Diet, Genetics, and the Gut Microbiome Drive Dynamic Changes in Plasma Metabolites

Shiho Fujisaka; Julian Avila-Pacheco; Marion Soto; Aleksandar Kostic; Jonathan M Dreyfuss; Hui Pan; Siegfried Ussar; Emrah Altindis; Ning Li; Lynn Bry; Clary B Clish; C Ronald Kahn

doi:10.1016/j.celrep.2018.02.060

Diet, Genetics, and the Gut Microbiome Drive Dynamic Changes in Plasma Metabolites

Cell Rep. 2018 Mar 13;22(11):3072-3086. doi: 10.1016/j.celrep.2018.02.060.

Authors

Affiliations

¹ Section of Integrative Physiology and Metabolism, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA; First Department of Internal Medicine, University of Toyama, Toyama 930-0194, Japan.
² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Section of Integrative Physiology and Metabolism, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA.
⁴ Department of Microbiology and Immunobiology, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA.
⁵ Bioinformatics Core, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.
⁶ Section of Integrative Physiology and Metabolism, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA; Institute for Diabetes and Obesity, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
⁷ Center for Clinical and Translational Metagenomics. Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁸ Section of Integrative Physiology and Metabolism, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA. Electronic address: c.ronald.kahn@joslin.harvard.edu.

Abstract

Diet, genetics, and the gut microbiome are determinants of metabolic status, in part through production of metabolites by the gut microbiota. To understand the mechanisms linking these factors, we performed LC-MS-based metabolomic analysis of cecal contents and plasma from C57BL/6J, 129S1/SvImJ, and 129S6/SvEvTac mice on chow or a high-fat diet (HFD) and HFD-treated with vancomycin or metronidazole. Prediction of the functional metagenome of gut bacteria by PICRUSt analysis of 16S sequences revealed dramatic differences in microbial metabolism. Cecal and plasma metabolites showed multifold differences reflecting the combined and integrated effects of diet, antibiotics, host background, and the gut microbiome. Eighteen plasma metabolites correlated positively or negatively with host insulin resistance across strains and diets. Over 1,000 still-unidentified metabolite peaks were also highly regulated by diet, antibiotics, and genetic background. Thus, diet, host genetics, and the gut microbiota interact to create distinct responses in plasma metabolites, which can contribute to regulation of metabolism and insulin resistance.

Keywords: TMAO; antibiotics; bile acids; cecal metabolomics; diabetes; diet; gut microbiome; obesity; serum lipids; serum metabolomics.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Diet, High-Fat / methods*
Gastrointestinal Microbiome / genetics*
Humans
Metabolomics / methods*
Mice
Obesity / genetics*
Obesity / pathology

Abstract

Publication types

MeSH terms

Grants and funding