Year: 2024
Type: dissertation
Abstract: Advancing age is the primary non-modifiable risk factor influencing the development of cardiovascular diseases (CVDs), the leading cause of death in developed nations. Age-related arterial dysfunction, characterized by impaired vascular endothelial function and increased large elastic artery stiffness, serves as the fundamental precursor to CVD development. However, the precise upstream mechanisms driving these age-related arterial alterations remain incompletely elucidated. Changes to the gut microbiome, comprising trillions of microorganisms that reside within the gastrointestinal tract, represent an emerging mechanistic link through which aging may contribute to arterial dysfunction. Changes in gut microbiome composition and bacterial metabolic capacity have been reported with aging, potentially leading to unfavorable alterations in concentrations of health-adverse gut-derived metabolites and other bacterial components in the circulation, impacting arterial function. For example, lipopolysaccharide (LPS), a cell membrane component of Gram-negative bacteria found within the gut, has been implicated in arterial dysfunction by translocating into systemic circulation, leading to low-grade endotoxemia. Conversely, short-chain fatty acids (SCFAs), such as acetate, produced by gut microbiome-dependent fermentation of dietary fibers, exhibit anti-inflammatory properties, and benefit cardiovascular function. My dissertation investigated age-related changes in the gut microbiome and its influence on arterial dysfunction. In healthy, free-living older adults, I identified age-related shifts towards a pro-inflammatory gut microbial profile, characterized by reduced abundance of SCFA-producing and other anti-inflammatory bacteria. Statistical analysis established an associative link between these gut-related changes and arterial dysfunction. Next, fecal microbiota transplant (FMT) studies in mice demonstrated that age-related changes in the gut microbiome directly contribute to arterial dysfunction distinct from other influencing factors. Additionally, interventions aimed at positively influencing circulating levels of gut microbiome-derived metabolites, specifically through supplementation with the SCFA acetate, restored artery function in old mice. These studies establish the gut microbiome as a causal contributor to the age-related decline in arterial function and demonstrate that interventions positively modulating levels of gut microbiome-derived metabolites have efficacy for preserving artery function with aging. Thus, these findings open new avenues for the development of preventative and therapeutic interventions targeting the gut microbiome to improve cardiovascular health in aging populations.
Author: Greenberg, Nathan Thomas
Institutions: University of Colorado Boulder, University of Colorado System
Language: English
Topic: Gut microbiota and health
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W6986968326