title: Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis.
abstract: Intestinal microbiota metabolism of choline and phosphatidylcholine produces trimethylamine (TMA), which is further metabolized to a proatherogenic species, trimethylamine-N-oxide (TMAO). We demonstrate here that metabolism by intestinal microbiota of dietary L-carnitine, a trimethylamine abundant in red meat, also produces TMAO and accelerates atherosclerosis in mice. Omnivorous human subjects produced more TMAO than did vegans or vegetarians following ingestion of L-carnitine through a microbiota-dependent mechanism. The presence of specific bacterial taxa in human feces was associated with both plasma TMAO concentration and dietary status. Plasma L-carnitine levels in subjects undergoing cardiac evaluation (n = 2,595) predicted increased risks for both prevalent cardiovascular disease (CVD) and incident major adverse cardiac events (myocardial infarction, stroke or death), but only among subjects with concurrently high TMAO levels. Chronic dietary L-carnitine supplementation in mice altered cecal microbial composition, markedly enhanced synthesis of TMA and TMAO, and increased atherosclerosis, but this did not occur if intestinal microbiota was concurrently suppressed. In mice with an intact intestinal microbiota, dietary supplementation with TMAO or either carnitine or choline reduced in vivo reverse cholesterol transport. Intestinal microbiota may thus contribute to the well-established link between high levels of red meat consumption and CVD risk.
authors.affiliation: Department of Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Koeth
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Wang
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Levison
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Buffa
authors.forename: Elin
authors.initials: E
authors.lastname: Org
authors.forename: Brendan T
authors.initials: BT
authors.lastname: Sheehy
authors.forename: Earl B
authors.initials: EB
authors.lastname: Britt
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Fu
authors.forename: Yuping
authors.initials: Y
authors.lastname: Wu
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Smith
authors.forename: Joseph A
authors.initials: JA
authors.lastname: DiDonato
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Hongzhe
authors.initials: H
authors.lastname: Li
authors.forename: Gary D
authors.initials: GD
authors.lastname: Wu
authors.forename: James D
authors.initials: JD
authors.lastname: Lewis
authors.forename: Manya
authors.initials: M
authors.lastname: Warrier
authors.forename: J Mark
authors.initials: JM
authors.lastname: Brown
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Krauss
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
authors.forename: Frederic D
authors.initials: FD
authors.lastname: Bushman
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000209:etiology* / Q000382:microbiology / Q000503:physiopathology; D002331:Carnitine / Q000737:chemistry / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D002794:Choline / Q000737:chemistry; D003897:Desmosterol / Q000378:metabolism; D005260:Female; D006801:Humans; D007422:Intestines / Q000382:microbiology*; D008264:Macrophages / Q000378:metabolism; D013058:Mass Spectrometry; D008460:Meat; D054892:Metagenome; D008744:Methylamines / Q000097:blood / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012313:RNA / Q000378:metabolism; D013997:Time Factors
chemical_list: D008744:Methylamines; D003897:Desmosterol; D012313:RNA; D002784:Cholesterol; C005855:trimethyloxamine; D002794:Choline; D002331:Carnitine
references.citation: Am J Clin Nutr. 1999 Sep;70(3 Suppl):516S-524S
references.pmid: 10479225
references.citation: Am J Epidemiol. 1989 Apr;129(4):687-702
references.pmid: 2646917
references.citation: Science. 2008 Jun 20;320(5883):1647-51
references.pmid: 18497261
references.citation: Arch Microbiol. 1986 Jun;145(1):85-90
references.pmid: 3753143
references.citation: Arterioscler Thromb Vasc Biol. 2002 Jan;22(1):121-6
references.pmid: 11788471
references.citation: N Engl J Med. 2018 Jun 21;378(25):2441-2442
references.pmid: 29897867
references.citation: Eur J Clin Nutr. 2012 Jan;66(1):53-60
