Cholesterol Metabolism by Uncultured Human Gut Bacteria Influences Host Cholesterol Level.

Douglas J Kenny, Damian R Plichta, Dmitry Shungin, Nitzan Koppel, A Brantley Hall, Beverly Fu, Ramachandran S Vasan, Stanley Y Shaw, Hera Vlamakis, Emily P Balskus, Ramnik J Xavier

Journal: Cell host & microbe 2021;28(2):245-257.e6

PMID: 32544460

Abstract

The human microbiome encodes extensive metabolic capabilities, but our understanding of the mechanisms linking gut microbes to human metabolism remains limited. Here, we focus on the conversion of cholesterol to the poorly absorbed sterol coprostanol by the gut microbiota to develop a framework for the identification of functional enzymes and microbes. By integrating paired metagenomics and metabolomics data from existing cohorts with biochemical knowledge and experimentation, we predict and validate a group of microbial cholesterol dehydrogenases that contribute to coprostanol formation. These enzymes are encoded by ismA genes in a clade of uncultured microorganisms, which are prevalent in geographically diverse human cohorts. Individuals harboring coprostanol-forming microbes have significantly lower fecal cholesterol levels and lower serum total cholesterol with effects comparable to those attributed to variations in lipid homeostasis genes. Thus, cholesterol metabolism by these microbes may play important roles in reducing intestinal and serum cholesterol concentrations, directly impacting human health.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Address: Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Odontology, Umeå University, Umeå, Sweden.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.; Boston University and NHLBI's Framingham Heart Study, Framingham, MA, USA; Sections of Preventive Medicine and Epidemiology and Cardiovascular Medicine, Departments of Medicine and Epidemiology, Boston University Schools of Medicine and Public Health, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA; HMS and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA.; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA, USA.; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA. Electronic address: [email protected].; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA, USA; Center for Computational and Integrative Biology and Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: [email protected].
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