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N a t u r e A m e r i c a , I n c . A l l r i g h t s r e s e r v e d .
advance online publication
The high eve of meat consumption in the deveoped word is inked toCVD risk, presumaby owing to the arge content of saturated fats andchoestero in meat
. However, a recent meta-anaysis of prospectivecohort studies showed no association between dietary saturated fat intakeand CVD, prompting the suggestion that other environmenta exposuresinked to increased meat consumption are responsibe
. In fact, the sus-picion that the choestero and saturated fat content of red meat may not be sufficienty high enough to account for the observed associationbetween CVD and meat consumption has stimuated investigation of aternative disease-promoting exposures that accompany dietary meatingestion, such as high sat content or heterocycic compounds gener-ated during cooking
. To our knowedge, no studies have yet exporedthe participation of commensa intestina microbiota in modifying thediet-host interaction with reference to red meat consumption.The microbiota of humans has been inked to intestina heath,immune function, bioactivation of nutrients and vitamins, and, morerecenty, compex disease phenotypes such as obesity and insuin resist-ance
. We recenty reported a pathway in both humans and mice ink-ing microbiota metaboism of dietary choine and phosphatidychoineto CVD pathogenesis
. Choine, a trimethyamine-containing com-pound and part of the head group of phosphatidychoine, is metabo-ized by gut microbiota to produce an intermediate compound knownas TMA (
). TMA is rapidy further oxidized by hepatic favinmonooxygenases to form TMAO, which is proatherogenic and associ-ated with cardiovascuar risks. These findings raise the possibiity thatother dietary nutrients possessing a trimethyamine structure may aso generate TMAO from gut microbiota and promote acceeratedatheroscerosis. TMAO has been proposed to induce upreguation of macrophage scavenger receptors and thereby potentiay contributeto enhanced “forward choestero transport.”
. Whether TMAO isinked to the deveopment of acceerated atheroscerosis through addi-tiona mechanisms, and which specific microbia species contributeto TMAO formation, have not been fuy carified.l-carnitine is an abundant nutrient in red meat and containsa trimethyamine structure simiar to that of choine (
).Athough dietary ingestion is a major source of l-carnitine in omni- vores, it is aso endogenousy produced in mammas from ysineand serves an essentia function in transporting fatty acids into the
Department o Cellular & Molecular Medicine, Cleveland Clinic, Cleveland, Ohio, USA.
Center or Cardiovascular Diagnostics & Prevention, Cleveland Clinic,Cleveland, Ohio, USA.
Department o Medicine, Division o Cardiology, David Geen School o Medicine, University o Caliornia–Los Angeles, Los Angeles,Caliornia, USA.
Department o Mathematics, Cleveland State University, Cleveland, Ohio, USA.
Department o Cardiovascular Medicine, Cleveland Clinic,Cleveland, Ohio, USA.
Department o Microbiology, Center or Clinical Epidemiology and Biostatistics, Perelman School o Medicine at the University o Pennsylvania,Philadelphia, Pennsylvania, USA.
Division o Gastroenterology, Perelman School o Medicine at the University o Pennsylvania, Philadelphia, Pennsylvania, USA.
Department o Medicine, Perelman School o Medicine at the University o Pennsylvania, Philadelphia, Pennsylvania, USA.
Department o Pathology,Section on Lipid Sciences, Wake Forest School o Medicine, Winston-Salem, North Carolina, USA.
Children’s Hospital Oakland Research Institute, Oakland,Caliornia, USA. Correspondence should be addressed to S.L.H. (email@example.com).Received 7 December 2012; accepted 27 February 2013; published online 7 April 2013;doi:10.1038/nm.3145
Intestina microbiota metaboism of l-carnitine,a nutrient in red meat, promotes atheroscerosis
Robert A Koeth
, Zeeg Wag
, Bruce S Leviso
, Jeifer A Buffa
, Eli Org
, Breda T Sheehy
,Earl B Britt
, Xiaomig Fu
, Yupig Wu
, Li Li
, Joatha D Smith
, Joseph A DiDoato
, Ju Che
, Gary D Wu
, James D Lewis
, Maya Warrier
, J Mark Brow
, Roald M Krauss
,W H Wilso Tag
, Frederic D Bushma
, Aldos J Lusis
& Staley L Haze
Intestinal microbiota metabolism of choline and phosphatidylcholine produces trimethylamine (TMA), which is furthermetabolized to a proatherogenic species, trimethylamine-
-oxide (TMAO). We demonstrate here that metabolism by intestinalmicrobiota of dietary
-carnitine, a trimethylamine abundant in red meat, also produces TMAO and accelerates atherosclerosisin mice. Omnivorous human subjects produced more TMAO than did vegans or vegetarians following ingestion of
-carnitinethrough a microbiota-dependent mechanism. The presence of specific bacterial taxa in human feces was associated withboth plasma TMAO concentration and dietary status. Plasma
-carnitine levels in subjects undergoing cardiac evaluation(
= 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
-carnitinesupplementation in mice altered cecal microbial composition, markedly enhanced synthesis of TMA and TMAO, and increasedatherosclerosis, but this did not occur if intestinal microbiota was concurrently suppressed. In mice with an intact intestinalmicrobiota, dietary supplementation with TMAO or either carnitine or choline reduced
reverse cholesterol transport.Intestinal microbiota may thus contribute to the well-established link between high levels of red meat consumption and CVD risk.