title: Choline Diet and Its Gut Microbe-Derived Metabolite, Trimethylamine N-Oxide, Exacerbate Pressure Overload-Induced Heart Failure.
abstract: BACKGROUND
  Trimethylamine N-oxide (TMAO), a gut microbe-dependent metabolite of dietary choline and other trimethylamine-containing nutrients, is both elevated in the circulation of patients having heart failure and heralds worse overall prognosis. In animal studies, dietary choline or TMAO significantly accelerates atherosclerotic lesion development in ApoE-deficient mice, and reduction in TMAO levels inhibits atherosclerosis development in the low-density lipoprotein receptor knockout mouse.
  
  
  RESULTS
  C57BL6/J mice were fed either a control diet, a diet containing choline (1.2%) or a diet containing TMAO (0.12%) starting 3 weeks before surgical transverse aortic constriction. Mice were studied for 12 weeks after transverse aortic constriction. Cardiac function and left ventricular structure were monitored at 3-week intervals using echocardiography. Twelve weeks post transverse aortic constriction, myocardial tissues were collected to evaluate cardiac and vascular fibrosis, and blood samples were evaluated for cardiac brain natriuretic peptide, choline, and TMAO levels. Pulmonary edema, cardiac enlargement, and left ventricular ejection fraction were significantly (P<0.05, each) worse in mice fed either TMAO- or choline-supplemented diets when compared with the control diet. In addition, myocardial fibrosis was also significantly greater (P<0.01, each) in the TMAO and choline groups relative to controls.
  
  
  CONCLUSIONS
  Heart failure severity is significantly enhanced in mice fed diets supplemented with either choline or the gut microbe-dependent metabolite TMAO. The present results suggest that additional studies are warranted examining whether gut microbiota and the dietary choline → TMAO pathway contribute to increased heart failure susceptibility.
authors.affiliation: From the Department of Pharmacology, Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans (C.L.O., H.O., S.B., J.B., R.T., D.J.P., D.J.L.); Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, OH (Z.W., W.H.W.T., S.L.H.); and Department of Mathematics, Cleveland State University, OH (Y.W.).
authors.forename: Chelsea L
authors.initials: CL
authors.lastname: Organ
authors.affiliation: From the Department of Pharmacology, Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans (C.L.O., H.O., S.B., J.B., R.T., D.J.P., D.J.L.); Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, OH (Z.W., W.H.W.T., S.L.H.); and Department of Mathematics, Cleveland State University, OH (Y.W.).
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Otsuka
authors.forename: Shashi
authors.initials: S
authors.lastname: Bhushan
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Wang
authors.forename: Jessica
authors.initials: J
authors.lastname: Bradley
authors.forename: Rishi
authors.initials: R
authors.lastname: Trivedi
authors.forename: David J
authors.initials: DJ
authors.lastname: Polhemus
authors.forename: W H Wilson
authors.initials: WH
authors.lastname: Tang
authors.forename: Yuping
authors.initials: Y
authors.lastname: Wu
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.forename: David J
authors.initials: DJ
authors.lastname: Lefer
mesh_terms: D000818:Animals; D001419:Bacteria / Q000378:metabolism*; D006332:Cardiomegaly / Q000097:blood / Q000139:chemically induced / Q000473:pathology; D002794:Choline / Q000378:metabolism / Q000633:toxicity*; D004032:Diet / Q000009:adverse effects*; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis; D006333:Heart Failure / Q000097:blood / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D007422:Intestines / Q000382:microbiology*; D008297:Male; D008744:Methylamines / Q000097:blood / Q000633:toxicity*; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011654:Pulmonary Edema / Q000097:blood / Q000139:chemically induced; D012307:Risk Factors; D012720:Severity of Illness Index; D013318:Stroke Volume; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology; D016277:Ventricular Function, Left
chemical_list: D008744:Methylamines; C005855:trimethyloxamine; D002794:Choline
keywords: choline; fibrosis; left; metabolomics; pulmonary edema; ventricular dysfunction