Multitarget protection of Qiju Dihuang Formula in early-stage diabetic retinopathy is associated with modulation of gut microbiota-derived SCFAs/GPR43/GLP-1/GLP-1R signaling

Background Diabetic retinopathy (DR) is a major microvascular complication of diabetes mellitus and is increasingly recognized as a systemic neurovascular disorder associated with metabolic dysregulation and chronic inflammation. Accumulating evidence suggests that gut microbiota imbalance and impaired gut-derived endocrine signaling contribute to DR progression. Qiju Dihuang Formula (QDF), a traditional Chinese botanical drug prescription, has long been used for visual disorders and metabolic imbalance, yet its multitarget protective mechanisms in DR remain unclear. This study therefore aimed to investigate the protective effects of QDF in a type 2 diabetes–associated early-stage DR mouse model and to explore the association of these effects with gut microbiota modulation and gut microbiota–derived endocrine signaling. Methods A type 2 diabetes–associated DR model was established in C57BL/6J mice using a high-fat diet combined with low-dose streptozotocin. Mice were treated with low, medium, or high doses of QDF for 8 weeks. Metabolic parameters were assessed, retinal function and structure were evaluated, gut microbiota composition was analyzed by 16S rRNA sequencing, fecal short-chain fatty acids (SCFAs) were quantified, and intestinal barrier integrity and related signaling pathways were examined. Results QDF treatment significantly alleviated hyperglycemia and metabolic disturbances in a dose-dependent manner. Retinal electrophysiological dysfunction, microvascular abnormalities, and structural damage were markedly attenuated, particularly at medium and high doses. 16S rRNA sequencing revealed that QDF reshaped gut microbiota composition, modulated fecal SCFA concentrations, and enhanced intestinal barrier integrity. Moreover, QDF treatment was associated with increased intestinal expression of G protein–coupled receptor 43 (GPR43), elevated circulating glucagon-like peptide-1 (GLP-1), and preserved retinal glucagon-like peptide-1 receptor (GLP-1R) expression. Conclusion Collectively, these findings suggest that QDF exerts multitarget protective effects against early-stage DR, and these effects are associated with modulation of gut microbiota–derived SCFAs/GPR43/GLP-1/GLP-1R signaling, systemic metabolic homeostasis, and retinal neurovascular integrity. However, causal relationships remain to be established by future loss-of-function and gain-of-function experiments. This study provides experimental support for the traditional use of QDF in diabetes-related visual disorders.