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Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis

Wang, Zeneng ; Roberts, Adam B. ; Buffa, Jennifer A. ; Levison, Bruce S. ; Zhu, Weifei ; Org, Elin ; Gu, Xiaodong ; Huang, Ying ; Zamanian-Daryoush, Maryam ; Culley, Miranda K. ; DiDonato, Anthony J. ; Fu, Xiaoming ; Hazen, Jennie E. ; Krajcik, Daniel ; DiDonato, Joseph A. ; Lusis, Aldons J. ; Hazen, Stanley L.

Cell, 2015-12, Vol.163 (7), p.1585-1595 [Peer Reviewed Journal]

United States: Elsevier Inc

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Title:
Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis
Author: Wang, Zeneng ; Roberts, Adam B. ; Buffa, Jennifer A. ; Levison, Bruce S. ; Zhu, Weifei ; Org, Elin ; Gu, Xiaodong ; Huang, Ying ; Zamanian-Daryoush, Maryam ; Culley, Miranda K. ; DiDonato, Anthony J. ; Fu, Xiaoming ; Hazen, Jennie E. ; Krajcik, Daniel ; DiDonato, Joseph A. ; Lusis, Aldons J. ; Hazen, Stanley L.
Subjects: Animals ; Apolipoproteins E - genetics ; Atherosclerosis - drug therapy ; Atherosclerosis - metabolism ; Cholesterol - metabolism ; Choline - analogs & derivatives ; Choline - metabolism ; Diet ; Feces - chemistry ; Foam Cells - metabolism ; Gastrointestinal Tract - microbiology ; Hexanols - administration & dosage ; Humans ; Lyases - antagonists & inhibitors ; Lyases - metabolism ; Methylamines - metabolism ; Mice ; Mice, Inbred C57BL ; Microbiota
Is Part Of: Cell, 2015-12, Vol.163 (7), p.1585-1595
Notes: ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
Description: 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. [Display omitted] •Gut microbial trimethylamine lyases are a therapeutic target for atherosclerosis•3,3-dimethyl-1-butanol inhibits microbial trimethylamine formation•3,3-dimethyl-1-butanol attenuates choline diet-enhanced atherosclerosis•Non-lethal gut microbial enzyme inhibition can impact host cardiometabolic phenotypes Drugging the gut microbiota with a non-lethal inhibitor that blocks production of the metabolite trimethylamine reduces the formation of atherosclerotic lesions and represents the first step toward treatment of cardiometabolic diseases by targeting the microbiome.
Publisher: United States: Elsevier Inc
Language: English

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Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis

United States: Elsevier Inc

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