Qin Xinran, Sun Jiaqi, Xu Yi, Lu Lina, Ma Yingyan, Lou Fangzhou, Zou Haidong
Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
Shanghai Eye Disease Prevention and Treatment Center/Shanghai Eye Hospital, Shanghai, China.
Invest Ophthalmol Vis Sci. 2025 Jun 2;66(6):23. doi: 10.1167/iovs.66.6.23.
Gut microbiota is involved in the pathophysiology of diabetes and its complications, yet the mechanistic link of short-chain fatty acids (SCFAs) produced by gut microbes in the pathogenesis of diabetic retinopathy (DR) remains unclear. The objective of the current study was to investigate the involvement of SCFAs in the development of DR.
We collected blood samples from 165 participants with diabetes mellitus and quantified plasma SCFAs using gas chromatography-mass spectrometry. Additionally, we explored proteomic profiles reflecting host responses to circulating SCFAs using the Olink platform. Using a streptozotocin-induced diabetic mouse model, we evaluated retinal morphological, pathological, and epigenetic changes following a 16-week acetate supplementation.
Our data showed that the circulating SCFA profiles of patients with DR significantly differed from those of non-DR controls. Lower levels of acetic, butyric, iso-butyric, and iso-valeric acids were strongly associated with DR risk. Proteomic analysis revealed immune dysregulation in patients with DR, with cytokine expression closely correlated with SCFA levels. In diabetic mice, acetate supplementation improved intestinal barrier function, alleviated retinal thinning, and prevented vessel loss. Moreover, acetate decreased the frequency of CD45+ CD11b+ cells and F4/80+ CD206+ CD11c- cells, indicating a significant inhibition of the overactive immune system in the diabetic retina. Finally, we observed significant changes in retinal DNA methylation, including downregulation of key pathways like vascular endothelial growth factor and nuclear factor-kappa B.
These findings reveal mechanistic and translationally relevant inter-relationships among the circulating SCFAs, immune regulation, and the development of DR.
肠道微生物群参与糖尿病及其并发症的病理生理过程，然而肠道微生物产生的短链脂肪酸（SCFAs）在糖尿病视网膜病变（DR）发病机制中的机制联系仍不清楚。本研究的目的是探讨SCFAs在DR发生发展中的作用。
我们收集了165名糖尿病患者的血液样本，并用气相色谱-质谱法对血浆SCFAs进行定量。此外，我们使用Olink平台探索了反映宿主对循环SCFAs反应的蛋白质组学特征。使用链脲佐菌素诱导的糖尿病小鼠模型，我们评估了16周醋酸盐补充后视网膜的形态、病理和表观遗传变化。
我们的数据显示，DR患者的循环SCFA谱与非DR对照组有显著差异。乙酸、丁酸、异丁酸和异戊酸水平较低与DR风险密切相关。蛋白质组学分析显示DR患者存在免疫失调，细胞因子表达与SCFA水平密切相关。在糖尿病小鼠中，补充醋酸盐可改善肠道屏障功能，减轻视网膜变薄，并防止血管丢失。此外，醋酸盐降低了CD45+CD11b+细胞和F4/80+CD206+CD11c-细胞的频率，表明对糖尿病视网膜中过度活跃的免疫系统有显著抑制作用。最后，我们观察到视网膜DNA甲基化有显著变化，包括血管内皮生长因子和核因子-κB等关键通路的下调。
这些发现揭示了循环SCFAs、免疫调节和DR发生发展之间的机制性和与转化相关的相互关系。
