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We hypothesized that obesity impairs REG3\u03b1-mediated epithelial defense, promoting intestinal barrier disruption and inflammation. Circulating REG3\u03b1 was analyzed in 84 individuals with normal weight, obesity, and type 2 diabetes (T2D). Jejunal REG3A expression was assessed in a subgroup undergoing bariatric surgery. Additional studies were performed in rats with diet-induced obesity and after sleeve gastrectomy and in HT-29 intestinal epithelial cells exposed to inflammatory and metabolic stimuli, recombinant REG3\u03b1, and REG3A silencing. Circulating REG3\u03b1 concentrations were markedly reduced (P\u00a0&amp;lt;0.001) in obesity, independent of glycemic status, and positively associated with insulin sensitivity. Jejunal REG3A expression was decreased (P\u00a0&amp;lt;0.05) in individuals with obesity and T2D and correlated with circulating levels. In rats with obesity, jejunal Reg3g expression was suppressed (P\u00a0&amp;lt;0.05) and restored (P\u00a0&amp;lt;0.05) after weight loss induced by sleeve gastrectomy. In HT-29 cells, inflammatory cytokines (IL-33, IL-18), glucose, and lipopolysaccharide induced REG3A expression (P\u00a0&amp;lt;0.01). REG3\u03b1 modulated epithelial homeostasis by suppressing NLRP3 inflammasome signaling and extracellular matrix remodeling genes (COL1A1, COL6A3, ELN, MMP9; P\u00a0&amp;lt;0.01) and enhancing acute inflammatory mediators (IL1B, IL6; P\u00a0&amp;lt;0.01), tight-junction proteins (CLDN1; P\u00a0&amp;lt;0.01), mucus (MUC2; P\u00a0&amp;lt;0.01), and anti-inflammatory markers (KLF4; P\u00a0&amp;lt;0.01). Conversely, REG3A silencing impaired epithelial repair pathways and CLDN1 expression. Reduced REG3\u03b1 in obesity and T2D is linked to alterations in epithelial integrity and low-grade inflammation, suggesting that modulation of REG3\u03b1 may represent a potential strategy to reinforce gut barrier function and metabolic homeostasis.<\/jats:p>","DOI":"10.1042\/cs20250686","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T14:54:48Z","timestamp":1774018488000},"page":"607-624","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Reduced REG3\u03b1 in obesity and type 2 diabetes is linked to altered intestinal barrier homeostasis and inflammation"],"prefix":"10.1042","volume":"140","author":[{"given":"Mar\u00eda","family":"Cadena","sequence":"first","affiliation":[{"name":"1Metabolic Research Laboratory, Cancer Center Cl\u00ednica Universidad de Navarra (CCUN), Pamplona, 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Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beatriz","family":"Ram\u00edrez","sequence":"additional","affiliation":[{"name":"1Metabolic Research Laboratory, Cancer Center Cl\u00ednica Universidad de Navarra (CCUN), Pamplona, Spain"},{"name":"3Institute for Nutrition and Health, University of Navarra, Pamplona, Spain"},{"name":"4CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain"},{"name":"5Obesity and Adipobiology Group, Instituto de Investigaci\u00f3n Sanitaria de Navarra (IdiSNA) Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Becerril","sequence":"additional","affiliation":[{"name":"1Metabolic Research Laboratory, Cancer Center Cl\u00ednica Universidad de Navarra (CCUN), Pamplona, Spain"},{"name":"3Institute for Nutrition and Health, University of Navarra, Pamplona, Spain"},{"name":"4CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain"},{"name":"5Obesity and Adipobiology Group, Instituto de Investigaci\u00f3n Sanitaria de Navarra (IdiSNA) Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amaia","family":"Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"1Metabolic Research Laboratory, Cancer Center Cl\u00ednica Universidad de Navarra (CCUN), Pamplona, Spain"},{"name":"3Institute for Nutrition and Health, University of Navarra, Pamplona, Spain"},{"name":"4CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n (CIBEROBN), Instituto de Salud Carlos III, Pamplona, Spain"},{"name":"5Obesity and Adipobiology Group, Instituto de Investigaci\u00f3n Sanitaria de Navarra (IdiSNA) Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victor","family":"Valent\u00ed","sequence":"additional","affiliation":[{"name":"6Department of Surgery, Cl\u00ednica Universidad de Navarra, Pamplona, 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