Large-scale metaproteomics of human gut microbiota reveals microbial functions in metabolic diseases and aging

IF 37 1区生物学 Q1 CELL BIOLOGY

Cell metabolism Pub Date : 2026-03-13 DOI:10.1016/j.cmet.2026.02.012

Shuang Liang, Yingying Sun, Zelei Miao, Bang-yan Li, Ziyuan Xing, Yuting Xie, Enci Cai, Sainan Li, Pu Liu, Min Yang, Menglei Shuai, Wanglong Gou, Wenhao Jiang, Youming Wang, Huanhuan Gao, Ke Zhang, Jing Yu, Xue Cai, Xingbing Wang, Yi Zhu, Yu-ming Chen, Ju-Sheng Zheng, Tiannan Guo

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Abstract

The protein-level functionalities of the human gut microbiota in large populations, and their associations with host factors, remain unexplored. This study reports a metaproteomic study of 1,967 fecal samples from 1,399 middle-aged and elderly Chinese individuals, identifying microbial functions linked to 44 phenotypes. We uncover aging-associated functional shifts in carbon metabolism and energy production driven by species within the Bacillota, Bacteroidota, Actinomycetota, and Pseudomonadota. Across metabolic diseases, we observe the consistent depletion of Bacillota species and their proteins involved in carbohydrate, energy, amino acid metabolism, and short-chain fatty acid production. We also identify medication-associated features across diabetes, hypertension, and dyslipidemia. Validated in an independent cohort, Megasphaera elsdenii emerged as a hub species in type 2 diabetes. Experimental validation indicates that M. elsdenii is promoted by antidiabetic drugs and may regulate glucose homeostasis through butyrate production. This study provides protein-level evidence of microbial functions in health and disease, highlighting potential therapeutic targets.

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人类肠道菌群的大规模宏蛋白质组学揭示了微生物在代谢疾病和衰老中的功能

在大量人群中，人类肠道微生物群的蛋白质水平功能及其与宿主因素的关联仍未被探索。本研究报告了一项来自1399名中国中老年个体的1967份粪便样本的元蛋白质组学研究，确定了与44种表型相关的微生物功能。我们发现了由杆状菌门、拟杆菌门、放线菌门和假单胞菌门内的物种驱动的碳代谢和能量产生的与衰老相关的功能变化。在代谢性疾病中，我们观察到杆状菌物种及其涉及碳水化合物、能量、氨基酸代谢和短链脂肪酸产生的蛋白质的一致消耗。我们还确定了糖尿病、高血压和血脂异常的药物相关特征。在一项独立的队列研究中，elsdenii Megasphaera成为2型糖尿病的中心物种。实验证实，抗糖尿病药物可促进elsdenii的生长，并可能通过丁酸盐的产生调节葡萄糖稳态。这项研究为微生物在健康和疾病中的功能提供了蛋白质水平的证据，突出了潜在的治疗靶点。

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来源期刊

Cell metabolism 生物-内分泌学与代谢

CiteScore

48.60

自引率

1.40%

发文量

173

审稿时长

2.5 months

期刊介绍： Cell Metabolism is a top research journal established in 2005 that focuses on publishing original and impactful papers in the field of metabolic research.It covers a wide range of topics including diabetes, obesity, cardiovascular biology, aging and stress responses, circadian biology, and many others. Cell Metabolism aims to contribute to the advancement of metabolic research by providing a platform for the publication and dissemination of high-quality research and thought-provoking articles.