Targeting of microbe-derived metabolites to improve human health: The next frontier for drug discovery

  1. Stanley L. Hazen,§,2
  1. From the Departments of Cellular and Molecular Medicine and
  2. Cardiovascular Medicine and
  3. §Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, Ohio 44195
  1. 1 To whom correspondence may be addressed: 9500 Euclid Ave., NC-10, Cleveland Clinic, Cleveland, OH 44195. Tel.: 216-444-8340; Fax: 216-444-9404; E-mail: brownm5{at}ccf.org.
  2. 2 To whom correspondence should be addressed: 9500 Euclid Ave., NC-10, Cleveland Clinic, Cleveland, OH 44195. Tel.: 216-445-9763; Fax: 216-636-0392; E-mail: hazens{at}ccf.org.
  1. Edited by Ruma Banerjee

Abstract

Recent advances in metabolomic and genome mining approaches have uncovered a poorly understood metabolome that originates solely or in part from bacterial enzyme sources. Whether living on exposed surfaces or within our intestinal tract, our microbial inhabitants produce a remarkably diverse set of natural products and small molecule metabolites that can impact human health and disease. Highlighted here, the gut microbe-derived metabolite trimethylamine N-oxide has been causally linked to the development of cardiovascular diseases. Recent studies reveal drugging this pathway can inhibit atherosclerosis development in mice. Building on this example, we discuss challenges and untapped potential of targeting bacterial enzymology for improvements in human health.

Footnotes

  • This work was supported by National Institutes of Health Grants R01 HL122283 (to J. M. B.), P50 AA024333 (to J. M. B.), R01 HL103866 (to S. L. H.), P01 HL076491 (to S. L. H.), R01DK10600 (to S. L. H.), and R01HL126827 (to S. L. H.) from NHLBI and Office of Dietary Supplements. This is the third article in the Host-Microbiome metabolic interplay Minireview series. Dr. Hazen reports being listed as co-inventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics. Dr. Hazen reports having been paid as a consultant for the following companies: Esperion, Proctor & Gamble, and Takeda. Dr. Hazen reports receiving research funds from Astra Zeneca, Pfizer, Proctor & Gamble, Roche Diagnostics, and Takeda. Dr. Hazen reports having the right to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics and therapeutics for the following companies: Cleveland Heart Laboratory, Esperion, Frantz Biomarkers, LLC, and Siemens. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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