| dc.description.abstract | In the past two decades, human gut microbiome variation has been associated with numerous biological processes as well as beneficial and deleterious health outcomes. While many interrelated, environmental factors contribute to gut microbiome variation within and between individuals, the effects of modulating these factors to maintain health and treat disease are not fully established nor are the rules determining which factors modify which microbial traits. Diet, geography, and social interactions are consistent influences and require extrication before associating with health outcomes. In contrast, human genetic variation has a subtle but significant impact on the composition of the human gut microbiome, yet the influence of microbiome- associated genetic variants on human traits remains largely unknown. Host genetic influences over microbial diversity and abundance may undercut attempts to modify the microbiome, often presumed to be a malleable target. Interrogating the factors that modulate the microbiome is a crucial next step toward utilizing the microbiome as a diagnostic and therapeutic tool.
I demonstrate that human gut microbiome taxonomic and functional metagenomic variation recurrently associates with social factors including self-identified race/ethnicity when accounting for many other sources of variation. Additionally, I incorporate multiomic profiling to support that while total metabolomes converge during a controlled dietary intervention, gut microbial taxa and functions remain distinct between groups. Furthermore, I compile the largest catalog of microbiome-associated human genetic variants to date to show that variation within the human genome associated with the abundance and composition of the gut microbes is reproducibly connected with a range of disease phenotypes, tissue-specific gene expression profiles, and enriched in many tissues and immunological pathways. Together, these findings contribute new resolution to the study of the microbiome in health and disease by i) expanding the catalog of taxa and functions and their associated human factors at the metagenomic level, ii) testing the relative impact of short-term diet on oral and gut microbiome variation associated with social identity, iii) characterizing tissue-specific gene expression profiles of microbiome-associated variants, and iv) connecting microbiome variation in healthy individuals with differential disease risks in two large, independent populations. | |
