title: Transmission of atherosclerosis susceptibility with gut microbial transplantation.
abstract: Recent studies indicate both clinical and mechanistic links between atherosclerotic heart disease and intestinal microbial metabolism of certain dietary nutrients producing trimethylamine N-oxide (TMAO). Here we test the hypothesis that gut microbial transplantation can transmit choline diet-induced TMAO production and atherosclerosis susceptibility. First, a strong association was noted between atherosclerotic plaque and plasma TMAO levels in a mouse diversity panel (n = 22 strains, r = 0.38; p = 0.0001). An atherosclerosis-prone and high TMAO-producing strain, C57BL/6J, and an atherosclerosis-resistant and low TMAO-producing strain, NZW/LacJ, were selected as donors for cecal microbial transplantation into apolipoprotein e null mice in which resident intestinal microbes were first suppressed with antibiotics. Trimethylamine (TMA) and TMAO levels were initially higher in recipients on choline diet that received cecal microbes from C57BL/6J inbred mice; however, durability of choline diet-dependent differences in TMA/TMAO levels was not maintained to the end of the study. Mice receiving C57BL/6J cecal microbes demonstrated choline diet-dependent enhancement in atherosclerotic plaque burden as compared with recipients of NZW/LacJ microbes. Microbial DNA analyses in feces and cecum revealed transplantation of donor microbial community features into recipients with differences in taxa proportions between donor strains that were transmissible to recipients and that tended to show coincident proportions with TMAO levels. Proportions of specific taxa were also identified that correlated with plasma TMAO levels in donors and recipients and with atherosclerotic lesion area in recipients. Atherosclerosis susceptibility may be transmitted via transplantation of gut microbiota. Gut microbes may thus represent a novel therapeutic target for modulating atherosclerosis susceptibility.
authors.affiliation: From the Department of Cellular and Molecular Medicine, Center for Cardiovascular Diagnostics and Prevention, and.
authors.forename: Jill C
authors.initials: JC
authors.lastname: Gregory
authors.affiliation: From the Department of Cellular and Molecular Medicine, Center for Cardiovascular Diagnostics and Prevention, and.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Buffa
authors.affiliation: the Departments of Human Genetics and Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, 90095, and.
authors.forename: Elin
authors.initials: E
authors.lastname: Org
authors.affiliation: From the Department of Cellular and Molecular Medicine, Center for Cardiovascular Diagnostics and Prevention, and.
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: From the Department of Cellular and Molecular Medicine, Center for Cardiovascular Diagnostics and Prevention, and.
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Levison
authors.affiliation: From the Department of Cellular and Molecular Medicine, Center for Cardiovascular Diagnostics and Prevention, and.
authors.forename: Weifei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: From the Department of Cellular and Molecular Medicine, Center for Cardiovascular Diagnostics and Prevention, and.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Wagner
authors.affiliation: the Department of Genetics, Nutrition Research Institute, University of North Carolina, Chapel Hill, North Carolina 28081.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bennett
authors.affiliation: From the Department of Cellular and Molecular Medicine, Center for Cardiovascular Diagnostics and Prevention, and.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: From the Department of Cellular and Molecular Medicine, Center for Cardiovascular Diagnostics and Prevention, and.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: DiDonato
authors.affiliation: the Departments of Human Genetics and Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, 90095, and.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.affiliation: From the Department of Cellular and Molecular Medicine, Center for Cardiovascular Diagnostics and Prevention, and Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195, hazens@ccf.org.
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology / Q000382:microbiology*; D002432:Cecum / Q000382:microbiology*; D002794:Choline / Q000008:administration & dosage; D004032:Diet / Q000009:adverse effects; D004198:Disease Susceptibility / Q000097:blood / Q000150:complications / Q000382:microbiology*; D005260:Female; D041981:Gastrointestinal Tract / Q000382:microbiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D008297:Male; D008744:Methylamines / Q000097:blood / Q000378:metabolism; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008822:Mice, Transgenic; D064307:Microbiota / Q000502:physiology*; D013045:Species Specificity
chemical_list: D008744:Methylamines; C005855:trimethyloxamine; C023336:trimethylamine; D002794:Choline
keywords: Atherosclerosis; Choline; Dyslipidemia; Gut Microbiota; Koch's Postulate; Lipid; Nutrition; Phospholipid; Trimethylamine N-Oxide (TMAO)