Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential
| Autor: | Xiaodong Gu, Stanley L. Hazen, Matthew W Russell, Jennifer A. Buffa, Jose C. Garcia-Garcia, Aldons J. Lusis, Nilaksh Gupta, Jodie Michelle Reed, Sarah M. Skye, Zeneng Wang, Alex G Hurd, Bruce S. Levison, David B. Cody, William T. Barrington, Joseph A. DiDonato, Lin Li, Adam B. Roberts, J. Mark Brown, Ashraf Duzan, Xiaoming Fu, Jennifer M. Lang, Alex J Myers, Weifei Zhu, Suguna Rachakonda, Valentin Gogonea |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Platelet Aggregation Metabolite Microbial metabolism Trimethylamine 030204 cardiovascular system & hematology Pharmacology General Biochemistry Genetics and Molecular Biology Choline 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine In vivo Animals Platelet chemistry.chemical_classification Bacteria Chemistry Oxidoreductases N-Demethylating Thrombosis General Medicine Metabolism Diet Gastrointestinal Microbiome 3. Good health Mice Inbred C57BL 030104 developmental biology Enzyme Toxicity Hexanols |
| Zdroj: | Nature Medicine. 24:1407-1417 |
| ISSN: | 1546-170X 1078-8956 |
| DOI: | 10.1038/s41591-018-0128-1 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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