Microbial Transplantation With Human Gut Commensals Containing CutC Is Sufficient to Transmit Enhanced Platelet Reactivity and Thrombosis Potential.

Abstract

RATIONALE:

Gut microbes influence cardiovascular disease and thrombosis risks through the production of trimethylamine N-oxide (TMAO). Microbiota-dependent generation of trimethylamine (TMA)-the precursor to TMAO-is rate limiting in the metaorganismal TMAO pathway in most humans and is catalyzed by several distinct microbial choline TMA-lyases, including the proteins encoded by the cutC/D (choline utilization C/D) genes in multiple human commensals.

OBJECTIVE:

Direct demonstration that the gut microbial cutC gene is sufficient to transmit enhanced platelet reactivity and thrombosis potential in a host via TMA/TMAO generation has not yet been reported.

METHODS AND RESULTS:

Herein, we use gnotobiotic mice and a series of microbial colonization studies to show that microbial cutC-dependent TMA/TMAO production is sufficient to transmit heightened platelet reactivity and thrombosis potential in a host. Specifically, we examine in vivo thrombosis potential employing germ-free mice colonized with either high TMA-producing stable human fecal polymcrobial communities or a defined CutC-deficient background microbial community coupled with a CutC-expressing human commensal±genetic disruption of its cutC gene (ie, Clostridium sporogenes Δ cutC).

CONCLUSIONS:

Collectively, these studies point to the microbial choline TMA-lyase pathway as a rational molecular target for the treatment of atherothrombotic heart disease.

• Authors: Sarah M Skye, Weifei Zhu, Kymberleigh A Romano, Chun-Jun Guo, Zeneng Wang, Xun Jia, Jennifer Kirsop, Bridget Haag, Jennifer M Lang, Joseph A DiDonato, W H Wilson Tang, Aldons J Lusis, Federico E Rey, Michael A Fischbach, Stanley L Hazen
• Journal: Circulation research (Circ Res) Vol. 123 Issue 10 Pg. 1164-1176 (10 26 2018) ISSN: 1524-4571 [Electronic] United States
• PMID: 30359185 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Bacterial Proteins
• Methylamines
• Lyases
• trimethyloxamine
• trimethylamine
• Choline

Topics

• Adult
• Animals
• Bacterial Proteins (genetics, metabolism)
• Choline (metabolism)
• Clostridium (enzymology, genetics)
• Fecal Microbiota Transplantation
• Female
• Gastrointestinal Microbiome
• Humans
• Lyases (genetics, metabolism)
• Male
• Methylamines (metabolism)
• Mice
• Mice, Inbred C57BL
• Middle Aged
• Platelet Activation
• Thrombosis (blood, microbiology)