title: Modulating the Gut Microbiota Improves Glucose Tolerance, Lipoprotein Profile and Atherosclerotic Plaque Development in ApoE-Deficient Mice.
abstract: The importance of the gut microbiota (GM) in disease development has recently received increased attention, and numerous approaches have been made to better understand this important interplay. For example, metabolites derived from the GM have been shown to promote atherosclerosis, the underlying cause of cardiovascular disease (CVD), and to increase CVD risk factors. Popular interest in the role of the intestine in a variety of disease states has now resulted in a significant proportion of individuals without coeliac disease switching to gluten-free diets. The effect of gluten-free diets on atherosclerosis and cardiovascular risk factors is largely unknown. We therefore investigated the effect of a gluten-free high-fat cholesterol-rich diet, as compared to the same diet in which the gluten peptide gliadin had been added back, on atherosclerosis and several cardiovascular risk factors in apolipoprotein E-deficient (Apoe-/-) mice. The gluten-free diet transiently altered GM composition in these mice, as compared to the gliadin-supplemented diet, but did not alter body weights, glucose tolerance, insulin levels, plasma lipids, or atherosclerosis. In parallel, other Apoe-/- mice fed the same diets were treated with ampicillin, a broad-spectrum antibiotic known to affect GM composition. Ampicillin-treatment had a marked and sustained effect on GM composition, as expected. Furthermore, although ampicillin-treated mice were slightly heavier than controls, ampicillin-treatment transiently improved glucose tolerance both in the absence or presence of gliadin, reduced plasma LDL and VLDL cholesterol levels, and reduced aortic atherosclerotic lesion area. These results demonstrate that a gluten-free diet does not seem to have beneficial effects on atherosclerosis or several CVD risk factors in this mouse model, but that sustained alteration of GM composition with a broad-spectrum antibiotic has beneficial effects on CVD risk factors and atherosclerosis. These findings support the concept that altering the microbiota might provide novel treatment strategies for CVD.
authors.affiliation: Section of Experimental Animal Models, Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Thorvaldsensvej 57, 1871 Frederiksberg C, Denmark.
authors.forename: Ida
authors.initials: I
authors.lastname: Rune
authors.affiliation: Global Research, Novo Nordisk A/S, Novo Nordisk Park 1, 2760 Måløv, Denmark.
authors.forename: Bidda
authors.initials: B
authors.lastname: Rolin
authors.affiliation: Section of Experimental Animal Models, Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Thorvaldsensvej 57, 1871 Frederiksberg C, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Larsen
authors.affiliation: Department of Food Science, Faculty of Science, University of Copenhagen, Rolighedsvej 26, 1958 Frederiksberg C, Denmark.
authors.forename: Dennis Sandris
authors.initials: DS
authors.lastname: Nielsen
authors.affiliation: Department of Medicine, Diabetes and Obesity Center of Excellence, University of Washington, Seattle, WA, 98109, United States of America.
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Kanter
authors.affiliation: Department of Medicine, Diabetes and Obesity Center of Excellence, University of Washington, Seattle, WA, 98109, United States of America.
authors.forename: Karin E
authors.initials: KE
authors.lastname: Bornfeldt
authors.affiliation: Section of Experimental Animal Models, Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Thorvaldsensvej 57, 1871 Frederiksberg C, Denmark.
authors.forename: Jens
authors.initials: J
authors.lastname: Lykkesfeldt
authors.affiliation: The Bartholin Institute, Rigshospitalet Dept. 3733, Copenhagen Biocenter, Ole Maaløes Vej 5, 2200 København N, Denmark.
authors.forename: Karsten
authors.initials: K
authors.lastname: Buschard
authors.affiliation: Global Research, Novo Nordisk A/S, Novo Nordisk Park 1, 2760 Måløv, Denmark.
authors.forename: Rikke Kaae
authors.initials: RK
authors.lastname: Kirk
authors.affiliation: Global Research, Novo Nordisk A/S, Novo Nordisk Park 1, 2760 Måløv, Denmark.
authors.forename: Berit
authors.initials: B
authors.lastname: Christoffersen
authors.affiliation: Global Research, Novo Nordisk A/S, Novo Nordisk Park 1, 2760 Måløv, Denmark.
authors.forename: Johannes Josef
authors.initials: JJ
authors.lastname: Fels
authors.affiliation: The Bartholin Institute, Rigshospitalet Dept. 3733, Copenhagen Biocenter, Ole Maaløes Vej 5, 2200 København N, Denmark.
authors.forename: Knud
authors.initials: K
authors.lastname: Josefsen
authors.affiliation: Section of Experimental Animal Models, Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Thorvaldsensvej 57, 1871 Frederiksberg C, Denmark.
authors.forename: Pernille
authors.initials: P
authors.lastname: Kihl
authors.affiliation: Section of Experimental Animal Models, Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Thorvaldsensvej 57, 1871 Frederiksberg C, Denmark.
authors.forename: Axel Kornerup
authors.initials: AK
authors.lastname: Hansen
mesh_terms: D000667:Ampicillin / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000453:epidemiology*; D002318:Cardiovascular Diseases / Q000453:epidemiology*; D002784:Cholesterol / Q000097:blood; D055050:Diet, Gluten-Free; D059305:Diet, High-Fat; D000069196:Gastrointestinal Microbiome / Q000187:drug effects* / Q000502:physiology; D005903:Gliadin / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000097:blood / Q000473:pathology*
chemical_list: D001057:Apolipoproteins E; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D000667:Ampicillin; D005903:Gliadin; D002784:Cholesterol; D005947:Glucose