title: High-Fiber Diet and Acetate Supplementation Change the Gut Microbiota and Prevent the Development of Hypertension and Heart Failure in Hypertensive Mice.
abstract: BACKGROUND
  Dietary intake of fruit and vegetables is associated with lower incidence of hypertension, but the mechanisms involved have not been elucidated. Here, we evaluated the effect of a high-fiber diet and supplementation with the short-chain fatty acid acetate on the gut microbiota and the prevention of cardiovascular disease.
  
  
  METHODS
  Gut microbiome, cardiorenal structure/function, and blood pressure were examined in sham and mineralocorticoid excess-treated mice with a control diet, high-fiber diet, or acetate supplementation. We also determined the renal and cardiac transcriptome of mice treated with the different diets.
  
  
  RESULTS
  We found that high consumption of fiber modified the gut microbiota populations and increased the abundance of acetate-producing bacteria independently of mineralocorticoid excess. Both fiber and acetate decreased gut dysbiosis, measured by the ratio of Firmicutes to Bacteroidetes, and increased the prevalence ofBacteroides acidifaciens. Compared with mineralocorticoid-excess mice fed a control diet, both high-fiber diet and acetate supplementation significantly reduced systolic and diastolic blood pressures, cardiac fibrosis, and left ventricular hypertrophy. Acetate had similar effects and markedly reduced renal fibrosis. Transcriptome analyses showed that the protective effects of high fiber and acetate were accompanied by the downregulation of cardiac and renalEgr1, a master cardiovascular regulator involved in cardiac hypertrophy, cardiorenal fibrosis, and inflammation. We also observed the upregulation of a network of genes involved in circadian rhythm in both tissues and downregulation of the renin-angiotensin system in the kidney and mitogen-activated protein kinase signaling in the heart.
  
  
  CONCLUSIONS
  A diet high in fiber led to changes in the gut microbiota that played a protective role in the development of cardiovascular disease. The favorable effects of fiber may be explained by the generation and distribution of one of the main metabolites of the gut microbiota, the short-chain fatty acid acetate. Acetate effected several molecular changes associated with improved cardiovascular health and function.
authors.affiliation: From Heart Failure Research Group (F.Z.M., E.N., P.-Y.C., D.H., A.F., N.W.R., D.M.K.) and Human Epigenetics Group (M.Z., A.E.-O.), Baker Heart and Diabetes Institute, Melbourne, Australia; Central Clinical School, Faculty of Medicine Nursing and Health Sciences (F.Z.M., A.E.-O., D.M.K.), Infection and Immunity Program, Monash Biomedicine Discovery Institute (J.K.T., C.R.M.), Department of Biochemistry and Molecular Biology (J.K.T., S.K., C.R.M.), and Department of Physiology (N.W.R.), Monash University, Melbourne, Australia; Department of Pathology, University of Melbourne, Australia (A.E.-O.); and Institute the Heart Centre, Alfred Hospital, Melbourne, Australia (D.M.K.). david.kaye@baker.edu.au francine.marques@baker.edu.au.
authors.forename: Francine Z
authors.initials: FZ
authors.lastname: Marques
authors.affiliation: From Heart Failure Research Group (F.Z.M., E.N., P.-Y.C., D.H., A.F., N.W.R., D.M.K.) and Human Epigenetics Group (M.Z., A.E.-O.), Baker Heart and Diabetes Institute, Melbourne, Australia; Central Clinical School, Faculty of Medicine Nursing and Health Sciences (F.Z.M., A.E.-O., D.M.K.), Infection and Immunity Program, Monash Biomedicine Discovery Institute (J.K.T., C.R.M.), Department of Biochemistry and Molecular Biology (J.K.T., S.K., C.R.M.), and Department of Physiology (N.W.R.), Monash University, Melbourne, Australia; Department of Pathology, University of Melbourne, Australia (A.E.-O.); and Institute the Heart Centre, Alfred Hospital, Melbourne, Australia (D.M.K.).
authors.forename: Erin
authors.initials: E
authors.lastname: Nelson
authors.affiliation: From Heart Failure Research Group (F.Z.M., E.N., P.-Y.C., D.H., A.F., N.W.R., D.M.K.) and Human Epigenetics Group (M.Z., A.E.-O.), Baker Heart and Diabetes Institute, Melbourne, Australia; Central Clinical School, Faculty of Medicine Nursing and Health Sciences (F.Z.M., A.E.-O., D.M.K.), Infection and Immunity Program, Monash Biomedicine Discovery Institute (J.K.T., C.R.M.), Department of Biochemistry and Molecular Biology (J.K.T., S.K., C.R.M.), and Department of Physiology (N.W.R.), Monash University, Melbourne, Australia; Department of Pathology, University of Melbourne, Australia (A.E.-O.); and Institute the Heart Centre, Alfred Hospital, Melbourne, Australia (D.M.K.).
