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
Affiliations
Shiho Fujisaka
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
Julian Avila-Pacheco
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Marion Soto
Section of Integrative Physiology and Metabolism, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA
Aleksandar Kostic
Department of Microbiology and Immunobiology, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA
Jonathan M. Dreyfuss
Bioinformatics Core, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA
Hui Pan
Bioinformatics Core, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA
Siegfried Ussar
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
Emrah Altindis
Section of Integrative Physiology and Metabolism, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA
Ning Li
Center for Clinical and Translational Metagenomics. Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA
Lynn Bry
Center for Clinical and Translational Metagenomics. Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA
Clary B. Clish
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
C. Ronald Kahn
Section of Integrative Physiology and Metabolism, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA; Corresponding author
Summary: 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. : Fujisaka et al. show that mice with differing propensities to obesity and diabetes have differing metabolomic responses to diet and antibiotic treatment. Several serum metabolites correlate with changes in the gut microbiota or with insulin resistance across strains. Thus, diet, genetics, and the gut microbiota interact to create distinct plasma metabolomic responses. Keywords: gut microbiome, serum metabolomics, cecal metabolomics, obesity, diabetes, serum lipids, TMAO, bile acids, antibiotics, diet
