The Role of the Gut Microbiome in Post-Sepsis Skeletal Muscle Atrophy

PROJECT SUMMARY This K08 proposal outlines the plan for Kale Bongers, M.D. Ph.D.’s to complete training toward his long-term goal of improving our understanding of post-sepsis muscle atrophy and weakness through investigation of the microbiome. Dr. Bongers is a physician-scientist in Pulmonary and Critical Care Medicine at the University of Michigan with an established record of success in skeletal muscle biology and microbiome studies. This proposal builds on Dr. Bongers’ previously acquired skillset in skeletal muscle biology, critical illness pathophysiology, and microbial ecology with new training in metabolomics and metagenomics. These skills will be integrated to improve our understanding of the role of the gut microbiome in mediating skeletal muscle atrophy after sepsis. This research will be conducted under the guidance of mentor Robert Dickson, M.D., co- mentor Kathleen Stringer, Pharm.D., and an advisory board of renowned investigators with experience in metabolomics, microbial ecology, microbiome studies, skeletal muscle in critical illness, and sepsis pathophysiology. The five-year plan includes intensive mentorship, formal didactic coursework, professional development, and increasingly independent research, with milestones to encourage productive research output and transition to independence. Sepsis is a common and deadly condition of organ dysfunction and immune dysregulation secondary to infection that often leaves its survivors severely debilitated due to muscle atrophy. Studies have suggested that the gut microbiome plays a critical role in the regulation of skeletal muscle size and strength, but to date no study has evaluated the role of the gut microbiome in the pathogenesis of post- sepsis skeletal muscle atrophy. This proposal tests the hypothesis that the gut microbiome plays a critical role in post-sepsis skeletal muscle atrophy via two specific Aims. Aim 1 will identify the key bacterial taxa that contribute to or prevent muscle atrophy in multiple models of murine sepsis, while Aim 2 will identify key bacterially-derived metabolites that mediate these changes in muscle. To accomplish these Aims, Dr. Bongers will leverage both in vivo and in vitro models of skeletal muscle with cutting-edge techniques in metabolomics and metagenomics to identify and mechanistically interrogate how gut bacteria influence skeletal muscle size and function during sepsis. This will lay crucial groundwork for future R01 proposals to 1) determine whether supplementation of key bacteria or key bacterially-derived metabolites can prevent skeletal muscle atrophy and 2) translate these findings to humans using morphomics and pre-existing bacterial swabs. In addition to building a strong line of research to understand the role of the microbiome in muscle atrophy, this proposal will provide Dr. Bongers with new research skills applicable to microbiome and metabolomics research. This K08 award will enable Dr. Bongers to establish himself as an independent physician-scientist and rising leader in this important field.