Fishbein, M. C. | Search bioRxiv

bioRxiv2024

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

Alterations 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 of Akkermansia muciniphila and Faecalibacterium 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 from A. 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. Jena et al. observe alterations in the intestinal microbiota composition of mice developing vasculitis, characterized by reduced A. muciniphila and F. 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 of A. muciniphila, was sufficient to alleviate the development of cardiovascular lesions in mice by promoting intestinal barrier function. HIGHLIGHTSO_LIAbsence or depletion of the microbiota decreases the severity of vasculitis in a murine model mimicking KD vasculitis. C_LIO_LISupplementation of B. wadsworthia and B. fragilis promotes murine KD vasculitis. C_LIO_LIDecreased abundances of F. prausnitzii and A. muciniphila are associated with the development of cardiovascular lesions in mice. C_LIO_LISupplementation with either live or pasteurized A. muciniphila and F. prausnitzii, or the TLR-2 signaling Amuc_1100, reduces the severity of vasculitis by promoting gut barrier function. C_LI

immunology↗

bioRxiv2023

Flexible 3-D Electrochemical Impedance Spectroscopy Sensors Incorporating Phase Delay for Comprehensive Characterization of Atherosclerosis

BackgroundDistinguishing quiescent from rupture-prone atherosclerotic lesions has significant translational and clinical implications. Electrochemical impedance spectroscopy (EIS) characterizes biological tissues by assessing impedance and phase delay responses to alternating current at multiple frequencies. We evaluated invasive 6-point stretchable EIS sensors over a spectrum of experimental atherosclerosis and compared results with intravascular ultrasound (IVUS), molecular positron emission tomography (PET) imaging, and histology. MethodsMale New Zealand White rabbits (n=16) were placed on a high-fat diet for 4 or 8 weeks, with or without endothelial denudation via balloon injury of the infrarenal abdominal aorta. Rabbits underwent in vivo micro-PET imaging of the abdominal aorta with 68Ga-DOTATATE, 18F-NaF, and 18F-FDG, followed by invasive interrogation via IVUS and EIS. Background signal corrected values of impedance and phase delay were determined. Abdominal aortic samples were collected for histological analyses. Analyses were performed blindly. ResultsPhase delay correlated with anatomic markers of plaque burden, namely intima/media ratio (r=0.883 at 1 kHz, P=0.004) and %stenosis (r=0.901 at 0.25 kHz, P=0.002), similar to IVUS. Moreover, impedance was associated with markers of plaque activity including macrophage infiltration (r=0.813 at 10 kHz, P=0.008) and macrophage/smooth muscle cell (SMC) ratio (r=0.813 at 25 kHz, P=0.026). 68Ga-DOTATATE correlated with intimal macrophage infiltration (r=0.861, P=0.003) and macrophage/SMC ratio (r=0.831, P=0.021), 18F-NaF with SMC infiltration (r=-0.842, P=0.018), and 18F-FDG correlated with macrophage/SMC ratio (r=0.787, P=0.036). ConclusionsEIS with phase delay integrates key atherosclerosis features that otherwise require multiple complementary invasive and non-invasive imaging approaches to capture. These findings indicate the potential of invasive EIS as a comprehensive modality for evaluation of human coronary artery disease. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/558681v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@1d02071org.highwire.dtl.DTLVardef@101ec0eorg.highwire.dtl.DTLVardef@130bff7org.highwire.dtl.DTLVardef@18b0955_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIElectrochemical impedance spectroscopy (EIS) characterizes both anatomic features - via phase delay; and inflammatory activity - via impedance profiles, of underlying atherosclerosis. C_LIO_LIEIS can serve as an integrated, comprehensive metric for atherosclerosis evaluation by capturing morphological and compositional plaque characteristics that otherwise require multiple imaging modalities to obtain. C_LIO_LITranslation of these findings from animal models to human coronary artery disease may provide an additional strategy to help guide clinical management. C_LI

bioengineering↗