammatory balance. Active DNA demethylation, mediated by the ten-eleven translocation family of dioxygenases (TET1, TET2, and TET3), has emerged as an important epigenetic mechanism linking environmental and metabolic cues to gene regulatory programs in the gut. In the intestinal epithelium, TET-dependent DNA hydroxymethylation contributes to intestinal stem cell maintenance, epithelial differentiation, regeneration, and barrier integrity. Perturbations in TET activity are associated with epithelial dysfunction, chronic inflammation, and increased susceptibility to colorectal tumorigenesis. Within the immune compartment, TET-mediated demethylation is required for the epigenetic stabilization of gut-associated immune cells. Altered TET function has been implicated in immune imbalance in inflammatory bowel disease, Hirschsprung\u2019s disease, and colitis-associated colorectal cancer. Emerging evidence further indicates that intestinal microbiota-derived metabolites, including short-chain fatty acids and aryl hydrocarbon receptor ligands, modulate TET activity, positioning TET enzymes as epigenetic sensors of microbial and metabolic signals. In turn, TET-dependent programs shape immune responses to commensal microbes and pathogens, establishing a bidirectional microbiota\u2013epigenetic axis that influences both intestinal and systemic immunity. In this review, we summarize and critically evaluate current evidence on the roles of TET enzymes in intestinal epithelial biology, immune cell regulation, and host\u2013microbiota interactions in colorectal inflammation and disease.<\/jats:p>","DOI":"10.3390\/jpm16070375","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T10:12:53Z","timestamp":1784023973000},"page":"375","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TET Enzymes as Epigenetic Integrators in Intestinal Immunity, Inflammation, and Disease"],"prefix":"10.3390","volume":"16","author":[{"given":"Dhirendra K.","family":"Singh","sequence":"first","affiliation":[{"name":"Department of Rheumatology and Inflammation Research, University of Gothenburg, 40530 Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukihiro","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1996-944X","authenticated-orcid":false,"given":"Lei","family":"Huang","sequence":"additional","affiliation":[{"name":"Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7571-7333","authenticated-orcid":false,"given":"Chieko","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Biology, American University, Washington, DC 20016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia G.","family":"Cassidy","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keita","family":"Nishiyama","sequence":"additional","affiliation":[{"name":"Laboratory of Animal Food Function, School of Agricultural Science, Tohoku University, Sendai 980-8572, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Yi, J.M. 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