Transfer of Young Gut Microbiota Ameliorates Age‐ and Western‐Style Diet‐Related Vascular Endothelial Dysfunction in Mice

Abstract

Aging is associated with vascular endothelial dysfunction largely driven by reduced nitric oxide (NO) bioavailability, which increases the risk of cardiovascular diseases (CVD). Consumption of a Western‐style diet (WD; high fat, high sugar, low fiber) exacerbates this dysfunction and CVD risk. Adverse changes to the gut microbiome (gut dysbiosis) are observed with aging and/or WD and are linked to atherosclerosis and clinical CVD. We have shown that suppression of the gut microbiome with broad‐spectrum antibiotics in old mice reverses endothelial dysfunction, as indicated by improved endothelium‐dependent dilation (EDD). As it is impractical to use prolonged antibiotic treatment to prevent CVD, a novel approach would be to improve vascular function via microbiome transfer from healthy donors to recipients with endothelial dysfunction.PURPOSETo determine whether fecal microbiota transfer (FMT) from young, healthy mice reverses age‐ and/or WD‐induced endothelial dysfunction.METHODSOlder male C57Bl/6 mice were fed either standard chow (OC) or WD chow (started at 22 mo; OWD). Beginning at age 25 mo, following 5–7 days of antibiotic administration to suppress endogenous microbiota, mice were administered FMTs (feces collected pre‐treatment) via oral gavage from either young, healthy (YC; age 3–6 mo) mice (OC+YC, N=6; OWD+YC, N=6) or their own cohort (“self” recipients: OC+OC, N=7; OWD+OWD, N=5) weekly for 8 weeks. Following sacrifice at 27 mo, EDD was measured ex vivo in common carotid arteries as dilation to increasing doses of acetylcholine (10−9 to 10−4M). NO‐mediated dilation was assessed as the difference in EDD in the presence vs. absence of the endothelial NO synthase inhibitor L‐NAME. Endothelium‐independent dilation (EID) was assessed as dilation to the NO donor sodium nitroprusside (10−10 to 10−4M). These outcomes were also assessed in the group of YC donors (N=11), as a healthy reference. Data are mean±S.E.% of maximal dilation; p‐values determined by unpaired t‐test.RESULTSAge‐ and WD‐induced decreases in peak EDD (YC: 93.0±1.6%; OC+OC: 63.8±3.0%, p<0.001 vs. YC; OWD+OWD: 53.6±9.1%, p<0.001 vs. YC) were or tended to be ameliorated by FMT from YC mice (OC+YC: 77.4±2.5%, p<0.01 vs. OC+OC; OWD+YC: 76.7±8.3%, p=0.09 vs. OWD+OWD). These effects were likely mediated by improvements in NO bioavailability, as age‐ and WD‐induced reductions in NO‐mediated dilation (YC: 43.4±7.0%; OC+OC: 29.4±6.4%, p<0.001 vs. YC; OWD+OWD: 29.9±8.8%, p=0.21 vs. YC) were or tended to be improved by FMT from YC mice (OC+YC: 51.2±5.5%, p=0.04 vs. OC+OC; OWD+YC: 41.5±7.5%, p=0.34 vs. OWD+OWD). There were no differences in EID across groups (YC: 94.9±1.4%; OWD+OWD: 92.6±2.6%; OC+OC: 93.5±2.5%; OWD+YC: 98.7±0.6%; OC+YC: 93.6±3.9%, all p>0.05 vs. YC), indicating that the group differences in EDD were endothelium‐dependent.CONCLUSIONSThese preliminary data offer initial proof‐of‐concept evidence that the gut microbiome modulates endothelial function with aging and WD, and that alteration of the gut microbiome via FMT from healthy donors may confer improved endothelial function and possibly lower CVD risk.Support or Funding InformationSupported by: R01 HL134887, F32 HL140875This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.