Patterns and processes of community assembly in the human microbiome

The following dissertation presents an overview of host-associated microbial community assembly, focusing on the question: How do you acquire your microbiome, and what determines how it develops and matures over time? Chapter 1 highlights selected concepts in the fields of ecology, microbiology, and immunology that provide context to the subsequent chapters of this dissertation. Chapter 2 provides a conceptual overview of how the timing and order of colonization can impact assembly of the microbiome in early life -- as a phenomenon known as priority effects. I also highlight the importance of both maternal and non-maternal sources of infant-colonizing microbes, and examine factors that may alter assembly patterns, including regional or cultural differences in infant care associated behaviors (ICABs). Chapter 3 details the process of community assembly in a large cohort of indigenous Bolivians called the Tsimane people. I applied a neutral model of community assembly and estimated the relative importance of stochastic dispersal during assembly. I then further used this model to place Tsimane infants in a global context through a comparative analysis with two other large infant populations from Bangladesh and Finland. Finally, I identified microbes that are changing in response to large-scale societal changes experienced by the Tsimane, including increased market access, and speculated on the consequences that these shifts may have on traditional modes of infant colonization. Chapter 4 identifies heritable features of the oral microbiome and oral metabolome using saliva samples collected from the TwinsUK cohort. I report that the saliva of monozygotic twin pairs harbor more similar microbial communities and metabolites, on average, than do dizygotic twins, which is consistent with the hypothesis that there is an affect of host genetics on the oral microbiome and metabolome. I also identified a wide range of heritable bacterial taxa and metabolites present in human saliva using two different statistical approaches for quantifying heritability, Falconer's Heritability (H2) and the A.C.E. model of heritability. A network analysis of the microbial co-occurrence patterns revealed that the majority of species interactions in adult saliva were positive, and that there is also a positive correlation between the heritably of a microbe and the number of positive ecological interactions it participates in with other microbes. Finally, I observed that the three most abundant and prevalent Absconditabacteriales (SR1) ASVs had linear correlations and strong positive associations with Prevotella shahii and Alloprevotella, suggesting that these bacterial taxa may be candidate symbiotic partners of Absconditabacteriales, a highly heritable and prevalent clade in the Candidate Phyla Radiation. Chapter 5 characterizes the effects of dual antibiotic administration of metronidazole and azithromycin versus the standard of care, metronidazole alone, in a randomized controlled trial using a large, multinational cohort of children with Crohn's Disease. We report variable effects of the dual vs. single antibiotics on the gut microbiome, and somewhat limited associations with disease remission or treatment outcome. However, we did observe that the microbiome configurations from patients who went into remission were significantly different between the antibiotic treatment regimens, suggesting that there is no single "remission compatible" microbiome, a finding which should inform the design of future clinical studies. Chapter 6 summarizes what I've learned through the course of this work, and highlights some areas that I think are deserving of more attention in the coming years.

Keywords: Microbiology and Immunology.
Advisor: Relman David A. 
Banfield Jillian F. (Jillian Fiona) 
Fukami Tadashi
Schneider David (David Samuel)
Sonnenburg Justin