Impact of gut bacterial metabolites on lung function and disease

Project Summary/Abstract Acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury (ALI), is common in COVID-19 and was a major driver of the now >1 million deaths in the USA since March 2020. Rigorous work has emphasized the key role the immune system and the microbiome plays in lung diseases like ALI. This includes an important role for pro-inflammatory T helper 17 (Th17) cells, which expand and increase their activation in lung tissue during ALI and lead to pulmonary fluid accumulation. While select gut bacteria can induce Th17 cells, the causal role of the microbiome in ALI and ARDS remains a major knowledge gap. Bifidobacterium adolescentis is a gut isolate with the highest Th17 inducing capacity of any human gut bacterium. My own preliminary data show that colonization of germ-free (GF) mice with B. adolescentis is sufficient to markedly alter the expression of many genes in lung tissue, including hundreds of genes implicated in ARDS. My data also indicates that B. adolescentis and other bifidobacteria secrete small molecules that activate Th17 cells, providing a plausible mechanism by which bifidobacteria could contribute to lung injury. My K08 application will build on a set of tools based on our laboratory’s recent discovery that the host ketone body, β-hydroxybuytrate (βHB), uniquely suppresses the growth of Bifidobacterium species. I hypothesize that Bifidobacterium, which are suppressed by gut epithelial βHB, secrete small molecules that reach lung tissue and activate Th17 cells during ALI. The proposed research plan will provide multiple training opportunities leading to a unique and sustainable research program. As a clinical fellow in the Turnbaugh lab (UCSF), I have learned microbiome data analysis, anaerobic microbiology, and gnotobiotic mouse husbandry. This project, coupled to in-depth support by lung experts Drs. Sheppard and Matthay (UCSF), will help me develop an independent research area that builds upon my past training. I will develop skills quantifying ALI severity in two ALI models and pair these ALI models with state-of-the-art tools in microbiome research. This proposal is both technologically and conceptually innovative. We will leverage resources available in our laboratory to selectively manipulate Bifidobacterium colonization levels in conventionally raised mice using βHB. My proposed experiments will help elucidate the metabolites produced by gut Bifidobacterium that induce pulmonary Th17 phenotypes, emphasizing the importance of considering bacterial metabolism for immune function and lung physiologic impairment. Our proposed studies will shift the focus to remote communication between prevalent human gut bacteria and lung tissues, mediated by secreted bacterial metabolites. For patients with ALI, this work will define putative mechanisms by which gut microorganisms contribute to devastating physiologic impairment and provide a conceptual basis to understand the scope and molecular impact of the gut microbiome on lung function in both health and disease.