Chronic Ileitis Ameliorates Hyperglycemia via a 3-HB/NKX6.1 Axis in Mice

Clinical evidence suggests a complex link between inflammatory bowel disease and systemic glucose homeostasis, yet the underlying molecular mechanisms remain elusive. Here, we report that chronic ileitis, induced by dextran sulfate sodium (DSS) or IL10 deficiency under a high-fat diet(HFD), paradoxically ameliorates systemic glucose intolerance and preserves pancreatic β-cell mass in mice. Multi-omics analysis of ileal contents revealed a specific enrichment of Akkermansia muciniphila (AKK) and elevated levels of the metabolite 3-hydroxybutyrate (3-HB). Mechanistically, 3-HB activated HCAR2/CREB-associated signaling and increased NKX6.1 expression. NKX6.1 loss-of-function markedly attenuated 3-HB-induced insulin gene expression and glucose-stimulated insulin secretion, establishing NKX6.1 as an important functional mediator of the β-cell response to 3-HB. Furthermore, exogenous administration of 3-HB recapitulated these protective effects in diabetic mice. This study identifies a novel gut-islet axis where microbiota-derived 3-HB preserves β-cell functional identity via HCAR2 dependent regulation of NKX6.1, offering a potential therapeutic strategy for type 2 diabetes.