authors.forename: Po-Yin
authors.initials: PY
authors.lastname: Chu
authors.affiliation: From Heart Failure Research Group (F.Z.M., E.N., P.-Y.C., D.H., A.F., N.W.R., D.M.K.) and Human Epigenetics Group (M.Z., A.E.-O.), Baker Heart and Diabetes Institute, Melbourne, Australia; Central Clinical School, Faculty of Medicine Nursing and Health Sciences (F.Z.M., A.E.-O., D.M.K.), Infection and Immunity Program, Monash Biomedicine Discovery Institute (J.K.T., C.R.M.), Department of Biochemistry and Molecular Biology (J.K.T., S.K., C.R.M.), and Department of Physiology (N.W.R.), Monash University, Melbourne, Australia; Department of Pathology, University of Melbourne, Australia (A.E.-O.); and Institute the Heart Centre, Alfred Hospital, Melbourne, Australia (D.M.K.).
authors.forename: Duncan
authors.initials: D
authors.lastname: Horlock
authors.affiliation: From Heart Failure Research Group (F.Z.M., E.N., P.-Y.C., D.H., A.F., N.W.R., D.M.K.) and Human Epigenetics Group (M.Z., A.E.-O.), Baker Heart and Diabetes Institute, Melbourne, Australia; Central Clinical School, Faculty of Medicine Nursing and Health Sciences (F.Z.M., A.E.-O., D.M.K.), Infection and Immunity Program, Monash Biomedicine Discovery Institute (J.K.T., C.R.M.), Department of Biochemistry and Molecular Biology (J.K.T., S.K., C.R.M.), and Department of Physiology (N.W.R.), Monash University, Melbourne, Australia; Department of Pathology, University of Melbourne, Australia (A.E.-O.); and Institute the Heart Centre, Alfred Hospital, Melbourne, Australia (D.M.K.).
authors.forename: April
authors.initials: A
authors.lastname: Fiedler
authors.affiliation: From Heart Failure Research Group (F.Z.M., E.N., P.-Y.C., D.H., A.F., N.W.R., D.M.K.) and Human Epigenetics Group (M.Z., A.E.-O.), Baker Heart and Diabetes Institute, Melbourne, Australia; Central Clinical School, Faculty of Medicine Nursing and Health Sciences (F.Z.M., A.E.-O., D.M.K.), Infection and Immunity Program, Monash Biomedicine Discovery Institute (J.K.T., C.R.M.), Department of Biochemistry and Molecular Biology (J.K.T., S.K., C.R.M.), and Department of Physiology (N.W.R.), Monash University, Melbourne, Australia; Department of Pathology, University of Melbourne, Australia (A.E.-O.); and Institute the Heart Centre, Alfred Hospital, Melbourne, Australia (D.M.K.).
authors.forename: Mark
authors.initials: M
authors.lastname: Ziemann
authors.affiliation: From Heart Failure Research Group (F.Z.M., E.N., P.-Y.C., D.H., A.F., N.W.R., D.M.K.) and Human Epigenetics Group (M.Z., A.E.-O.), Baker Heart and Diabetes Institute, Melbourne, Australia; Central Clinical School, Faculty of Medicine Nursing and Health Sciences (F.Z.M., A.E.-O., D.M.K.), Infection and Immunity Program, Monash Biomedicine Discovery Institute (J.K.T., C.R.M.), Department of Biochemistry and Molecular Biology (J.K.T., S.K., C.R.M.), and Department of Physiology (N.W.R.), Monash University, Melbourne, Australia; Department of Pathology, University of Melbourne, Australia (A.E.-O.); and Institute the Heart Centre, Alfred Hospital, Melbourne, Australia (D.M.K.).
authors.forename: Jian K
authors.initials: JK
authors.lastname: Tan
authors.affiliation: From Heart Failure Research Group (F.Z.M., E.N., P.-Y.C., D.H., A.F., N.W.R., D.M.K.) and Human Epigenetics Group (M.Z., A.E.-O.), Baker Heart and Diabetes Institute, Melbourne, Australia; Central Clinical School, Faculty of Medicine Nursing and Health Sciences (F.Z.M., A.E.-O., D.M.K.), Infection and Immunity Program, Monash Biomedicine Discovery Institute (J.K.T., C.R.M.), Department of Biochemistry and Molecular Biology (J.K.T., S.K., C.R.M.), and Department of Physiology (N.W.R.), Monash University, Melbourne, Australia; Department of Pathology, University of Melbourne, Australia (A.E.-O.); and Institute the Heart Centre, Alfred Hospital, Melbourne, Australia (D.M.K.).
