RT Journal Article SR Electronic T1 Lung Immune Tone Regulation by the Gut-Lung Immune Axis: Short-chain Fatty Acid Receptors FFAR2 and FFAR3, and IL-1β Expression Profiling in Mouse and Human Lung JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.08.28.213439 DO 10.1101/2020.08.28.213439 A1 Qing Liu A1 Xiaoli Tian A1 Daisuke Maruyama A1 Mehrdad Arjomandi A1 Arun Prakash YR 2020 UL http://biorxiv.org/content/early/2020/08/29/2020.08.28.213439.abstract AB Microbial metabolites produced by the gut microbiome, such as short-chain fatty acids (SCFA), can influence both local intestinal and distant lung physiology and response to injury. However, how lung immune activity is regulated by SCFAs is unknown. We examined fresh human lung tissue and observed the presence of SCFAs with large inter-individual and even intra-lobe variability. In vitro, SCFAs were capable of modifying the metabolic programming in both resting and LPS-exposed alveolar macrophages (AM). Additionally, since we hypothesized that lung immune tone could be defined through priming of the inflammasome (aka signal 1), we interrogated naïve mouse lungs for pro-IL-1β message and localized its presence within the alveolar space in situ, specifically in AM subsets, and in close proximity to alveolar type 2 epithelial (AT2) cells. We established that metabolically active gut microbiota, that produce SCFAs, can transmit LPS and SCFAs to the lung (potential sources of signal 1), and thereby could regulate lung immune tone and metabolic programming. To understand how murine lung cells sensed and upregulated IL-1β in response to gut-microbiome factors, we determined that in vitro, AM and AT2 cells expressed SCFA receptors, FFAR2, FFAR3, and IL-1β but with different expression patterns and LPS-inducibility. Finally, we observed that IL-1β, FFAR2 and FFAR3 were expressed both in isolated human AM and AT2 cells ex-vivo, but in fresh human lung sections in situ, only AM expressed IL-1β at rest and after LPS challenge. Together, this translational study using mouse and human lung tissue and cells supports an important role for the gut microbiome and SCFAs in regulating lung immune tone.Competing Interest StatementThe authors have declared no competing interest.