Omega-3 polyunsaturated fatty acids are associated with microbiota-related 18β-glycyrrhetinic acid alterations and M2 macrophage polarization in type 1 diabetes mellitus.

INTRODUCTION: Omega-3 polyunsaturated fatty acids (PUFAs) have been widely reported to exert beneficial effects in type 1 diabetes mellitus (T1DM). However, the mechanisms by which Omega-3 PUFAs influence pancreatic islet function through the gut-islet axis remain incompletely understood. This study aimed to investigate whether Omega-3 PUFAs-associated alterations in gut microbiota composition and their metabolites are involved in the modulation of the pancreatic islet microenvironment in T1DM, and to explore the potential immunological mechanisms underlying these effects.

METHODS: Fecal microbiota transplantation (FMT) was performed to evaluate the effects of Omega-3 PUFAs-associated gut microbiota in non-obese diabetic (NOD) mice. Immune cell composition and inflammatory status within pancreatic islets were analyzed using transcriptomic profiling, flow cytometry, and immunohistochemistry. Metabolomics analysis was performed to investigate the association among Omega-3 PUFAs, gut microbiota, and microbiota-related metabolites. In vitro co-culture systems were further established to evaluate the effects of selected metabolites on macrophage polarization and insulin production and secretion in pancreatic β-cells.

RESULTS: Omega-3 PUFAs treatment and FMT were associated with reduced islet inflammation and a marked enrichment of the Eubacterium coprostanoligenes group (E. coprostanoligenes). Enhanced M2 macrophage polarization was observed in the islet microenvironment of FMT mice. Among gut microbiota metabolites, 18β-glycyrrhetinic acid (18β-GA) showed a strong association with E. coprostanoligenes, and in vitro experiments suggested a potential involvement of E. coprostanoligenes in the metabolic conversion process related to 18β-GA. In co-culture systems, 18β-GA promoted macrophage polarization toward an M2-like phenotype, which was accompanied by increased insulin production and secretion in pancreatic β-cells.

CONCLUSION: These findings suggest that Omega-3 PUFAs-associated alterations in gut microbiota composition and 18β-GA-related metabolic changes may contribute to the modulation of the pancreatic immune microenvironment and β-cells function in T1DM. This study provides additional insights into lipid-microbiota-immune interactions relevant to T1DM and supports further investigation of microbiota-associated immune regulation.