Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
Genome Med. 2024 Apr 20;16(1):59. doi: 10.1186/s13073-024-01336-1.
Gut dysbiosis has been linked with both HIV infection and diabetes, but its interplay with metabolic and inflammatory responses in diabetes, particularly in the context of HIV infection, remains unclear.
We first conducted a cross-sectional association analysis to characterize the gut microbial, circulating metabolite, and immune/inflammatory protein features associated with diabetes in up to 493 women (~ 146 with prevalent diabetes with 69.9% HIV +) of the Women's Interagency HIV Study. Prospective analyses were then conducted to determine associations of identified metabolites with incident diabetes over 12 years of follow-up in 694 participants (391 women from WIHS and 303 men from the Multicenter AIDS Cohort Study; 166 incident cases were recorded) with and without HIV infection. Mediation analyses were conducted to explore whether gut bacteria-diabetes associations are explained by altered metabolites and proteins.
Seven gut bacterial genera were identified to be associated with diabetes (FDR-q < 0.1), with positive associations for Shigella, Escherichia, Megasphaera, and Lactobacillus, and inverse associations for Adlercreutzia, Ruminococcus, and Intestinibacter. Importantly, the associations of most species, especially Adlercreutzia and Ruminococcus, were largely independent of antidiabetic medications use. Meanwhile, 18 proteins and 76 metabolites, including 3 microbially derived metabolites (trimethylamine N-oxide, phenylacetylglutamine (PAGln), imidazolepropionic acid (IMP)), 50 lipids (e.g., diradylglycerols (DGs) and triradylglycerols (TGs)) and 23 non-lipid metabolites, were associated with diabetes (FDR-q < 0.1), with the majority showing positive associations and more than half of them (59/76) associated with incident diabetes. In mediation analyses, several proteins, especially interleukin-18 receptor 1 and osteoprotegerin, IMP and PAGln partially mediate the observed bacterial genera-diabetes associations, particularly for those of Adlercreutzia and Escherichia. Many diabetes-associated metabolites and proteins were altered in HIV, but no effect modification on their associations with diabetes was observed by HIV.
Among individuals with and without HIV, multiple gut bacterial genera, blood metabolites, and proinflammatory proteins were associated with diabetes. The observed mediated effects by metabolites and proteins in genera-diabetes associations highlighted the potential involvement of inflammatory and metabolic perturbations in the link between gut dysbiosis and diabetes in the context of HIV infection.
肠道菌群失调与 HIV 感染和糖尿病都有关，但它与糖尿病代谢和炎症反应的相互作用，尤其是在 HIV 感染的背景下，仍不清楚。
我们首先进行了一项横断面关联分析，以描述与糖尿病相关的肠道微生物、循环代谢物和免疫/炎症蛋白特征，共纳入了妇女艾滋病研究机构（Women's Interagency HIV Study，WIHS）中的 493 名女性（约 146 名患有糖尿病，其中 69.9% 感染了 HIV）。然后进行了前瞻性分析，以确定在 694 名参与者（391 名来自 WIHS 的女性和 303 名来自多中心艾滋病队列研究的男性；记录了 166 例新发糖尿病病例）中，在有和没有 HIV 感染的情况下，鉴定出的代谢物与 12 年的随访期间新发糖尿病之间的关联。进行中介分析以探索肠道细菌与糖尿病的关联是否可以用改变的代谢物和蛋白质来解释。
确定了 7 种与糖尿病相关的肠道细菌属（FDR-q<0.1），其中与糖尿病呈正相关的有志贺氏菌属、埃希氏菌属、巨球形菌属和乳杆菌属，而与糖尿病呈负相关的有 Adlercreutzia 菌属、瘤胃球菌属和 Intestinibacter 菌属。重要的是，大多数物种的关联，尤其是 Adlercreutzia 和 Ruminococcus 的关联，在很大程度上与抗糖尿病药物的使用无关。同时，鉴定出 18 种蛋白质和 76 种代谢物，包括 3 种微生物衍生代谢物（三甲胺 N-氧化物、苯乙酰谷氨酰胺（PAGln）、咪唑丙酸（IMP））、50 种脂质（如二酰基甘油（DG）和三酰基甘油（TG））和 23 种非脂类代谢物，与糖尿病相关（FDR-q<0.1），其中大多数呈正相关，超过一半（59/76）与新发糖尿病相关。在中介分析中，几种蛋白质，特别是白细胞介素 18 受体 1 和骨保护素，IMP 和 PAGln 部分介导了观察到的细菌属与糖尿病之间的关联，尤其是与 Adlercreutzia 和 Escherichia 菌属之间的关联。在 HIV 感染者中，许多与糖尿病相关的代谢物和蛋白质发生了改变，但 HIV 并未改变它们与糖尿病的关联。
在有和没有 HIV 的个体中，多种肠道细菌属、血液代谢物和促炎蛋白与糖尿病相关。在细菌属与糖尿病的关联中，观察到代谢物和蛋白质的中介作用，强调了在 HIV 感染背景下，肠道菌群失调与糖尿病之间的联系可能涉及炎症和代谢紊乱。
