Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis

By Zeneng Wang, Adam B. Roberts, J. Buffa, B. Levison, Weifei Zhu, E. Org, Xiaodong Gu, Ying Huang, M. Zamanian-Daryoush, M. Culley and 7 more. Cell, 2015

1,190 citations recorded by the source corpus.

SUMMARY Trimethylamine 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 trimethylamine (TMA) production, on diet-induced atherosclerosis. A structural analogue 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 (eg intestinal contents, human feces) and reduce TMAO levels in mice fed a high choline or 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 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.

Subfields: Biological Psychiatry, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/6db88eb65791aeb01687bfedb7e6483d0729196e

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In Molecular Biology

1. Y. Taur
2. W. Tang
3. Stanley L Hazen
4. Eric G. Pamer
5. J. Durack
6. S. Lynch
7. E. Balskus
8. T. Kitai

In Physiology

1. W. Tang
2. Stanley L Hazen
3. Eric G. Pamer
4. T. Kitai

Citations in the corpus

• Ischemia/Reperfusion (2016, neutral): “formation, and atherosclerotic lesion development in atheroprone mice fed high choline or L-carnitine diets (830).”
• Gut Microbiome: Profound Implications for Diet and Disease (2019, background): “A structural analog of choline and natural product found in some foods, 3,3-dimethyl-1-butanol (DMB), has been shown in mice to reduce TMAO levels by non-lethal inhibition of TMA lyase [139], giving credence to the notion of “drugging the microbiome.”
• Antibiotic-Induced Changes in the Intestinal Microbiota and Disease. (2016, background): “Interestingly, a follow-up study showed that feeding mice an analog of choline, which inhibits TMA production by blocking microbial TMA lyases, could prevent atherosclerosis in mice [71].”
• The gut microbiome: Relationships with disease and opportunities for therapy (2018, background): “, 2013), and inhibition of this enzyme reduced atherosclerotic plaque development in susceptible Apoe−/− mice (Wang et al., 2015).”
• Chemical transformation of xenobiotics by the human gut microbiota (2017, background): “The discovery of CutC has aided interventions to modulate choline metabolism in vivo, including the design of gut communities with decreased TMA production (116) and small-molecule inhibitors targeting this pathway (117).”
• Gut Microbiota in Cardiovascular Health and Disease (2017, background): “Proof of concept for this strategy was recently shown through development of a small-molecule tool drug for the inhibition of microbial choline TMA lyase activity.(65) Use of a choline structural by gest on A ril 1, 2017 http://circhajournals.”