Obesity-prone (OP) individuals have a significant predisposition to obesity and diabetes. Previously, we have found that OP individuals, despite being normal in weight and BMI, have already exhibited diabetes-related DNA methylation signatures. However, the underlying mechanisms remain obscure. Here we determined the effects of gut microbiota on DNA methylation and investigated the underlying mechanism from microbial-derived short-chain fatty acids (SCFAs). Diabetes-related DNA methylation loci were screened and validated in a new OP cohort. Moreover, the OP group was revealed to have distinct gut microbiota compositions, and fecal microbiota transplantation (FMT) demonstrated the role of gut microbiota in inducing diabetes-related DNA methylations and glucolipid disorders. UPLC-ESI-MS/MS analysis indicated a significantly lower level of total fecal SCFAs in the OP group. The gut microbiota from OP subjects yielded markedly decreased total SCFAs, while notably enriched propionate. Additionally, propionate was also identified by variable importance in projection (VIP) score as the most symbolic SCFAs of the OP group. Further cellular experiments verified that propionate could induce hypermethylation at locus cg26345888 and subsequently inhibit the expression of the target gene DAB1, which was crucially associated with clinical vitamin D deficiency and thus may affect the development and progression of diabetes. In conclusion, our study revealed that gut microbiota-derived propionate induces specific DNA methylation, thus predisposing OP individuals to diabetes. The findings partially illuminate the mechanisms of diabetes susceptibility in OP populations, implying gut microbiota and SCFAs may serve as promising targets both for clinical treatment and medication development of diabetes.

肥胖倾向 (OP) 个体对肥胖和糖尿病具有显着的易感性。以前，我们发现 OP 个体尽管体重和 BMI 正常，但已经表现出与糖尿病相关的 DNA 甲基化特征。然而，潜在的机制仍然模糊不清。在这里，我们确定了肠道微生物群的影响研究了 DNA 甲基化并研究了微生物来源的短链脂肪酸 (SCFA) 的潜在机制。在一个新的 OP 队列中筛选和验证了糖尿病相关的 DNA 甲基化基因座。此外，发现 OP 组具有不同的肠道微生物群组成，粪便微生物群移植 (FMT) 证明了肠道微生物群在诱导糖尿病相关 DNA 甲基化和糖脂紊乱中的作用。UPLC-ESI-MS/MS 分析表明 OP 组的总粪便 SCFA 水平显着降低。来自 OP 受试者的肠道微生物群产生的总 SCFA 显着减少，同时显着富集丙酸盐。此外，丙酸盐还通过投影中的可变重要性 (VIP) 评分被确定为 OP 组最具象征意义的 SCFA。进一步的细胞实验证实，丙酸盐可以诱导基因座 cg26345888 的高甲基化并随后抑制靶基因 DAB1 的表达，这与临床维生素 D 缺乏症密切相关，因此可能影响糖尿病的发展和进展。总之，我们的研究表明，肠道微生物群衍生的丙酸盐会诱导特定的 DNA 甲基化，从而使 OP 个体易患糖尿病。这些发现部分阐明了 OP 人群中糖尿病易感性的机制，这意味着肠道微生物群和 SCFA 可能作为糖尿病临床治疗和药物开发的有希望的靶点。