Gut microbiota associate with disease severity and survival in idiopathic pulmonary fibrosis

RATIONALE: Gut microbiota modify immunity. Dysregulated immunity plays a key role in the pathogenesis of IPF. However, the role of gut microbiota in IPF pathogenesis is unknown. OBJECTIVES: Determine associations between gut microbiota, disease severity and lung transplant-free survival in IPF. METHODS: Gut microbiota from patients enrolled in the CleanUP-IPF trial were characterized using fecal swab samples (n = 411). CleanUP-IPF investigated the clinical efficacy of long-term anti-microbials in IPF. 16S rRNA gene amplicon sequencing and shotgun metagenomic sequencing were performed to comprehensively profile gut microbial communities. Associations between baseline microbiota with disease severity, transplant-free survival, and treatment heterogeneity were analyzed using principal component analysis, multivariate generalized linear models, additive models and Cox regression models. MEASUREMENTS AND MAIN RESULTS: Gut microbiota composition varied significantly with sex, age, and proton pump inhibitor use. Gut microbial diversity and community composition were significantly associated with impaired gas exchange (percent predicted (pp) DLCO). Several genera including the Lachnospiraceae unclassified genus were associated with improved transplant-free survival (HR 0.34 95% CI 0.14-0.87, P = .02) in patients not assigned to anti-microbial treatment. Patients with a higher abundance of the Lachnospiraceae unclassified genus exposed to long term co-trimoxazole had worse survival (HR 6.09 95% CI 1.36-27.27, P = .02). Survival in pirfenidone treated patients was significantly associated with a higher abundance of the gut Lachnospiraceae unclassified genus. CONCLUSIONS: In exploratory post-hoc analysis, gut microbiota correlated with disease severity, associated with treatment heterogeneity and transplant-free survival in patients with IPF.