From here to eternity: gut microbial response to drug therapy and inflammation

ABSTRACT The genomic revolution has provided us with an “embarrassment of riches” with respect to our understanding of the composition of gut microbial communities in disease, but we are still far from understanding how microbial genes and pathways impact host health. While a wealth of studies show that the microbiome is associated with disease states, we know little about the microbial genes that respond to disease-associated perturbations, such as inflammation or drug therapy, and how these microbial responses contribute to disease and drug response. Lack of knowledge of how microbial genes respond and contribute to disease-associated perturbations limits our ability to rationally design microbiome-targeted therapies, such as fecal microbiota transplant, live biotherapeutics, and small molecule microbial inhibitors. My lab’s long-term goal is to understand how the microbiome contributes to the resolution of systemic inflammation. The overall objective of this R35 NIGMS MIRA grant is to support the aspect of my research program focused on deciphering the microbial genetic determinants of responses to inflammation and drug therapy and how these impact the host. With the support of the R35 MIRA grant, over the next 5 years, I aim to establish a unique and productive niche at the intersection of microbiology, genetics, and systemic inflammatory disease by investigating the following key questions / themes: (1) which microbial genes are important for responding to host inflammation and drug treatment, (2) how do these microbial genes subsequently contribute to host inflammation, and (3) can drugs targeting specific microbial genes impact gut microbial ecology and evolution in the setting of host inflammation. The proposed research program seeks to fill these knowledge gaps by harnessing cutting-edge technologies and my unique backgrounds in computer science, genomics, microbiology, clinical immunology, and gnotobiology. The human gut microbiome is with us “from here to eternity” but we are just beginning to uncover the powerful forces in vivo that shape the microbial community and its evolution. The microbial genetic basis of these shifts in the setting of inflammation and drug therapy is not commonly studied; filling this fundamental knowledge gap will pay dividends in the future by improving the efficacy of therapeutic strategies that are currently underway in patients with inflammatory disease.