Abstract

IntroductionEndothelial dysfunction and arterial stiffness are commonly observed in obese individuals and are both independent risk factors for cardiovascular disease. Recent preclinical data from our laboratory suggest that alterations in the gut microbiota may be an important factor linking obesity to endothelial dysfunction and arterial stiffness. The purpose of this study was to begin to translate these preclinical data to a human population by examining whether vascular phenotypes in humans are transmissible by fecal microbiota transplantation to germ‐free mice. We hypothesized that germ‐free mice receiving transplantation of an obesity‐associated microbiota would display impaired vascular function compared to germ free mice receiving transplantation of a lean microbiota.MethodsTwenty lean and obese participants were screened for vascular dysfunction and stool samples were collected. One representative obese and one lean age‐ and sex‐matched participant with disparate vascular function were selected as donors for fecal microbiota transplantation. Following transplantation, mice consumed a maintenance diet for 12 weeks. During weeks 11 and 12, mice underwent a glucose tolerance test and a FITC‐dextran test to assess intestinal permeability. After 12 weeks, vascular phenotypes were determined via in vivo aortic pulse wave velocity and ex vivo endothelium‐dependent and ‐independent dilation. 16S rRNA sequencing was used to analyze the microbiota in all samples and sequence data was analyzed using QIIME2 and myPhyloDB.ResultsPrincipal Component Analysis of mouse and donor samples revealed separation of global microbiota profiles with species (human vs mouse) being the factor accounting for the greatest variability (Axis 1; ~24%) in the microbiota, followed by vascular phenotype of the donor (Axis 2; ~19%).Endothelium‐dependent dilation was significantly impaired (p<0.05) in mice receiving microbiota from the obese donor relative to those with lean donor microbiota (maximal dilation to ACH: 50.1% vs 76.9%, p=0.013). Glucose tolerance was also impaired in mice receiving the obese microbiota (AUC: 1577.3 vs 1168.13 mg/dL, p=0.064; minute 90: 372.0 vs 219.2 mg/dL, p=0.043; minute 120: 371.7 vs 211.5 mg/dL, p=0.032). No significant differences were seen with endothelium‐independent dilation, aortic pulse wave velocity, or body weight.ConclusionsThese data provide further evidence that the gut microbiota is an important regulator of vascular function, and suggest that directly targeting the microbiota may be a novel therapeutic strategy for altering vascular phenotypes.Support or Funding InformationNIH R01 HL14411; American Heart Association #18TPA34170585; NIFA AES COL00766

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