The gut-retina axis in diabetic retinopathy: a new paradigm for pathogenesis and therapeutic intervention.

Diabetic retinopathy (DR) remains a leading cause of preventable blindness worldwide. However, current therapies predominantly target downstream vascular pathology and leave upstream drivers largely unaddressed. The emerging gut-retina axis paradigm reframes DR as a systemic disorder intricately linked to intestinal homeostasis. This review provides a comprehensive and updated synthesis of the gut-retina axis in DR, with three distinctive contributions that set it apart from earlier overviews. First, we systematically dissect the differential roles of specific microbial metabolites. We distinguish the opposing effects of primary versus secondary bile acids, the divergent bioactivities of conjugated versus unconjugated forms, and the dual inflammatory and protective functions of short-chain fatty acids. This analysis offers a nuanced mechanistic framework that moves beyond generalized descriptions of dysbiosis. Second, we critically evaluate the methodological heterogeneity that currently impedes cross-study comparability and propose practical standardization strategies to accelerate clinical translation. Third, we present an integrated overview of emerging therapeutic modalities, including next-generation probiotics, metabolite-targeted interventions, fecal microbiota transplantation, and natural product-based nanomedicines, while candidly addressing the translational gap between robust preclinical findings and limited human evidence. Importantly, we highlight how Mendelian randomization studies are beginning to establish causal links between specific gut taxa and DR risk, complementing traditional association-based reports. By integrating multi-omics perspectives, methodological rigor, and therapeutic innovation, this review offers a forward-looking roadmap for transforming gut-retina axis insights into actionable precision medicine strategies for DR.