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Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential

Nature Medicine volume 24, pages 1407–1417 (2018)Cite this article

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Abstract

Trimethylamine N-oxide (TMAO) is a gut microbiota–derived metabolite that enhances both platelet responsiveness and in vivo thrombosis potential in animal models, and TMAO plasma levels predict incident atherothrombotic event risks in human clinical studies. TMAO is formed by gut microbe–dependent metabolism of trimethylamine (TMA) moiety-containing nutrients, which are abundant in a Western diet. Here, using a mechanism-based inhibitor approach targeting a major microbial TMA-generating enzyme pair, CutC and CutD (CutC/D), we developed inhibitors that are potent, time-dependent, and irreversible and that do not affect commensal viability. In animal models, a single oral dose of a CutC/D inhibitor significantly reduced plasma TMAO levels for up to 3 d and rescued diet-induced enhanced platelet responsiveness and thrombus formation, without observable toxicity or increased bleeding risk. The inhibitor selectively accumulated within intestinal microbes to millimolar levels, a concentration over 1-million-fold higher than needed for a therapeutic effect. These studies reveal that mechanism-based inhibition of gut microbial TMA and TMAO production reduces thrombosis potential, a critical adverse complication in heart disease. They also offer a generalizable approach for the selective nonlethal targeting of gut microbial enzymes linked to host disease limiting systemic exposure of the inhibitor in the host.

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Fig. 1: Proof of concept that microbial choline TMA lyase inhibition can attenuate choline diet–enhanced platelet aggregation and in vivo thrombus formation.
Fig. 2: IMC and FMC are nonlethal, irreversible, and noncompetitive CutC/D inhibitors.
Fig. 3: The in vivo pharmacokinetic and pharmacodynamic properties of FMC and IMC.
Fig. 4: The mechanism-based CutC/D inhibitors IMC and FMC reverse choline diet–enhanced platelet responsiveness and thrombus formation.
Fig. 5: A microbial choline TMA lyase inhibitor reverses diet-induced changes in cecal microbial community composition associated with plasma TMAO levels, platelet responsiveness, and in vivo thrombosis potential.

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  • 21 September 2018

    In the Supplementary Information originally published with this article, Supplementary Fig. 1 was inadvertently omitted. The full version of the Supplementary Information is now available online.

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Acknowledgements

We appreciate the aid of J. A. Drazba and G. Deshpande of the Lerner Research Institute Imaging Core in studies using the Cellix microfluidic system. This research was supported by grants from the National Institutes of Health (NIH) and the Office of Dietary Supplements (HL103866, HL126827 and DK106000 (to S.L.H.), HL122283 and AA024333 (to J.M.B.), and HL28481 and HL30568 (to A.J.L.)). S.L.H. reports being supported in part by a grant from the Leducq Foundation. V.G. acknowledges a Faculty Research Development Award from Cleveland State University. A.B.R. was supported in part by a grant from the American Heart Association (15POST25750053). W.Z. was supported in part by an AHA Scientist Development Grant and an NIH StrokeNet Clinical Research and Training Grant. S.M.S. was supported in part by training grant T32DK007470 from the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) of the NIH. Some of the toxicology and safety studies were performed by Pharmaron. Mass spectrometry studies were performed on instrumentation housed in a facility supported in part through a Shimadzu Center of Excellence award. Computational resources were provided by the Extreme Science and Engineering Discovery Environment (National Science Foundation).

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Author notes

  1. Alex G. Hurd

    Present address: Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA

  2. Alex J. Myers

    Present address: Heritage College of Osteopathic Medicine, Ohio University, Athens, OH, USA

  3. These authors contributed equally: Adam B. Roberts, Xiaodong Gu, Jennifer A. Buffa.

Authors and Affiliations

  1. Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    Adam B. Roberts, Xiaodong Gu, Jennifer A. Buffa, Alex G. Hurd, Zeneng Wang, Weifei Zhu, Nilaksh Gupta, Sarah M. Skye, Bruce S. Levison, Matthew W. Russell, Xiaoming Fu, Lin Li, Alex J. Myers, Suguna Rachakonda, Joseph A. DiDonato, J. Mark Brown, Valentin Gogonea & Stanley L. Hazen

  2. Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH, USA

    Adam B. Roberts, Xiaodong Gu, Jennifer A. Buffa, Alex G. Hurd, Zeneng Wang, Weifei Zhu, Nilaksh Gupta, Sarah M. Skye, Matthew W. Russell, Ashraf Duzan, Xiaoming Fu, Lin Li, Suguna Rachakonda, Joseph A. DiDonato, J. Mark Brown, Valentin Gogonea & Stanley L. Hazen

  3. Life Sciences Transformative Platform Technologies, Procter & Gamble, Cincinnati, OH, USA

    David B. Cody, Jodie M. Reed & Jose Carlos Garcia-Garcia

  4. Departments of Human Genetics and Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    William T. Barrington, Jennifer M. Lang & Aldons J. Lusis

  5. Department of Chemistry, Cleveland State University, Cleveland, OH, USA

    Ashraf Duzan & Valentin Gogonea

  6. Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH, USA

    Stanley L. Hazen

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Contributions

A.B.R, J.A.B., and X.G designed, performed, and analyzed data from most of the studies. They also helped write the manuscript with input from all authors. A.G.H., A.D., V.G., A.J.M., and B.S.L aided in chemical synthesis and characterization of all compounds, computational drug design efforts, docking analyses, and quantum mechanical calculations. Z.W. and X.F. helped with design and performance of mass spectrometry analyses. W.Z., N.G., and M.W.R. helped in the design and performance of platelet functional studies, in vivo thrombosis, and other mouse experiments. S.M.S., J.M.L., L.L, W.T.B., and A.J.L. participated in microbe composition analyses and cut gene cluster transcription quantification studies. D.B.C., J.M.R., and J.C.G.-G. helped design and perform some of the human commensal and polymicrobial bioreactor studies characterizing inhibitor efficacy. J.A.D. provided overall advice, as well as performing plasmid cloning and construction use in multiple bacterial inhibitor studies. S.R., J.M.B., and J.C.G.-G. provided critical scientific input and discussions. S.L.H conceived, designed, and supervised all studies, and participated in the drafting and editing of the manuscript. All authors contributed to the critical review of the manuscript.

Corresponding author

Correspondence to Stanley L. Hazen.

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Competing interests

S.L.H., X.G., Z.W., and B.S.L. are named as co-inventors on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics or therapeutics. S.L.H., Z.W., and B.S.L. report having the right to receive royalty payment for inventions or discoveries related to cardiovascular diagnostics from Cleveland Heart Lab, Inc. and Quest Diagnostics. S.L.H. also reports having been paid as a consultant for P&G and receiving research funds from Astra Zeneca, P&G, Pfizer Inc., and Roche Diagnostics.

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Roberts, A.B., Gu, X., Buffa, J.A. et al. Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential. Nat Med 24, 1407–1417 (2018). https://doi.org/10.1038/s41591-018-0128-1

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