Beyond glycemia: The influence of systemic inflammation, lipids, and the gut-retina axis in diabetic retinopathy

Diabetic retinopathy is a primary cause of visual impairment in individuals with diabetes and represents a multifaceted process that transcends glucose dysregulation. This review analyzes the interconnected roles of systemic inflammation, lipid metabolism, and the gut-retina axis in retinal vascular and neuronal damage. A systematic search of PubMed and Scopus spanning January 2014 to August 2025, revealed experimental and clinical research associating inflammatory cytokines, lipid dysregulation, and abnormalities in gut microbiota with diabetic retinopathy. Evidence suggests that persistent low-grade inflammation, characterized by elevated levels of interleukin-6, tumor necrosis factor-alpha, and interleukin-1 beta, compromises the blood-retinal barrier and accelerates microvascular degeneration. Alterations in lipid pathways, such as reduced docosahexaenoic acid levels, hinder cholesterol efflux and ceramide buildup, exacerbating oxidative stress and neurovascular impairment. Gut microbial dysbiosis diminishes short-chain fatty acid production and fosters endotoxemia, thereby exacerbating retinal inflammation through systemic immune activation. Novel therapeutic strategies that regulate peroxisome proliferator-activated receptor-alpha and restore the microbiota demonstrate synergistic potential to reduce disease progression. The integration of these systems offers a biological foundation for the prevention andtherapy of diabetic retinopathy.