Role of intestinal microbiome and gut permeability in the development of Kawasaki Disease vasculitis

Cedars-Sinai Medical Center, West Hollywood CA

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Abstract

PROJECT ABSTRACT The intestinal microbiota influences many biological processes, including gastrointestinal and systemic immune responses. Alterations in its composition have been associated with the pathogenesis of cardiovascular (CV) diseases, including Kawasaki disease (KD), an acute pediatric vasculitis, and the leading cause of acquired heart disease in children in the USA. However, the functional contributions of these alterations remain unknown. Using a murine model of KD vasculitis, the Lactobacillus casei cell wall extract (LCWE)-induced KD, which mimics crucial immunopathologic features of human KD, we have generated critical data on the contribution of intestinal permeability, the microbiota, and microbiota-derived metabolites to the development of vasculitis. We observed that LCWE-induced KD in mice is associated with alterations in the intestinal microbiota composition, and we identified specific microbiota members and metabolites that influence the severity of vasculitis. LCWE-injected mice also exhibit increased circulating levels of trimethylamine N-oxide (TMAO), an inflammatory metabolite associated with CV diseases, and the blooming of bacteria involved in trimethylamine (TMA) generation. Blocking TMAO production pharmacologically in mice reduces the severity of LCWE-induced KD lesions, suggesting a detrimental effect of TMAO in LCWE-induced KD. Conversely, we observed decreased relative abundance of A. muciniphila in LCWE-injected mice that developed robust CV lesions. Exogenous supplementation of A. muciniphila or bacteria-derived metabolites short-chain fatty acids (SCFAs) reduce the severity of LCWE-induced vasculitis. A. muciniphilia and SCFAs stimulate the secretion by intestinal L cells of glucagon-like peptide 1 (GLP-1), an incretin hormone with beneficial metabolic and anti-inflammatory effects. Indeed, LCWE-injected mice also exhibit decreased levels of circulating GLP-1. Here, we propose to characterize the molecular and cellular mechanisms underlying this host and specific bacteria/metabolite interactions in the development of LCWE-induced CV lesions. We suggest that LCWE-induced changes in gut microbiota composition lead to increased TMAO production and subsequent immune activation that promotes vasculitis. We also hypothesize that A. muciniphila, which is significantly reduced in abundance in the gut microbiota of LCWE-injected mice, is beneficial by promoting GLP-1 production. We will test these hypotheses by i) Determining the biological role of TMAO in LCWE-induced KD vasculitis and ii) Determining the role of the A. muciniphila–GLP-1 axis during LCWE-induced KD vasculitis. The integrative strategies proposed herein will directly address critical gaps in our knowledge of the development of CV lesions in KD, leading to the identification of novel therapeutic approaches.