Gut microbiota modulates lung fibrosis severity following acute lung injury in mice

Abstract

Independent studies demonstrate the significance of gut microbiota on the pathogenesis of chronic lung diseases; yet little is known regarding the role of the gut microbiota in lung fibrosis progression. Here we show, using the bleomycin murine model to quantify lung fibrosis in C57BL/6 J mice housed in germ-free, animal biosafety level 1 (ABSL-1), or animal biosafety level 2 (ABSL-2) environments, that germ-free mice are protected from lung fibrosis, while ABSL-1 and ABSL-2 mice develop mild and severe lung fibrosis, respectively. Metagenomic analysis reveals no notable distinctions between ABSL-1 and ABSL-2 lung microbiota, whereas greater microbial diversity, with increased Bifidobacterium and Lactobacilli, is present in ABSL-1 compared to ABSL-2 gut microbiota. Flow cytometric analysis reveals enhanced IL-6/STAT3/IL-17A signaling in pulmonary CD4 + T cells of ABSL-2 mice. Fecal transplantation of ABSL-2 stool into germ-free mice recapitulated more severe fibrosis than transplantation of ABSL-1 stool. Lactobacilli supernatant reduces collagen 1 A production in IL-17A- and TGFβ1-stimulated human lung fibroblasts. These findings support a functional role of the gut microbiota in augmenting lung fibrosis severity.

Low Gut Microbial Diversity Augments Estrogen-driven Pulmonary Fibrosis in Female-Predominant Interstitial Lung Disease

“…Using linear discriminant analysis (LDA) to examine species-level differences in the gut microbiota, 10 taxa were overrepresented in ABSL-1 mice and 5 taxa were overrepresented in ABSL-2 mice. The overrepresented taxa in ABSL-2 mice included Lachnospiraceae bacterium A2, Lachnospiraceae bacterium 28-4, Firmicutes bacterium ASF500 , and Romboutsia ilealis [39]. Higher relative abundance of Firmicutes in the lung microbiota of bleomycin-treated mice with fibrosis has been reported[40].…”

“…Higher relative abundance of Firmicutes in the lung microbiota of bleomycin-treated mice with fibrosis has been reported[40]. Species overrepresented in ABSL-1 mice included Staphylococcus nepalensis, Dubosiella newyorkensis, Acetatifactor muris, Lactobacillus animalis, Lactobacillus murinus , and Acutalibacter muris [39].…”

“…Romboutsia ilealis [39]. Higher relative abundance of Firmicutes in the lung microbiota of bleomycin- treated mice with fibrosis has been reported [40].…”

“…The gDNA concentration and quality were confirmed using the Bioanalyzer 2100 system (Agilent, Santa Clara, CA). Metagenomic sequencing of fecal pellets is detailed as previously described [39]. Sequence of gut microbiota have been deposited into BioProject ID PRJNA899808.…”

“…We recently reported that gut microbiota play an important role in lung fibrosis severity. ABSL-1 housing conditions favor gut microbiota diversity, whereas ABSL-2 conditions favor reduced gut microbiota diversity [39]. Using linear discriminant analysis (LDA) to examine species-level differences in the gut microbiota, 10 taxa were overrepresented in ABSL-1 mice and 5 taxa were overrepresented in ABSL-2 mice.…”