Changes in Gut Microbiome Composition with Healthy Aging in Humans: Links to Vascular Endothelial Function

Abstract

Aging is the primary risk factor for cardiovascular diseases, primarily due to development of vascular endothelial dysfunction. The gut microbiome is a strong influencer of host physiology, but few studies have investigated how gut microbiome composition changes with primary (healthy) aging in humans, or how such changes may influence endothelial function. PURPOSE To: 1) determine changes in gut microbiome composition and their relation to endothelial function in healthy late middle‐aged to older (MA/O) vs. young (Y) adults; and 2) investigate potential mechanisms of this link. METHODS & RESULTS N=14/group (MA/O: 60‐79 yrs; Y: 18‐29 yrs). Data are mean ± SE. Gut microbiome composition was assessed via fecal 16S rRNA sequencing. α‐diversity, phylogenetic diversity within each sample, was higher in MA/O vs Y adults (Faith’s PD: 22.2 ± 1.8 vs 15.5 ± 1.3, P = 0.02). β‐diversity, difference in overall composition between samples, was also altered with aging (PERMANOVA: P < 0.05; unweighted UniFrac). Both α‐diversity (R = ‐0.60, P = 0.04) and β‐diversity (R = ‐0.58, P = 0.04) were inversely related to age‐related impairments in endothelial function, measured by brachial artery flow‐mediated dilation (MA/O: 4.5 ± 0.4 vs Y: 7.9 ± 1.7%, P < 0.05). Potential Mechanisms: In preliminary analyses (unpaired t‐tests), changes in gut microbiome composition were accompanied by altered relative abundance of gram‐negative bacteria (e.g., Bacteroides [MA/O: 33 ± 4% vs Y: 20 ± 4%, P = 0.02]) and Enterobacteriaceae [MA/O: 1.5 ± 0.1% vs Y: 0.4 ± 0.1%, P = 0.02]), which contain pro‐inflammatory lipopolysaccharide (LPS) in their cell walls. Translocation of LPS into systemic circulation is facilitated by increased intestinal permeability, which we found was higher with aging, as measured by a lactulose‐mannitol (L:M) test (1‐hour serum L:M ratio, MA/O: 0.012 ± 0.002 vs Y: 0.007 ± 0.001, P = 0.04). As such, plasma LPS‐binding protein, a readily detectable marker of LPS in peripheral blood, was higher in MA/O vs Y adults (31.3 ± 4.1 vs 17.7 ± 2.0 ng/mL, P = 0.01). Once in circulation, LPS is recognized as a pathogen‐associated molecular pattern and can trigger an inflammatory response. Consistent with this, circulating levels of the pro‐inflammatory markers IL‐6 [MA/O: 1.56 ± 0.29 vs Y: 0.70 ± 0.13 pg/ml, P = 0.01] and CRP [MA/O: 1.65 ± 0.27 vs Y: 0.78 ± 0.11 pg/ml, P = 0.02]) were increased with aging. In biopsied venous endothelial cells from a subset of subjects (n = 4‐8/group), abundance of phosphorylated (i.e., activated) NF□B was higher in MA/O vs Y adults (0.40 ± 0.05 vs 0.31 ± 0.04 ng/ml, P = 0.24), with no difference in total NFkB, indicating potentially increased vascular inflammation. CONCLUSIONS Our findings represent initial evidence in humans that the gut microbiome changes with healthy aging and may be an important mediator of age‐related endothelial dysfunction, possibly via increasing circulating LPS and vascular inflammation.

Exercise to Prevent Accelerated Vascular Aging in People Living With HIV

“…243 Further, a small but growing body of translational evidence has indicated that gut microbial diversity and intestinal permeability contribute to age-related vascular dysfunction in people without HIV. [244][245][246][247] For example, both α-and β-diversity have been reported to be inversely related to FMD in adults. 245 In support of these findings, Menni et al 246 reported a significant, independent, inverse relation between α-diversity and cfPWV in women from the Twin-sUK cohort study.…”

“…[244][245][246][247] For example, both α-and β-diversity have been reported to be inversely related to FMD in adults. 245 In support of these findings, Menni et al 246 reported a significant, independent, inverse relation between α-diversity and cfPWV in women from the Twin-sUK cohort study. Therefore, this emerging body of evidence describes an important gut-immune-vascular axis and implicates adverse changes in gut microbiome composition and intestinal permeability as potential contributors to age-related vascular dysfunction in PLWH.…”