Abstract

The gut microbiota plays a pivotal part in human health, yet the molecular mechanisms that underlie its effects are largely unexplored. Bacteroides, a dominant genus in the human gut microbiota, is depleted in patients with atherosclerosis, but its causal relationship with disease remains unclear. Here, using a mouse model, we show that administration of Bacteroides uniformis alleviates atherosclerosis through the upregulation of hepatic low-density lipoprotein receptor expression. Bioactivity-guided screening revealed pentadecanoic acid (PA, C15:0), a saturated odd-chain fatty acid, as a principal bioactive metabolite. PA supplementation reduced atherosclerotic plaque burden by around 50% and significantly improved plasma lipid profiles, a result that underscores its therapeutic potential. Mechanistically, PA enhances cholesterol clearance by directly inhibiting HMG-CoA reductase, suppressing hepatic cholesterol biosynthesis and promoting plasma low-density lipoprotein cholesterol removal. Analyses of 100 gut bacterial strains revealed that PA production occurs across multiple Bacteroidota genera. Notably, PA is markedly depleted in patients with dyslipidaemia. In summary, a Bacteroidota-derived odd-chain fatty acid regulates gut–liver crosstalk, and modulation of the microbial–metabolic axis has atheroprotective potential.

Title

A gut microbial odd-chain fatty acid alleviates atherosclerosis in mice

Authors

Chao Yin, Youzhe Chen, Gan Lin, Mingwei Cai, Cuiping Pang, Xianzun Xiao, Kaining Han, Chaoxiong Mei, Miaomiao Qin, Peizhi Fan, Yibo Zhao, Lihong Du, Yanqin Xie, Jiang Wang, Yudan Mao, Xiangting Zhou, Xue Gao, Li Jin, Peijie Li, Zepeng Qu, Zhipeng Tan, Ruolan Sun, Xiahong Lin, Yang Zhang, Lei Dai, Zhaofan Luo, Xiangyu Mou, Xiaoyu Tang & Wenjing Zhao

Journal Information

Nature (2026)

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