Porto Conte Ricerche, Tramariglio, Alghero, Italy.
Dipartimento di Scienze Biomediche, Università di Sassari, Sassari, Italy.
mSphere. 2018 Oct 24;3(5):e00492-18. doi: 10.1128/mSphere.00492-18.
Increasing evidence suggests that the intestinal microbiota is involved in the pathogenesis of type 1 diabetes (T1D). Here we sought to determine which gut microbial taxa and functions vary between nonobese diabetic (NOD) mice and genetically modified NOD mice protected from T1D (Eα16/NOD) at 10 weeks of age in the time window between insulitis development and T1D onset. The gut microbiota of NOD mice were investigated by analyzing stool samples with a metaproteogenomic approach, comprising both 16S rRNA gene sequencing and microbial proteome profiling through high-resolution mass spectrometry. A depletion of (particularly, several members of ) in the NOD gut microbiota was observed compared to the level in the Eα16/NOD mice microbiota. Moreover, the analysis of proteins actively produced by the gut microbiota revealed different profiles between NOD and Eα16/NOD mice, with the production of butyrate biosynthesis enzymes being significantly reduced in diabetic mice. Our results support a model for gut microbiota influence on T1D development involving bacterium-produced metabolites as butyrate. Alterations of the gut microbiota early in age have been hypothesized to impact T1D autoimmune pathogenesis. In the NOD mouse model, protection from T1D has been found to operate via modulation of the composition of the intestinal microbiota during a critical early window of ontogeny, although little is known about microbiota functions related to T1D development. Here, we show which gut microbial functions are specifically associated with protection from T1D in the time window between insulitis development and T1D onset. In particular, we describe that production of butyrate biosynthesis enzymes is significantly reduced in NOD mice, supporting the hypothesis that modulating the gut microbiota butyrate production may influence T1D development.
越来越多的证据表明，肠道微生物群与 1 型糖尿病 (T1D) 的发病机制有关。在这里，我们试图确定在胰岛炎发展和 T1D 发病之间的时间窗口内，10 周龄时非肥胖型糖尿病 (NOD) 小鼠和从 T1D 中得到保护的基因修饰型 NOD 小鼠 (Eα16/NOD) 之间，肠道微生物群的哪些细菌分类群和功能会发生变化。我们通过分析粪便样本，采用元蛋白质组学方法（包括 16S rRNA 基因测序和通过高分辨率质谱进行微生物蛋白质组分析）来研究 NOD 小鼠的肠道微生物群。与 Eα16/NOD 小鼠的微生物组相比，NOD 肠道微生物组中明显缺乏 （特别是 的几个成员）。此外，对肠道微生物群积极产生的蛋白质的分析揭示了 NOD 和 Eα16/NOD 小鼠之间的不同图谱，糖尿病小鼠中丁酸生物合成酶的产生显著减少。我们的结果支持肠道微生物群影响 T1D 发展的模型，涉及细菌产生的代谢物如丁酸。人们假设，早期肠道微生物群的改变会影响 T1D 自身免疫发病机制。在 NOD 小鼠模型中，通过在发育的关键早期窗口期间调节肠道微生物群的组成，已经发现对 T1D 的保护作用，尽管关于与 T1D 发展相关的微生物群功能知之甚少。在这里，我们展示了在胰岛炎发展和 T1D 发病之间的时间窗口内，哪些肠道微生物功能与 T1D 的保护作用特别相关。特别是，我们描述了 NOD 小鼠中丁酸生物合成酶的产生显著减少，这支持了调节肠道微生物群丁酸产生可能影响 T1D 发展的假说。
