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

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.

• Authors: 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, Lemin Zheng
• Journal: Nature communications (Nat Commun) Vol. 13 Issue 1 Pg. 1757 (04 01 2022) ISSN: 2041-1723 [Electronic] England
• PMID: 35365608 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Amino Acids, Neutral
• Fatty Acids
• N,N,N-trimethyl-5-aminovaleric acid
• Valerates
• 5-aminovaleric acid

Topics

• Amino Acids, Neutral
• Animals
• Cardiomegaly (metabolism)
• Fatty Acids (metabolism)
• Gastrointestinal Microbiome
• Humans
• Mice
• Prospective Studies
• Valerates