Understanding the role of the human gut microbiome in mediating chronic disease and healthy aging

Abstract

The human gut microbiome is considered by many clinicians and researchers to be one of thefinal frontiers of discovery in medicine, or a “second brain” for the body. The gut microbiome encodes 100-fold more genes than the human genome and many of these foreign genes influence our phenotypes through the production of small molecules, like neurotransmitters or short-chain fatty acids (SCFAs). The bidirectional relationship between the human gut microbiota and the host, including the gut-brain axis, gut-kidney-heart axis, and gut-liver axis, comprise a complex ecosystem that influences aging and long-term health. Here, I describe my dissertation work, which focused on signatures of chronic disease and healthy aging in the body and how these signatures were related to ecological variation in the gut microbiome. I leveraged deep phenotyping data from the Arivale Scientific Wellness Program, which concluded in 2019. I found significant associations between microbiome composition and function, bowel movement frequency, frailty, and biomarkers of pro-inflammatory diseases and chronic kidney disease (CKD). Uremic toxins and biomarkers of inflammation were elevated in otherwise healthy individuals experiencing constipation or diarrhea, respectively. Microbially-derived uremic toxins enriched in the blood of constipated individuals were also negatively associated with kidney function. Enriched inflammatory proteins and genera, as well as immunological metabolites found in the Arivale cohort blood plasma imply a stressful cellular environment in the frail. Frailty negatively associates with estimated SCFA (propionate) production independent of age. These findings reveal some of the biological networks and mechanisms underlying the previously observed relationships between gut microbiome composition, healthy aging, and chronic disease development, warranting further investigation into the role of the gut microbiome as a mediator of health and disease throughout the lifespan.