GPR109a Regulates Phenotypic and Functional Alterations in Macrophages and the Progression of Type 1 Diabetes

Scope Dietary fibers can alter gut microbiota and microbial metabolite profiles. SCFAs are produced by bacterial fermentation of fiber, mediating immune homeostasis through G-protein-coupled receptors (GPCRs). GPR109a, a receptor for niacin and butyrate, expressed by immune cells and non-immune cells, is a key factor regulating immune responses. However, the role and underlying mechanisms of GPR109a in type 1 diabetes (T1D) remain unclear. Methods and results Experimental T1D was induced by streptozotocin in GPR109a-deficient ( Gpr109a −/− ) and wild type mice. The study found that Gpr109a −/− mice were more susceptible to T1D with dysregulated immune responses, along with increased M1 macrophage polarization (from 10.55% to 21.48%). Further, an adoptive transfer experiment demonstrated that GPR109a-deficient macrophages promoted the homing of intestine-derived type 1 cytotoxic T cells to pancreas (from 18.91% to 24.24%), thus disturbing the pancreatic immune homeostasis in non-obese diabetic mice. Mechanistically, GPR109a deficiency promoted M1 macrophage polarization associated with the activation of suppressor of cytokine signaling 3-signal transducer and activator of transcription 1 signaling pathway. Conclusion The findings reveal that macrophage GPR109a deficiency accelerates the development of T1D. Activation of GPR109a on macrophage by dietary components may provide a new strategy for preventing or treating T1D.