Pathogenesis and potential therapeutic targets of idiopathic pulmonary fibrosis: analysis of data from a large-scale genome-wide association study

Abstract

BACKGROUND: The gut–lung axis has emerged as a critical factor in the development of various pulmonary diseases. However, its role in idiopathic pulmonary fibrosis (IPF) remains insufficiently investigated, and the underlying causal relationships are yet to be clarified. This study integrates genome-wide association studies (GWAS), expression quantitative trait loci (eQTL) analysis, and colocalization-based molecular docking to comprehensively assess how gut microbiota may influence IPF through immune regulation, inflammatory mediators, and metabolic pathways. The research aims to provide mechanistic insights from genetic, transcriptional, and pharmacological perspectives. OBJECTIVE: To explore the causal relationship between gut microbiota and IPF, to elucidate the mediating effects of immune cells, inflammatory proteins, and circulating metabolites, to screen key microbial taxa and potential target genes, and to predict candidate therapeutic agents that may contribute to early diagnosis and drug development for IPF. METHODS: Using publicly available GWAS summary statistics for gut microbiota (473 species), immune cells (731 types), inflammatory proteins (91), metabolites (233), and IPF data from Finnish and eQTLGen databases, we performed univariate Mendelian randomization (MR) with inverse variance weighting and sensitivity analyses to explore causal links. Two-step mediation MR assessed whether immune cells, inflammatory proteins, and metabolites mediate the gut microbiota–IPF relationship. Additionally, MR and summary-data-based MR (SMR) were used to investigate causal relationships between gut microbiota and gene expression, followed by colocalization and druggability prediction, with molecular docking validation. RESULTS AND CONCLUSION: Bacteroides faecis, Megasphaera, and Pandoraea abundances showed causal relationships with IPF. B. faecis mediated IPF risk via 18:2 linoleic acid ratio and multiple CD4+ T cell subsets; Pandoraea risk was also influenced by different CD4+ T cell subsets; Megasphaera exerted protective effects mainly through interleukin-33, low-density lipoprotein-related metabolites, and CD4-CD8- T cell subsets. Further analysis identified GNF-Pf-2272, 5155877, and PpIX as potential drugs targeting KDM4C, CBR3, and YWHAG. Although the IPF GWAS data were predominantly from European populations, given the commonality of human genetic backgrounds across core pathways, these findings provide valuable reference for exploring gut microbiota modulation to reduce IPF risk in Chinese populations.

1. Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive respiratory disease characterized by collagen deposition in lung tissue. Current clinical treatments, such as nintedanib and pirfenidone, cannot reverse the fibrotic process, and lung transplantation remains the most effective therapy. The etiology of IPF is unclear, but various risk factors, including smoking, environmental air pollution, and alterations in gut microbiota, may significantly impact lung health. However, the relationship between gut microbiota and IPF has not been fully established, and the mediating roles of immune cells, inflammatory proteins, and metabolites remain unclear. Given the limited targeted therapeutic options for IPF, interventions based on gut microbiota hold significant potential.

The gut–lung axis is linked to the common embryonic origin of the gastrointestinal and respiratory mucosa. Gut microbiota play a key role in regulating host physiology, metabolism, and immune function, and are implicated in the pathogenesis and progression of IPF. Specifically, gut microbiota interact with the host intestinal microenvironment through metabolites and antigens, altering immune cell behavior and modulating inflammatory responses. For example, overgrowth of Candida albicans in the gut can mobilize Th17 cells to the lungs and secrete IL-17A, promoting endothelial-to-mesenchymal transition and accelerating IPF progression. Similarly, pathogens such as Haemophilus influenzae and Moraxella catarrhalis are associated with respiratory diseases. This study aims to systematically investigate the causal relationships and mediating mechanisms between gut microbiota and IPF using a multi-omics approach, potentially identifying novel therapeutic targets.