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

Dec 22, 2015Cell

Reducing Gut Bacteria’s Production of Trimethylamine Without Killing Them to Help Treat Atherosclerosis

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

3,3-dimethyl-1-butanol (DMB) significantly reduces TMAO levels in mice fed a high-choline diet.

TMAO is linked to increased atherosclerosis in animal models and cardiovascular risks in humans.
DMB inhibits TMA production from gut microbes without causing lethal effects.
Inhibition of TMA formation leads to reduced macrophage foam cell formation and atherosclerotic lesions in specific mouse models.
No changes in circulating cholesterol levels were observed despite reduced atherosclerosis.
Targeting gut microbial TMA production may represent a potential therapeutic strategy for cardiometabolic diseases.

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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.

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

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