Modulating the Gut Microbiota Improves
Glucose Tolerance, Lipoprotein Profile and
therosclerotic Plaque Development in ApoE-Deficient
Mice
Ida Rune1*, Bidda Rolin2, Christian Larsen1, Dennis Sandris Nielsen3, Jenny E. Kanter4,
Karin E. Bornfeldt4, Jens Lykkesfeldt1, Karsten Buschard5, Rikke Kaae Kirk2,
Berit Christoffersen2, Johannes Josef Fels2, Knud Josefsen5, Pernille Kihl1, Axel
Kornerup Hansen1
1Section of Experimental Animal Models, Department of Veterinary Disease Biology, Faculty of Health and
Medical Sciences, University of Copenhagen, Thorvaldsensvej 57, 1871 Frederiksberg C, Denmark,
2Global Research, Novo Nordisk A/S, Novo Nordisk Park 1, 2760 Måløv, Denmark,
3Department of Food
Science, Faculty of Science, University of Copenhagen, Rolighedsvej 26, 1958 Frederiksberg C, Denmark,
4Department of Medicine, Diabetes and Obesity Center of Excellence, University of Washington, Seattle,
WA, 98109, United States of America,
5The Bartholin Institute, Rigshospitalet Dept. 3733, Copenhagen
Biocenter, Ole Maaløes Vej 5, 2200 København N, Denmark
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 glutenfree
high-fat cholesterol-rich diet, as compared to the same diet in which the glutenpeptide
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.
Plos One DOI:10.1371/journal.pone.0146439