Determinants of Microbiome Stability Following Pathogen Infection

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PROJECT SUMMARY - Determinants of Microbiome Stability Following Pathogen Infection The human microbiome (i.e., the consortium of microbes that reside in and on the body) affects human health and development. Microbiome composition (the microbial species that are present) and diversity (the number of species) can affect microbiome function. Disturbances such as antibiotics, dietary shifts, environmental stress or pathogen infection can cause changes (perturbations) in the microbiome, which can affect microbiome function and human health. The impacts of disturbances on the microbiome and human health can be mitigated by microbiome stability, which is the microbiome’s capacity to maintain stable structure (diversity and composition) and function despite disturbances. Understanding the factors that control microbiome stability is therefore important for human health. Infectious disease and temperature stress are two disturbances of growing concern to human health due to recurring disease outbreaks and human-induced climate change. The long-term goal of the proposed research is to understand how climate and disease affect the microbiome and what factors control microbiome resistance and resilience to these disturbances. The specific aims are: (1) to determine how microbiome diversity and composition affect microbiome stability during pathogen infection; (2) to determine how long-term temperature change affects the microbiome’s response to pathogen infection. The project will leverage the model organism Drosophila melanogaster for its tractability and relevance to human health and wild Drosophila species for their diversity and ecological realism. In Specific Aim 1, Hawaiian Drosophila species, which have naturally diverse microbiomes, will be used to identify relationships between microbiome structure (diversity and composition) and stability during infection by a bacterial pathogen. Next, causal relationships between microbiome structure and stability will be tested by manipulating the microbiome of D. melanogaster and exposing the flies to the pathogen. Specific Aim 2 will use populations of a single Drosophila species, which have naturally evolved under different temperatures, to test if adaptation to temperature affects how the microbiome and host respond to pathogen infection. In both specific aims, microbiome structure will be measured by DNA sequencing of microbial phylogenetic markers (16S, ITS), which identify the microbial taxa present and their relative abundances. Microbiome function will be assessed using shotgun metagenomics and transcriptomics, which predict functional capacity based on gene orthologues. Pathogen-induced microbiome perturbation will be measured as the change (before and after infection) in microbiome structure and function. Stability is the inverse of perturbation, i.e., the ability to avoid change despite disturbance. Effects of microbiome structure on stability will be determined by testing how microbiome structure prior to infection affects the magnitude of perturbation after infection. This project will generate knowledge on microbiome structure-stability relationships, which will provide a foundation for future research to understand the mechanisms underlying stability and resilience and consequences for host health.