“Building a systems biology toolkit for the microbiome to transform the study of host-microbe interactions critical to health”

Host: Prof Nicola Stanley-Wall 

Venue: Online only 

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Abstract 

The important role of the gut microbiome in health is becoming increasingly apparent. However, disentangling cause and effect in this microbial community and revealing how it drives health outcomes remain some of the largest unsolved challenges in microbiology and medicine. There is a pressing need to know more about the fundamental biology of microbiome species if we are going to meet this challenge. Yet, we lack this information for the vast majority of community members. My background in systems biology and microbial genetics has put me in a unique position to tackle this problem. I’ve leveraged my expertise to develop a generalized systems biology toolkit with the potential to transform the way we study the microbiome and its influence on us. 

I’ve focused on two microbiome members, Bacteroides thetaiotaomicron (B. theta) and Bifidobacterium breve (B. breve), to prototype a systems-level approach and demonstrate its effectiveness. First, I’ve lowered the barrier of genetic intractability that is common in the microbiome by developing new transformation protocols and technologies. Major outcomes from this effort include a generalized protocol for transformation of the Bifidobacterium genus and a high-volume electroporation device known as M-TUBE that was created in a collaborative effort. Next, I’ve revealed gene function on a global scale in these organisms using randomly barcoded transposon mutagenesis, chemical genomics, and colonization of germ-free animals. In B. theta, developing a deeper understanding of gene function revealed an unexpected interaction between host diet and nitrogen metabolism that has interesting implications for the control of microbiome physiology during therapeutic interventions. 

Small molecules produced by Bifidobacterium species play a critical role in training the immune system in early life, but the mechanism, physiology, and regulation of production remain unclear. To better understand this process, I established a protocol for assembling genome-scale collections of mutant isolates from barcoded transposon pools. This advance has broad potential to bring genome-scale mechanistic analysis to microbiome members that lack sophisticated genetic tools. Measuring the metabolic capabilities of individual mutants from this collection allowed me to expand our knowledge of the pathway producing immunomodulatory small molecules, identify a specific physiological role for the pathway in B. breve, and explore strategies for controlling small molecule production. This is an exciting first step towards designing immunomodulatory microbiome interventionse more precise, effective, and robust. 

Building on these results in my future lab, we will work to develop a deep understanding of the different molecular mechanisms used by Bifidobacterium species to train the immune system in early life. We will also continue to expand the toolkit to new microbiome members and emerging pathogens. Bringing systems biology approaches to the microbiome promises to transform the way we study this microbial community and accelerate the path to designing better microbiome-based therapies.