The intestinal microbiota contributes to the development of immune-mediated cardiovascular inflammation and vasculitis in mice

Abstract

SUMMARYAlterations in the intestinal microbiota contribute to the pathogenesis of various cardiovascular disorders, but how they affect the development of Kawasaki disease (KD), an acute pediatric vasculitis, remains unclear. We report that depleting the gut microbiota reduces the development of cardiovascular inflammation in a murine model mimicking KD vasculitis. The development of cardiovascular lesions was associated with alterations in the intestinal microbiota composition and, notably, a decreased abundance ofAkkermansia muciniphilaandFaecalibacterium prausnitzii.Oral supplementation with either of these live or pasteurized individual bacteria, or with short-chain fatty acids (SCFAs) produced by them, attenuated cardiovascular inflammation. Treatment with Amuc_1100, the TLR-2 signaling outer membrane protein fromA. muciniphila, also decreased the severity of vascular inflammation. This study reveals an underappreciated gut microbiota-cardiovascular inflammation axis in KD vasculitis pathogenesis and identifies specific intestinal commensals that regulate vasculitis in mice by producing metabolites or via extracellular proteins acting on gut barrier function.IN BRIEFIt remains unclear whether changes in the intestinal microbiota composition are involved in the development of cardiovascular lesions associated with Kawasaki disease (KD), an immune-mediated vasculitis. Jenaet al.observe alterations in the intestinal microbiota composition of mice developing vasculitis, characterized by reducedA. muciniphilaandF. prausnitzii. Oral supplementation with either of these bacteria, live or pasteurized, or with bacteria-produced short-chain fatty acids (SCFAs) or Amuc_1100, the TLR-2 signaling outer membrane protein ofA. muciniphila, was sufficient to alleviate the development of cardiovascular lesions in mice by promoting intestinal barrier function.HIGHLIGHTSAbsence or depletion of the microbiota decreases the severity of vasculitis in a murine model mimicking KD vasculitis.Supplementation ofB. wadsworthiaandB. fragilispromotes murine KD vasculitis.Decreased abundances ofF. prausnitziiandA. muciniphilaare associated with the development of cardiovascular lesions in mice.Supplementation with either live or pasteurizedA. muciniphilaandF. prausnitzii,or the TLR-2 signaling Amuc_1100, reduces the severity of vasculitis by promoting gut barrier function.