Gut microbiota dysbiosis in the inflammatory pathogenesis of diabetic retinopathy

Abstract Diabetic retinopathy (DR), a leading cause of vision loss among working‐age adults, has traditionally been viewed through the lens of hyperglycaemia‐driven metabolic dysregulation. Yet mounting evidence positions inflammation, not as a side effect but as a central pathogenic driver across all stages of DR. This review synthesises the emerging paradigm of the gut‒retina axis: the proposition that gut microbiota dysbiosis actively contributes to DR pathogenesis through inflammatory mechanisms. We examine how diabetes‐induced alterations in microbial composition, characterised by reduced taxonomic diversity, depletion of short‐chain fatty acid (SCFA)‐producing bacteria and expansion of pro‐inflammatory taxa, compromise intestinal barrier integrity and permit translocation of microbial products such as lipopolysaccharide into the systemic circulation. The resulting metabolic endotoxaemia, compounded by a shift in the microbial metabolite landscape (elevated trimethylamine N‐oxide, p‐cresyl sulphate and branched‐chain amino acids; diminished SCFAs and indole‐3‐propionic acid), establishes a state of chronic low‐grade systemic inflammation or metaflammation. These gut‐derived signals converge with local metabolic stressors in the retina to activate microglial Toll‐like receptor 4 (TLR4) and NACHT, LRR, and PYD domains‐containing protein 3 (NLRP3) inflammasome signalling, disrupt the blood‒retinal barrier and amplify pro‐inflammatory cytokine cascades that drive progression from non‐proliferative to proliferative DR. We further evaluate emerging therapeutic strategies that target the gut microbiota, including probiotics, prebiotics, dietary interventions and faecal microbiota transplantation, and discuss the translational challenges that must be overcome before these approaches can complement conventional DR management.