Fu Xiangyu, Ren Xiang, Zhao Maoyuan, Li Lan, Zhou Yaojia, Lu Yanrong, Wang Chengshi
Department of Ophthalmology, West China Hospital, Sichuan University.
Research Laboratory of Ophthalmology and Vision Sciences, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University.
Exp Anim. 2025 Jan 17. doi: 10.1538/expanim.24-0125.
This study aims to clarify the disruption of gut barrier and dysbiosis of the microbiota in an experimental macaque model with 6-year diabetes mellitus (DM), and provide evidence for the application of therapeutic strategies targeting the human microbiota in the future. A single intravenous injection of high-dose streptozotocin was used to induce the type 1 diabetes (T1D) macaque model. Hematoxylin-Eosin (HE) and Periodic Acid Schiff (PAS) staining were conducted to observe colon morphological changes. The composition of gut microbiota was detected using 16S rRNA gene sequencing, and bioinformatics analysis was adopted to predict alterations in the microbial phenotype and function. Obvious intestinal inflammation and decreased goblet cells were observed in T1D macaques. 16S rRNA gene sequencing suggested a significantly different β diversity of the microbiota in the T1D group, where expanded Proteobacteria (dominantly Escherichia-Shigella) and Actinomycetota (formerly known as Actinobacteria) replaced the dominance of Bacillota (formerly known as Firmicutes) and Bacteroidota (formerly known as Bacteroidetes), indicating an imbalance in the microbial composition. Archaea was identified as a biomarker between groups. Moreover, with the reduction of beneficial bacteria (Lactobacillaceae) and the increase of pro-inflammatory bacteria and opportunistic pathogens (Enterobacteriaceae), the phenotypes of the microbiota were reversed, resulting in abnormal up- (e.g., carbohydrate and amino acid metabolism) or down-regulation (e.g., protein digestion and absorption) of multiple metabolic pathways. There were intestinal structural disorders and gut microbiota dysbiosis in T1D macaques, indicating that strategies targeting gut microbiota may be effective to treat metabolic diseases like DM.
本研究旨在阐明6年糖尿病（DM）实验猕猴模型中肠道屏障的破坏和微生物群的失调，并为未来针对人类微生物群的治疗策略的应用提供证据。通过单次静脉注射高剂量链脲佐菌素诱导1型糖尿病（T1D）猕猴模型。采用苏木精-伊红（HE）和过碘酸希夫（PAS）染色观察结肠形态变化。使用16S rRNA基因测序检测肠道微生物群的组成，并采用生物信息学分析预测微生物表型和功能的变化。在T1D猕猴中观察到明显的肠道炎症和杯状细胞减少。16S rRNA基因测序表明，T1D组微生物群的β多样性存在显著差异，其中变形菌门（主要是埃希氏菌-志贺氏菌属）和放线菌门（原称放线菌纲）取代了厚壁菌门（原称厚壁菌纲）和拟杆菌门（原称拟杆菌纲）的优势地位，表明微生物组成失衡。古菌被确定为组间生物标志物。此外，随着有益菌（乳杆菌科）减少，促炎菌和机会性病原体（肠杆菌科）增加，微生物群的表型发生逆转，导致多个代谢途径异常上调（如碳水化合物和氨基酸代谢）或下调（如蛋白质消化和吸收）。T1D猕猴存在肠道结构紊乱和肠道微生物群失调，表明针对肠道微生物群的策略可能对治疗DM等代谢性疾病有效。
