Abstract
Small molecule inhibition of gut microbial choline trimethylamine lyase activity alters host cholesterol and bile acid metabolism. Am J Physiol Heart Circ Physiol 318: H1474-H1486, 2020. First published April 24, 2020; doi:10.1152/ajpheart.00584.2019.-The gut microbe-derived metabolite trimethylamine-N-oxide (TMAO) has recently been linked to cardiovascular disease (CVD) pathogenesis, prompting the development of therapeutic strategies to reduce TMAO. Previous work has shown that experimental alteration of circulating TMAO levels via dietary alterations or inhibition of the host TMAO producing enzyme flavin containing monooxygenase 3 (FMO3) is associated with reorganization of host cholesterol and bile acid metabolism in mice. In this work, we set out to understand whether recently developed nonlethal gut microbe-Targeting small molecule choline trimethylamine (TMA) lyase inhibitors also alter host cholesterol and bile acid metabolism. Treatment of mice with the mechanism-based choline TMA lyase inhibitor, iodomethylcholine (IMC), increased fecal neutral sterol loss in the form of coprostanol, a bacteria metabolite of cholesterol. In parallel, IMC treatment resulted in marked reductions in the intestinal sterol transporter Niemann-pick C1-like 1 (NPC1L1) and reorganization of the gut microbial community, primarily reversing choline supplemented diet-induced changes. IMC also prevented diet-driven hepatic cholesterol accumulation, causing both upregulation of the host hepatic bile acid synthetic enzyme CYP7A1 and altering the expression of hepatic genes critical for bile acid feedback regulation. These studies suggest that the gut microbiota-driven TMAO pathway is closely linked to both microbe and host sterol and bile acid metabolism. Collectively, as gut microbe-Targeting choline TMA lyase inhibitors move through the drug discovery pipeline from preclinical models to human studies, it will be important to understand how these drugs impact both microbe and host cholesterol and bile acid metabolism.
| Original language | English |
|---|---|
| Pages (from-to) | H1474-H1486 |
| Journal | American Journal of Physiology - Heart and Circulatory Physiology |
| Volume | 318 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 2020 |
Bibliographical note
Publisher Copyright:© 2020 American Physiological Society. All rights reserved.
Funding
This work was supported by National Institutes of Health (NIH) and Office of Dietary Supplements Grants R01 HL122283 (to J. M. Brown), R01 DK120679 (J. M. Brown), P50 AA024333 (to J. M. Brown), P01 HL147823 (to S. L. Hazen and J. M. Brown), R01 HL130819 (to Z. Wang), and R01 HL103866 (to S. L. Hazen) and the American Heart Association (Postdoctoral Fellowship 17POST3285000 to R. N. Helsley). S. L. Hazen also reports partial support from an award from the Leducq Foundation. Development of lipid mass spectrometry methods reported here were supported in part by generous pilot grants from the Clinical and Translational Science Collaborative of Cleveland (4UL1TR000439) from the National Center for Advancing Translational Sciences (NCATS) component of NIH and the NIH Roadmap for Medical Research, the Case Comprehensive Cancer Center (P30 CA043703), the VeloSano Foundation, and a Cleveland Clinic Research Center of Excellence Award.
| Funders | Funder number |
|---|---|
| VeloSano Foundation | |
| National Institutes of Health (NIH) | |
| National Heart, Lung, and Blood Institute (NHLBI) | R01HL122283 |
| Office of Dietary Supplements | R01 DK120679, P50 AA024333, R01 HL130819, R01 HL103866, P01 HL147823 |
| American Heart Association | 17POST3285000 |
| National Center for Advancing Translational Sciences (NCATS) | |
| Case Comprehensive Cancer Center, Case Western Reserve University | P30 CA043703 |
| Fondation Leducq | 4UL1TR000439 |
Keywords
- TMA
- bile acid
- cardiovascular disease
- cholesterol
- metabolism
- microbiome
ASJC Scopus subject areas
- Physiology
- Cardiology and Cardiovascular Medicine
- Physiology (medical)
