Characterizing human-microbiome interactions via molecular and functional genomic approaches

Project Summary The human body hosts multiple complex microbial ecosystems consisting of bacteria, archaea, viruses, and fungi — collectively referred to as the microbiota. The microbiota impact human health and are associated with a wide variety of complex diseases. Therefore, understanding how the microbiota is maintained across the body is of major importance. My research program focuses on investigating the factors responsible for microbiota composition in the human host and determining how the microbiome influences human health. Specifically, I tackle these questions from the perspective of a human geneticist. I treat the microbiome as a complex trait and use human genetic approaches to understand its genetic underpinnings. Recent work from myself and others revealed the effect of host genetics in fecal microbiome composition. Major gaps in our understanding of microbiome heritability remain, however, which I aim to tackle in my lab. For example, we lack an understanding of whether host genetics impacts microbiota directly adjacent to mucosal surfaces, what the underlying host physiological mechanisms are, and whether host genetics influences the eukaryotic viruses, fungi, or other single-cell eukaryotic organisms in the microbiota, as the bacterial and archaeal components of the microbiota have been the focus to date. Research in my lab seeks to address these gaps by developing and applying a combination of microbiome and functional genomic research methods to gain a better understanding of the physiological underpinnings of host-microbiota interactions across the body. Over the next five years I will lead projects under three broad themes: (1) identify relationships between host genes and mucosal bacterial and archaeal abundance, (2) identify non-prokaryotic elements of the microbiota associated with human gene expression, and (3) determine causal relationships between the microbiome and host traits across two distinct body sites: gut and lung. Specifically, my efforts will focus on physiologically relevant sampling, including pairing sequencing of the microbiota from lung and gut mucosal surfaces with single-cell RNA-seq of adjacent host tissues. Using these data, I will identify individual microbial taxa, host cell types, and host pathways important for maintaining cross-kingdom interactions in healthy individuals. By examining two distinct organ systems, I will identify components both shared across and unique to the host tissue type. Application of genetic epidemiological methods and confirmation in vitro will establish direction of causality: Which aspects of the microbiota drive changes in gene expression in the host, and vice versa? Results from my research program will provide insights into the physiological mechanisms that underlie heritability of the microbiota. Ultimately, this will improve our understanding of host control of the microbiome and provide insight into which elements of the microbiome could be targeted for therapeutic benefit.