(850.4) Changes in Gut Microbiome Composition with Healthy Aging in Humans: Links to Vascular Endothelial Function
Tuesday, April 5, 2022
10:15 AM – 12:15 PM
Location: Exhibit/Poster Hall A-B - Pennsylvania Convention Center
Poster Board Number: E43
Nathan Greenberg (University of Colorado Boulder), Marissa Burnsed-Torres (University of Colorado Boulder), Antonio Gonzalez (University of California San Diego), Abigail Casso (University of Colorado Boulder), Kara Lubieniecki (University of Colorado Boulder), Brian Ziemba (University of Colorado Boulder), Matthew Rossman (University of Colorado Boulder), Emily Adam (University of Colorado Boulder), Michel Chonchol (University of Colorado Anschutz Medical Campus), Kevin Davy (Virginia Tech), Rob Knight (University of California San Diego), Douglas Seals (University of Colorado Boulder), Vienna Brunt (University of Colorado Boulder)
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 amp;
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 lt; 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 lt; 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) NF𝜅B 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.
