Systemic and Retinal Protective Effects of Butyrate in Early Type 2 Diabetes via Gut Microbiota-Lipid Metabolism Interaction.

Background: Early neurovascular unit (NVU) impairment plays a critical role in the pathogenesis of diabetic retinopathy (DR), often preceding clinically detectable changes. Butyrate, a short-chain fatty acid (SCFA) derived from gut microbiota, has shown promising metabolic and anti-inflammatory effects. Methods: This study investigated the protective potential of oral butyrate supplementation in a mouse model of early type 2 diabetes mellitus (T2DM) induced by a high-fat diet and streptozotocin. Mice (C57BL/6J) received sodium butyrate (5 g/L in drinking water) for 12 weeks. Retinal NVU integrity was assessed using widefield swept-source optical coherence tomography angiography (WF SS-OCTA), alongside evaluations of systemic glucose and lipid metabolism, hepatic steatosis, visual function, and gut microbiota composition via 16S rRNA sequencing. Results: Butyrate supplementation significantly reduced body weight, fasting glucose, serum cholesterol, and hepatic lipid accumulation. Microbiome analysis demonstrated a partial reversal of gut dysbiosis, characterized by increased SCFA-producing taxa (Ruminococcaceae, Oscillibacter, Lachnospiraceae) and decreased pro-inflammatory, lipid-metabolism-related genera (Rikenella, Ileibacterium). KEGG pathway analysis further revealed enrichment in microbial lipid metabolism functions (fabG, ABC.CD.A, and transketolase). Retinal vascular and neurodegenerative alterations-including reduced vessel density and retinal thinning-were markedly attenuated by butyrate, as revealed by WF SS-OCTA. OKN testing indicated partial improvement in visual function, despite unchanged ERG amplitudes. Conclusions: Butyrate supplementation mitigates early NVU damage in the diabetic retina by improving glucose and lipid metabolism and partially restoring gut microbial balance. This study also underscores the utility of WF SS-OCTA as a powerful noninvasive tool for detecting early neurovascular changes in DR.