1. Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis
- Author
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Xiaodong Gu, Jennie E. Hazen, Stanley L. Hazen, Joseph A. DiDonato, Anthony J. DiDonato, Elin Org, Jennifer A. Buffa, Weifei Zhu, Adam B. Roberts, Zeneng Wang, Miranda K. Culley, Bruce S. Levison, Ying Huang, Xiaoming Fu, Daniel M Krajcik, Aldons J. Lusis, and Maryam Zamanian-Daryoush
- Subjects
Apolipoprotein E ,Metabolite ,Lyases ,Trimethylamine ,Trimethylamine N-oxide ,Biology ,digestive system ,General Biochemistry, Genetics and Molecular Biology ,Choline ,Feces ,Methylamines ,Mice ,chemistry.chemical_compound ,Apolipoproteins E ,Animals ,Humans ,Macrophage ,Foam cell ,Biochemistry, Genetics and Molecular Biology(all) ,Cholesterol ,Microbiota ,Atherosclerosis ,Diet ,Gastrointestinal Tract ,Mice, Inbred C57BL ,chemistry ,Biochemistry ,Hexanols ,Foam Cells - Abstract
Trimethylamine (TMA) N-oxide (TMAO), a gut-microbiota-dependent metabolite, both enhances atherosclerosis in animal models and is associated with cardiovascular risks in clinical studies. Here, we investigate the impact of targeted inhibition of the first step in TMAO generation, commensal microbial TMA production, on diet-induced atherosclerosis. A structural analog of choline, 3,3-dimethyl-1-butanol (DMB), is shown to non-lethally inhibit TMA formation from cultured microbes, to inhibit distinct microbial TMA lyases, and to both inhibit TMA production from physiologic polymicrobial cultures (e.g., intestinal contents, human feces) and reduce TMAO levels in mice fed a high-choline or L-carnitine diet. DMB inhibited choline diet-enhanced endogenous macrophage foam cell formation and atherosclerotic lesion development in apolipoprotein e(-/-) mice without alterations in circulating cholesterol levels. The present studies suggest that targeting gut microbial production of TMA specifically and non-lethal microbial inhibitors in general may serve as a potential therapeutic approach for the treatment of cardiometabolic diseases.
- Published
- 2015