Microbiome-innate immune crosstalk in acute exacerbation of idiopathic pulmonary fibrosis: an amplification framework.

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) remains a major cause of short-term mortality, yet its biological drivers are incompletely understood. Increasing evidence indicates that the distal lung is not sterile and that microbial burden, ecological disruption, and host immune responses may interact within the fibrotic niche. Here, we summarize current evidence and propose a focused, hypothesis-generating framework for microbiome-immune crosstalk in AE-IPF. In this model, pulmonary dysbiosis and persistent microbial stimulation may converge with epithelial injury-derived danger signals to amplify pattern-recognition receptor signaling, reshape macrophage states, and promote injurious neutrophil responses, including excessive neutrophil extracellular trap formation. Emerging data from fibrotic lung disease also raise the possibility that SPP1-associated macrophage programs may contribute to both impaired host defense and maladaptive repair. These observations also support the view that immune-cell state transitions, rather than microbial burden alone, may shape how acute injury is translated into persistent fibroinflammatory remodeling. We also discuss how antimicrobial exposure and resistance-associated persistence traits, including biofilm formation, could contribute to impaired microbial clearance and sustained innate immune activation, while emphasizing that direct in situ evidence in AE-IPF remains limited. Rather than proposing a universal mechanism, this mini review highlights a testable amplification framework that may help refine pathogen-aware stratification, antimicrobial stewardship, and biomarker-guided host-directed strategies in future studies.