Unraveling host-microbiome interactions in lung fibrosis

Human idiopathic pulmonary fibrosis is a debilitating disease without effective cure. The microbiome has been implicated to potentially play an important role but a comprehensive understanding of how the host and the microbiota interact and how this may contribute to disease development remains elusive. Furthermore, it remains unknown to what extent permanent changes in the intestinal or respiratory microbiota contribute to chronic lung disease and how these changes in composition or function might affect responses to other inflammatory insults.

In this project, we aim to comprehensively dissect host-microbiome interplay in pulmonary fibrosis and elucidate key host and microbial drivers of the disease. In a first step, we plan to combine gnotobiotic mouse models with single cell transcriptomics to characterize microbiome-dependent host phenotypes at different time-points of disease development in order to generate a detailed kinetic map of host changes in fibrosis. This will be coupled to metagenomic sequencing of the intestinal microbiota as well as specialized low biomass analysis of the local respiratory microbes to build a detailed biogeography of the microbiome in the lung and the gut. This large and comprehensive analysis of the host and the microbiome will form the basis of the second step, where we want to identify and experimentally test potential associations between key features of the disease and microbes with the purpose of elucidating the underlying molecular disease mechanisms and how they are controlled by the microbiome. Finally, in a third step we will study the role of "microbial memory" in this context, investigating the impact of fibrosis-induced permanent microbiota changes on the host response when it is exposed to other inflammatory insults.

Taken together this project will provide fundamental insights into the molecular disease mechanisms of a debilitating human disease and potentially provide new avenues for microbiome-directed therapy.