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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\u2014including reduced vessel density and retinal thinning\u2014were 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.<\/jats:p>","DOI":"10.3390\/nu17142363","type":"journal-article","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T14:38:36Z","timestamp":1752849516000},"page":"2363","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Systemic and Retinal Protective Effects of Butyrate in Early Type 2 Diabetes via Gut Microbiota\u2013Lipid Metabolism Interaction"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1943-8128","authenticated-orcid":false,"given":"Haijun","family":"Gong","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Ophthalmology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyu","family":"Zuo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keling","family":"Wu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinbo","family":"Gao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqing","family":"Lan","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Ophthalmology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China"},{"name":"Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1055\/a-1018-9078","article-title":"Definition, Classification and Diagnosis of Diabetes Mellitus","volume":"127","author":"Petersmann","year":"2019","journal-title":"Exp. 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