Short-Chain Fatty Acids Are Potential Biomarkers of Immune Regulation in Diabetic Retinopathy

Purpose: Gut microbiota is involved in the pathophysiology of diabetes and its complications, yet the mechanistic link of short-chain fatty acids (SCFAs) produced by gut microbes in the pathogenesis of diabetic retinopathy (DR) remains unclear. The objective of the current study was to investigate the involvement of SCFAs in the development of DR.

Methods: We collected blood samples from 165 participants with diabetes mellitus and quantified plasma SCFAs using gas chromatography-mass spectrometry. Additionally, we explored proteomic profiles reflecting host responses to circulating SCFAs using the Olink platform. Using a streptozotocin-induced diabetic mouse model, we evaluated retinal morphological, pathological, and epigenetic changes following a 16-week acetate supplementation.

Results: Our data showed that the circulating SCFA profiles of patients with DR significantly differed from those of non-DR controls. Lower levels of acetic, butyric, iso-butyric, and iso-valeric acids were strongly associated with DR risk. Proteomic analysis revealed immune dysregulation in patients with DR, with cytokine expression closely correlated with SCFA levels. In diabetic mice, acetate supplementation improved intestinal barrier function, alleviated retinal thinning, and prevented vessel loss. Moreover, acetate decreased the frequency of CD45+ CD11b+ cells and F4/80+ CD206+ CD11c– cells, indicating a significant inhibition of the overactive immune system in the diabetic retina. Finally, we observed significant changes in retinal DNA methylation, including downregulation of key pathways like vascular endothelial growth factor and nuclear factor-kappa B.

Conclusions: These findings reveal mechanistic and translationally relevant inter-relationships among the circulating SCFAs, immune regulation, and the development of DR.