A Pro-Inflammatory Gut Microbiota Increases Systemic Inflammation and Accelerates Atherosclerosis

Abstract

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 pro-inflammatory microbiota from Caspase1-/- ( Casp1-/-) mice accelerates atherogenesis in Ldlr-/- mice. METHODS AND RESULTS: We treated female Ldlr-/- mice with antibiotics and subsequently transplanted them with fecal microbiota from Casp1-/- mice based on a co-housing approach. Autologous transplantation of fecal microbiota of Ldlr-/- mice served as control. Mice were co-housed for 8 or 13 weeks and fed chow or a high-fat cholesterol-rich (HFC) diet. Fecal samples were collected, and factors related to inflammation, metabolism, intestinal health and atherosclerotic phenotypes were measured. Unweighted Unifrac distances of 16S rDNA 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 HFC-fed Ldlr-/-( Casp1-/-) mice compared to Ldlr-/-( Ldlr-/-) mice. We found increased numbers of circulating monocytes and neutrophils and elevated pro-inflammatory cytokine levels in plasma in HFC-fed Ldlr-/-( Casp1-/-) compared to Ldlr-/-( Ldlr-/-) mice. Neutrophil accumulation in the aortic root of Ldlr-/-( Casp1-/-) mice was enhanced compared to Ldlr-/-( Ldlr-/-) mice. 16S-rDNA-encoding sequence analysis in feces identified a significant reduction in the short-chain fatty acid (SCFA)-producing taxonomies Akkermansia, Christensenellaceae, Clostridium and Odoribacter in Ldlr-/-( Casp1-/-) mice. Consistent with these findings, cumulative concentrations of the anti-inflammatory SCFAs proprionate, acetate and butyrate in the cecum were significantly reduced in 13-week HFC-fed Ldlr-/-( Casp1-/-) compared to Ldlr-/-( Ldlr-/-) mice. CONCLUSIONS: Introduction of the pro-inflammatory Casp1-/- microbiota into Ldlr-/- mice enhances systemic inflammation and accelerates atherogenesis.