authors.forename: Sanjaya
authors.initials: S
authors.lastname: Kuruppu
authors.affiliation: From Heart Failure Research Group (F.Z.M., E.N., P.-Y.C., D.H., A.F., N.W.R., D.M.K.) and Human Epigenetics Group (M.Z., A.E.-O.), Baker Heart and Diabetes Institute, Melbourne, Australia; Central Clinical School, Faculty of Medicine Nursing and Health Sciences (F.Z.M., A.E.-O., D.M.K.), Infection and Immunity Program, Monash Biomedicine Discovery Institute (J.K.T., C.R.M.), Department of Biochemistry and Molecular Biology (J.K.T., S.K., C.R.M.), and Department of Physiology (N.W.R.), Monash University, Melbourne, Australia; Department of Pathology, University of Melbourne, Australia (A.E.-O.); and Institute the Heart Centre, Alfred Hospital, Melbourne, Australia (D.M.K.).
authors.forename: Niwanthi W
authors.initials: NW
authors.lastname: Rajapakse
authors.affiliation: From Heart Failure Research Group (F.Z.M., E.N., P.-Y.C., D.H., A.F., N.W.R., D.M.K.) and Human Epigenetics Group (M.Z., A.E.-O.), Baker Heart and Diabetes Institute, Melbourne, Australia; Central Clinical School, Faculty of Medicine Nursing and Health Sciences (F.Z.M., A.E.-O., D.M.K.), Infection and Immunity Program, Monash Biomedicine Discovery Institute (J.K.T., C.R.M.), Department of Biochemistry and Molecular Biology (J.K.T., S.K., C.R.M.), and Department of Physiology (N.W.R.), Monash University, Melbourne, Australia; Department of Pathology, University of Melbourne, Australia (A.E.-O.); and Institute the Heart Centre, Alfred Hospital, Melbourne, Australia (D.M.K.).
authors.forename: Assam
authors.initials: A
authors.lastname: El-Osta
authors.affiliation: From Heart Failure Research Group (F.Z.M., E.N., P.-Y.C., D.H., A.F., N.W.R., D.M.K.) and Human Epigenetics Group (M.Z., A.E.-O.), Baker Heart and Diabetes Institute, Melbourne, Australia; Central Clinical School, Faculty of Medicine Nursing and Health Sciences (F.Z.M., A.E.-O., D.M.K.), Infection and Immunity Program, Monash Biomedicine Discovery Institute (J.K.T., C.R.M.), Department of Biochemistry and Molecular Biology (J.K.T., S.K., C.R.M.), and Department of Physiology (N.W.R.), Monash University, Melbourne, Australia; Department of Pathology, University of Melbourne, Australia (A.E.-O.); and Institute the Heart Centre, Alfred Hospital, Melbourne, Australia (D.M.K.).
authors.forename: Charles R
authors.initials: CR
authors.lastname: Mackay
authors.affiliation: From Heart Failure Research Group (F.Z.M., E.N., P.-Y.C., D.H., A.F., N.W.R., D.M.K.) and Human Epigenetics Group (M.Z., A.E.-O.), Baker Heart and Diabetes Institute, Melbourne, Australia; Central Clinical School, Faculty of Medicine Nursing and Health Sciences (F.Z.M., A.E.-O., D.M.K.), Infection and Immunity Program, Monash Biomedicine Discovery Institute (J.K.T., C.R.M.), Department of Biochemistry and Molecular Biology (J.K.T., S.K., C.R.M.), and Department of Physiology (N.W.R.), Monash University, Melbourne, Australia; Department of Pathology, University of Melbourne, Australia (A.E.-O.); and Institute the Heart Centre, Alfred Hospital, Melbourne, Australia (D.M.K.). david.kaye@baker.edu.au francine.marques@baker.edu.au.
authors.forename: David M
authors.initials: DM
authors.lastname: Kaye
mesh_terms: D000818:Animals; D001419:Bacteria / Q000235:genetics / Q000302:isolation & purification; D001794:Blood Pressure / Q000187:drug effects; D064791:Desoxycorticosterone Acetate / Q000494:pharmacology* / Q000627:therapeutic use; D004043:Dietary Fiber / Q000494:pharmacology* / Q000627:therapeutic use; D019587:Dietary Supplements; D004195:Disease Models, Animal; D005355:Fibrosis; D000069196:Gastrointestinal Microbiome / Q000187:drug effects*; D041981:Gastrointestinal Tract / Q000382:microbiology; D006973:Hypertension / Q000473:pathology / Q000517:prevention & control* / Q000662:veterinary; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D025341:Principal Component Analysis; D012336:RNA, Ribosomal, 16S / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects
chemical_list: D004043:Dietary Fiber; D012336:RNA, Ribosomal, 16S; D064791:Desoxycorticosterone Acetate
keywords: blood pressure; diet; fibrosis; gut microbiome; gut microbiota; heart failure; hypertension