references.pmid: 21811294
references.citation: Am J Cardiol. 2003 Aug 18;92(4A):42J-49J
references.pmid: 12957326
references.citation: J Pharmacol Toxicol Methods. 1998 Jul;40(1):39-45
references.pmid: 9920533
references.citation: J Nutr. 1991 Apr;121(4):539-46
references.pmid: 2007906
references.citation: Bioinformatics. 2012 Aug 15;28(16):2106-13
references.pmid: 22711789
references.citation: Nature. 1997 Mar 20;386(6622):292-6
references.pmid: 9069289
references.citation: Meat Sci. 2008 Mar;78(3):331-5
references.pmid: 22062286
references.citation: Arterioscler Thromb Vasc Biol. 2003 May 1;23(5):892-7
references.pmid: 12649089
references.citation: Am J Clin Nutr. 2010 Mar;91(3):535-46
references.pmid: 20071648
references.citation: Annu Rev Nutr. 1998;18:39-61
references.pmid: 9706218
references.citation: Nature. 2006 Dec 21;444(7122):1027-31
references.pmid: 17183312
references.citation: Circulation. 2010 Aug 31;122(9):876-83
references.pmid: 20713902
references.citation: Exp Biol Med (Maywood). 2012 Feb;237(2):194-200
references.pmid: 22302708
references.citation: Cell. 2012 Sep 28;151(1):138-52
references.pmid: 23021221
references.citation: Biosens Bioelectron. 2009 Dec 15;25(4):715-20
references.pmid: 19734032
references.citation: Vasc Health Risk Manag. 2011;7:169-76
references.pmid: 21490942
references.citation: Science. 2011 May 20;332(6032):970-4
references.pmid: 21596990
references.citation: Circulation. 2010 Jun 1;121(21):2271-83
references.pmid: 20479151
references.citation: Science. 2011 Oct 7;334(6052):105-8
references.pmid: 21885731
references.citation: Nature. 2006 Aug 10;442(7103):645-50
references.pmid: 16878137
references.citation: Science. 2004 Feb 20;303(5661):1201-4
references.pmid: 14976318
references.citation: Cell. 1997 May 2;89(3):331-40
references.pmid: 9150132
references.citation: Ann Nutr Metab. 2009;54(4):253-7
references.pmid: 19641302
references.citation: Nature. 2009 Jan 22;457(7228):480-4
references.pmid: 19043404
references.citation: Annu Rev Physiol. 2011;73:239-59
references.pmid: 20809793
references.citation: J Lipid Res. 1998 Sep;39(9):1833-43
references.pmid: 9741696
references.citation: Physiol Rev. 1983 Oct;63(4):1420-80
references.pmid: 6361812
references.citation: N Engl J Med. 2010 Feb 18;362(7):590-9
references.pmid: 20089957
references.citation: Am J Clin Nutr. 2005 Feb;81(2):341-54
references.pmid: 15699220
references.citation: Am J Clin Nutr. 2009 May;89(5):1607S-1612S
references.pmid: 19321569
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):11070-5
references.pmid: 16033867
references.citation: Cell. 2004 Jul 23;118(2):229-41
references.pmid: 15260992
references.citation: J Clin Invest. 2000 Apr;105(8):1049-56
references.pmid: 10772649
references.citation: Biochemistry. 1984 Dec 18;23(26):6422-6
references.pmid: 6529558
references.citation: Cell Metab. 2010 Aug 4;12(2):111-6
references.pmid: 20674856
references.citation: FEMS Microbiol Lett. 1999 May 15;174(2):295-301
references.pmid: 10339822
references.citation: J Biol Chem. 2000 Dec 15;275(50):39685-92
references.pmid: 11001949
references.citation: Nature. 2011 Apr 7;472(7341):57-63
references.pmid: 21475195
references.citation: J Med. 1998;29(3-4):125-36
references.pmid: 9865454
references.citation: Int J Vasc Med. 2012;2012:949672
references.pmid: 21918722
references.citation: Food Chem Toxicol. 1999 May;37(5):515-20
references.pmid: 10456680
references.citation: J Nutr. 2003 May;133(5):1302-7
references.pmid: 12730414
references.citation: Semin Dial. 2006 Jul-Aug;19(4):323-8
references.pmid: 16893411
references.citation: Science. 1974 Jul 5;185(4145):61-3
references.pmid: 4366052
references.citation: Protein Sci. 2003 Jul;12(7):1522-9
references.pmid: 12824497
references.citation: Science. 2005 Jun 10;308(5728):1635-8
references.pmid: 15831718
references.citation: Atherosclerosis. 2010 May;210(1):14-27
references.pmid: 19932478
references.citation: Mutat Res. 1990 Nov;239(3):163-79
references.pmid: 2233824
references.citation: Ann N Y Acad Sci. 2004 Nov;1033:42-51
references.pmid: 15591002
references.citation: FEMS Microbiol Lett. 1997 Feb 1;147(1):1-9
references.pmid: 9037756