Gut microbiota production of trimethyl-5-aminovaleric acid reduces fatty acid oxidation and accelerates cardiac hypertrophy

Mingming Zhao, Haoran Wei, Chenze Li, Rui Zhan, Changjie Liu, Jianing Gao, Yaodong Yi, Xiao Cui, Wenxin Shan, Liang Ji, Bing Pan, Si Cheng, Moshi Song, Haipeng Sun, Huidi Jiang, Jun Cai, Minerva T. Garcia-Barrio, Y. Eugene Chen, Xiangbao Meng, Erdan Dong, Dao Wen Wang () and Lemin Zheng ()
Additional contact information
Mingming Zhao: Peking University Third Hospital
Haoran Wei: Huazhong University of Science and Technology
Chenze Li: Zhongnan Hospital of Wuhan University
Rui Zhan: Peking University
Changjie Liu: Peking University
Jianing Gao: Peking University
Yaodong Yi: Zhejiang University
Xiao Cui: Zhejiang University
Wenxin Shan: Peking University
Liang Ji: Peking University
Bing Pan: Peking University
Si Cheng: The Capital Medical University
Moshi Song: Chinese Academy of Sciences
Haipeng Sun: Shanghai Jiao Tong University School of Medicine
Huidi Jiang: Zhejiang University
Jun Cai: Chinese Academy of Medical Sciences and Peking Union Medical College
Minerva T. Garcia-Barrio: University of Michigan Medical Center
Y. Eugene Chen: University of Michigan Medical Center
Xiangbao Meng: Peking University
Erdan Dong: Peking University Third Hospital
Dao Wen Wang: Huazhong University of Science and Technology
Lemin Zheng: Peking University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Numerous studies found intestinal microbiota alterations which are thought to affect the development of various diseases through the production of gut-derived metabolites. However, the specific metabolites and their pathophysiological contribution to cardiac hypertrophy or heart failure progression still remain unclear. N,N,N-trimethyl-5-aminovaleric acid (TMAVA), derived from trimethyllysine through the gut microbiota, was elevated with gradually increased risk of cardiac mortality and transplantation in a prospective heart failure cohort (n = 1647). TMAVA treatment aggravated cardiac hypertrophy and dysfunction in high-fat diet-fed mice. Decreased fatty acid oxidation (FAO) is a hallmark of metabolic reprogramming in the diseased heart and contributes to impaired myocardial energetics and contractile dysfunction. Proteomics uncovered that TMAVA disturbed cardiac energy metabolism, leading to inhibition of FAO and myocardial lipid accumulation. TMAVA treatment altered mitochondrial ultrastructure, respiration and FAO and inhibited carnitine metabolism. Mice with γ-butyrobetaine hydroxylase (BBOX) deficiency displayed a similar cardiac hypertrophy phenotype, indicating that TMAVA functions through BBOX. Finally, exogenous carnitine supplementation reversed TMAVA induced cardiac hypertrophy. These data suggest that the gut microbiota-derived TMAVA is a key determinant for the development of cardiac hypertrophy through inhibition of carnitine synthesis and subsequent FAO.

Date: 2022
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DOI: 10.1038/s41467-022-29060-7

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