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Independent reports note the significance of gut microbiota on lung disease severity; however, studies using murine models to define the role of the gut microbiome in pulmonary fibrosis progression are missing. We used the bleomycin murine model to quantify lung fibrosis in C57BL/6J mice housed in germ-free, animal biosafety level 1 (ABSL-1), or animal biosafety level 2 (ABSL-2) environments. Mice housed in gnotobiotic facilities are protected from bleomycin-induced pulmonary fibrosis, while ABSL-1 and ABSL-2 mice develop mild fibrosis and severe lung fibrosis, respectively. Metagenomic analysis of the gut microbiota revealed greater microbial diversity in ABSL-1 compared to ABSL-2 mice, with an increased presence of Lactobacilli and Bifidobacterium in ABSL-1 mice. Flow cytometric analysis of single-cell lung suspensions revealed enhanced IL-6/STAT3 /IL-17A signaling in CD4+ T cells of ABSL-2 mice, compared to ABSL-1 or germ-free mice. Fecal microbiota transplantation (FMT) of low microbial diverse stool (ABSL-2) into germ-free mice before bleomycin administration recapitulated the severe fibrosis phenotype, whereas FMT of ABSL-1 stool induced minimal fibrosis. These findings strongly support a causal role of the gut microbiota in augmenting pulmonary fibrosis severity after acute lung injury.

To gain a deeper understanding of pancreatic β-cell development, we used iterative weighted gene correlation network analysis to calculate a gene co-expression network (GCN) from 11 temporally and genetically defined murine cell populations. The GCN, which contained 91 distinct modules, was then used to gain three new biological insights. First, we found that the clustered protocadherin genes are differentially expressed during pancreas development. Pcdhγ genes are preferentially expressed in pancreatic endoderm, Pcdhβ genes in nascent islets, and Pcdhα genes in mature β-cells. Second, after extracting sub-networks of transcriptional regulators for each developmental stage, we identified 81 zinc finger protein (ZFP) genes that are preferentially expressed during endocrine specification and β-cell maturation. Third, we used the GCN to select three ZFPs for further analysis by CRISPR mutagenesis of mice. Zfp800 null mice exhibited early postnatal lethality, and at E18.5 their pancreata exhibited a reduced number of pancreatic endocrine cells, alterations in exocrine cell morphology, and marked changes in expression of genes involved in protein translation, hormone secretion and developmental pathways in the pancreas. Together, our results suggest that developmentally oriented GCNs have utility for gaining new insights into gene regulation during organogenesis.

There are trillions of microorganisms in the human body, consisting of bacteria, viruses, fungi, and archaea; these collectively make up the microbiome. Recent studies suggest that the microbiome may serve as a biomarker for disease, a therapeutic target, or provide an explanation for pathophysiology in lung diseases. Studies describing the impact of the microorganisms found in the respiratory tract on lung health have been published and are discussed here in the context of interstitial lung diseases. Additionally, epidemiological and experimental evidence highlights the importance of cross-talk between the gut microbiota and the lungs, called the gut–lung axis. The gut-lung axis postulates that alterations in gut microbial communities may have a profound effect on lung disease. Dysbiosis in the microbial community of the gut is linked with changes in immune responses, homeostasis in the airways, and inflammatory conditions in the gastrointestinal tract itself. In this review, we summarize studies describing the role of the microbiome in interstitial lung disease and discuss the implications of these findings on the diagnosis and treatment of these diseases. This paper describes the impact of the microbial communities on the pathogenesis of lung diseases by assessing recent original research and identifying remaining gaps in knowledge.