title: Microbiome and metabolome modifying effects of several cardiovascular disease interventions in apo-E-/-mice.
abstract: There is strong evidence indicating that gut microbiota have the potential to modify, or be modified by the drugs and nutritional interventions that we rely upon. This study aims to characterize the compositional and functional effects of several nutritional, neutraceutical, and pharmaceutical cardiovascular disease interventions on the gut microbiome, through metagenomic and metabolomic approaches. Apolipoprotein-E-deficient mice were fed for 24 weeks either high-fat/cholesterol diet alone (control, HFC) or high-fat/cholesterol in conjunction with one of three dietary interventions, as follows: plant sterol ester (PSE), oat β-glucan (OBG) and bile salt hydrolase-active Lactobacillus reuteri APC 2587 (BSH), or the drug atorvastatin (STAT). The gut microbiome composition was then investigated, in addition to the host fecal and serum metabolome.
  
  
  
  We observed major shifts in the composition of the gut microbiome of PSE mice, while OBG and BSH mice displayed more modest fluctuations, and STAT showed relatively few alterations. Interestingly, these compositional effects imparted by PSE were coupled with an increase in acetate and reduction in isovalerate (p < 0.05), while OBG promoted n-butyrate synthesis (p < 0.01). In addition, PSE significantly dampened the microbial production of the proatherogenic precursor compound, trimethylamine (p < 0.05), attenuated cholesterol accumulation, and nearly abolished atherogenesis in the model (p < 0.05). However, PSE supplementation produced the heaviest mice with the greatest degree of adiposity (p < 0.05). Finally, PSE, OBG, and STAT all appeared to have considerable impact on the host serum metabolome, including alterations in several acylcarnitines previously associated with a state of metabolic dysfunction (p < 0.05).
  
  
  
  We observed functional alterations in microbial and host-derived metabolites, which may have important implications for systemic metabolic health, suggesting that cardiovascular disease interventions may have a significant impact on the microbiome composition and functionality. This study indicates that the gut microbiome-modifying effects of novel therapeutics should be considered, in addition to the direct host effects.
authors.affiliation: Department of Food Biosciences, Teagasc Food Research Centre, Moorepark, Fermoy, Co. Cork, Ireland.|School of Microbiology, University College Cork, Co. Cork, Ireland.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Ryan
authors.affiliation: Department of Food Biosciences, Teagasc Food Research Centre, Moorepark, Fermoy, Co. Cork, Ireland.
authors.forename: Lis E E
authors.initials: LE
authors.lastname: London
authors.affiliation: Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada.
authors.forename: Trent C
authors.initials: TC
authors.lastname: Bjorndahl
authors.affiliation: Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada.
authors.forename: Rupasri
authors.initials: R
authors.lastname: Mandal
authors.affiliation: Department of Food Biosciences, Teagasc Food Research Centre, Moorepark, Fermoy, Co. Cork, Ireland.
authors.forename: Kiera
authors.initials: K
authors.lastname: Murphy
authors.affiliation: School of Microbiology, University College Cork, Co. Cork, Ireland.|APC Microbiome Institute, Biosciences Institute, University College Cork, Co. Cork, Ireland.
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Fitzgerald
authors.affiliation: Department of Medicine, University College Cork, National University of Ireland, Cork, Ireland.|APC Microbiome Institute, Biosciences Institute, University College Cork, Co. Cork, Ireland.
authors.forename: Fergus
authors.initials: F
authors.lastname: Shanahan
authors.affiliation: APC Microbiome Institute, Biosciences Institute, University College Cork, Co. Cork, Ireland.|College of Science, Engineering & Food Science, University College Cork, Co. Cork, Ireland.
authors.forename: R Paul
authors.initials: RP
authors.lastname: Ross
authors.affiliation: Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada.|Department of Computing Science, University of Alberta, Edmonton, AB, Canada.|National Institute for Nanotechnology, Edmonton, AB, Canada.
authors.forename: David S
authors.initials: DS
authors.lastname: Wishart
authors.affiliation: Centre for Research in Vascular Biology, University College Cork, Co. Cork, Ireland.
authors.forename: Noel M
authors.initials: NM
authors.lastname: Caplice
authors.affiliation: Department of Food Biosciences, Teagasc Food Research Centre, Moorepark, Fermoy, Co. Cork, Ireland. Catherine.Stanton@teagasc.ie.|APC Microbiome Institute, Biosciences Institute, University College Cork, Co. Cork, Ireland. Catherine.Stanton@teagasc.ie.
authors.forename: Catherine
authors.initials: C
authors.lastname: Stanton
mesh_terms: D000085:Acetates / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis; D000069059:Atorvastatin / Q000008:administration & dosage; D002087:Butyrates / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000188:drug therapy; D002331:Carnitine / Q000031:analogs & derivatives / Q000097:blood; D002784:Cholesterol / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D059305:Diet, High-Fat; D019587:Dietary Supplements; D005243:Feces / Q000382:microbiology*; D000069196:Gastrointestinal Microbiome; D045782:Hemiterpenes; D052200:Limosilactobacillus reuteri; D008297:Male; D055442:Metabolome; D051379:Mice; D009765:Obesity; D010421:Pentanoic Acids / Q000378:metabolism; D019936:Probiotics; D047071:beta-Glucans / Q000008:administration & dosage
chemical_list: D000085:Acetates; D001057:Apolipoproteins E; D002087:Butyrates; D002791:Cholesterol, Dietary; D045782:Hemiterpenes; D010421:Pentanoic Acids; C116917:acylcarnitine; D047071:beta-Glucans; C008216:isovaleric acid; C067858:beta-glucan, (1-3)(1-4)-; D002784:Cholesterol; D000069059:Atorvastatin; D002331:Carnitine
keywords: Apo-E-deficient; Atherosclerosis; Cardiovascular disease; Metabolome; Microbiome