Sex Differences and Androgen Regulation Shape Mucosal Immune Phenotype, Gut Microbiota, and Microbiota-Derived Lactate in SKG Arthritis Model.

OBJECTIVE

This study aimed to investigate the role of sex differences and androgen regulation in the development of arthritis, focusing on their effects on gut microbiota, metabolic profiles, and immune responses in the SKG mouse model of arthritis.

METHODS

Eight-week-old male and female SKG mice were injected with zymosan to explore sex-related differences in arthritis progression. Androgen regulation was assessed in 4-week-old male SKG mice through castration and sham surgeries. Flow cytometry, 16S rDNA sequencing, metabolomics, histopathology, and immunofluorescence were used to evaluate immune responses, microbiota composition, and metabolic alterations.

RESULTS

Sex differences significantly impacted immune cell composition, particularly dendritic cells (DCs), in the mesenteric and popliteal lymph nodes. Male mice exhibited an increased proportion of conventional type I DCs (cDC1), while female mice displayed a higher proportion of conventional type II DCs (cDC2). Androgen deprivation in male mice worsened disease severity, with reduced cDC1 cells and increased inflammatory infiltration. Sex differences also influenced gut microbiota, with higher levels of Lactobacillus in females, and castrated males resembling females in microbiota composition. Metabolomic analysis revealed significant sex-related differences, with lactate showing the most pronounced androgen-related changes. Additionally, androgen regulated hypoxia inducible factor-1 alpha (HIF1α) expression in mucosal DCs, promoting an immune tolerance phenotype.

CONCLUSION

This study highlights the significant role of sex and androgen regulation in arthritis development, revealing complex interactions between hormones, microbiota, and immune regulation. These findings suggest new avenues for sex-specific therapeutic strategies and precision interventions targeting microbiota and metabolic modulation in arthritis and other autoimmune diseases.