TY - JOUR
T1 - A Proinflammatory Gut Microbiota Increases Systemic Inflammation and Accelerates Atherosclerosis
AU - Brandsma, Eelke
AU - Kloosterhuis, Niels J.
AU - Koster, Mirjam
AU - Dekker, Daphne C.
AU - Gijbels, Marion J. J.
AU - van der Velden, Saskia
AU - Rios-Morales, Melany
AU - van Faassen, Martijn J. R.
AU - Loreti, Marco G.
AU - de Bruin, Alain
AU - Fu, Jingyuan
AU - Kuipers, Folkert
AU - Bakker, Barbara M.
AU - Westerterp, Marit
AU - de Winther, Menno P. J.
AU - Hofker, Marten H.
AU - van de Sluis, Bart
AU - Koonen, Debby P. Y.
N1 - Funding Information:
E. Brandsma, J. Fu, F. Kuipers, M. Hofker, and D.P.Y. Koonen are supported by a grant from CardioVasculair Onderzoek Nederland (CVON2012-03). Additional financial support was provided by the Jan Kornelis de Cock Foundation to E. Brandsma and the Graduate School for Drug Exploration, University of Groningen (E. Brandsma, M. Ríos Morales). J. Fu is supported by the Netherlands Organization for Scientific Research VIDI-grant (NWO-VIDI 864.13.013). M. Westerterp is supported by Netherlands Organization for Scientific Research VIDI-grant 917.15.350 and a Rosalind Franklin Fellowship from the University Medical Center Groningen.
Publisher Copyright:
© 2018 American Heart Association, Inc.
PY - 2019/1/4
Y1 - 2019/1/4
N2 - Rationale: Several studies have suggested a role for the gut microbiota in inflammation and atherogenesis. A causal relation relationship between gut microbiota, inflammation, and atherosclerosis has not been explored previously.Objective: Here, we investigated whether a proinflammatory microbiota from Caspase1(-/-) (Casp1(-/-)) mice accelerates atherogenesis in Ldlr(-/-)mice.Method and Results: We treated female Ldlr-/- mice with antibiotics and subsequently transplanted them with fecal microbiota from Casp1(-/-) mice based on a cohousing approach. Autologous transplantation of fecal microbiota of Ldlr(-/-) mice served as control. Mice were cohoused for 8 or 13 weeks and fed chow or high-fat cholesterol-rich diet. Fecal samples were collected, and factors related to inflammation, metabolism, intestinal health, and atherosclerotic phenotypes were measured. Unweighted Unifrac distances of 16S rDNA (ribosomal DNA) sequences confirmed the introduction of the Casp1(-/-) and Ldlr(-/-) microbiota into Ldlr(-/-) mice (referred to as Ldlr(-/-) (Casp1(-/-)) or Ldlr(-/-) ( Ldlr(-/-)) mice). Analysis of atherosclerotic lesion size in the aortic root demonstrated a significant 29% increase in plaque size in 13-week high-fat cholesterol-fed Ldlr-/-(Casp1-/-) mice compared with Ldlr(-/-) (Ldlr(-/-)) mice. We found increased numbers of circulating monocytes and neutrophils and elevated proinflammatory cytokine levels in plasma in high-fat cholesterol-fed Ldlr(-/-) (Casp1(-/-)) compared with Ldlr(-/-) (Ldlr(-/-)) mice. Neutrophil accumulation in the aortic root of Ldlr(-/-) (Casp1(-/-)) mice was enhanced compared with Ldlr(-/-) (Ldlr(-/-)) mice. 16S-rDNA-encoding sequence analysis in feces identified a significant reduction in the short-chain fatty acid-producing taxonomies Akkermansia, Christensenellaceae, Clostridium, and Odoribacter in Ldlr(-/-) (Casp1(-/-)) mice. Consistent with these findings, cumulative concentrations of the anti-inflammatory short-chain fatty acids propionate, acetate and butyrate in the cecum were significantly reduced in 13-week high-fat cholesterol-fed Ldlr(-/-) (Casp1(-/-)) compared with Ldlr(-/-)(Ldlr-/-) mice.Conclusions: Introduction of the proinflammatory Casp1(-/-) microbiota into Ldlr(-/-)mice enhances systemic inflammation and accelerates atherogenesis.
AB - Rationale: Several studies have suggested a role for the gut microbiota in inflammation and atherogenesis. A causal relation relationship between gut microbiota, inflammation, and atherosclerosis has not been explored previously.Objective: Here, we investigated whether a proinflammatory microbiota from Caspase1(-/-) (Casp1(-/-)) mice accelerates atherogenesis in Ldlr(-/-)mice.Method and Results: We treated female Ldlr-/- mice with antibiotics and subsequently transplanted them with fecal microbiota from Casp1(-/-) mice based on a cohousing approach. Autologous transplantation of fecal microbiota of Ldlr(-/-) mice served as control. Mice were cohoused for 8 or 13 weeks and fed chow or high-fat cholesterol-rich diet. Fecal samples were collected, and factors related to inflammation, metabolism, intestinal health, and atherosclerotic phenotypes were measured. Unweighted Unifrac distances of 16S rDNA (ribosomal DNA) sequences confirmed the introduction of the Casp1(-/-) and Ldlr(-/-) microbiota into Ldlr(-/-) mice (referred to as Ldlr(-/-) (Casp1(-/-)) or Ldlr(-/-) ( Ldlr(-/-)) mice). Analysis of atherosclerotic lesion size in the aortic root demonstrated a significant 29% increase in plaque size in 13-week high-fat cholesterol-fed Ldlr-/-(Casp1-/-) mice compared with Ldlr(-/-) (Ldlr(-/-)) mice. We found increased numbers of circulating monocytes and neutrophils and elevated proinflammatory cytokine levels in plasma in high-fat cholesterol-fed Ldlr(-/-) (Casp1(-/-)) compared with Ldlr(-/-) (Ldlr(-/-)) mice. Neutrophil accumulation in the aortic root of Ldlr(-/-) (Casp1(-/-)) mice was enhanced compared with Ldlr(-/-) (Ldlr(-/-)) mice. 16S-rDNA-encoding sequence analysis in feces identified a significant reduction in the short-chain fatty acid-producing taxonomies Akkermansia, Christensenellaceae, Clostridium, and Odoribacter in Ldlr(-/-) (Casp1(-/-)) mice. Consistent with these findings, cumulative concentrations of the anti-inflammatory short-chain fatty acids propionate, acetate and butyrate in the cecum were significantly reduced in 13-week high-fat cholesterol-fed Ldlr(-/-) (Casp1(-/-)) compared with Ldlr(-/-)(Ldlr-/-) mice.Conclusions: Introduction of the proinflammatory Casp1(-/-) microbiota into Ldlr(-/-)mice enhances systemic inflammation and accelerates atherogenesis.
KW - atherosclerosis
KW - cholesterol
KW - diet
KW - fatty acids, volatile
KW - feces
KW - inflammation
KW - CHAIN FATTY-ACIDS
KW - PROGRESSION
U2 - 10.1161/CIRCRESAHA.118.313234
DO - 10.1161/CIRCRESAHA.118.313234
M3 - Article
C2 - 30582442
SN - 0009-7330
VL - 124
SP - 94
EP - 100
JO - Circulation Research
JF - Circulation Research
IS - 1
ER -