From gut to lung: the microbiome-directed causal mechanisms and therapeutic horizons in asthma.

The gut-lung axis represents a predominantly gut-to-lung communication network through which gut microbiota and their metabolites influence pulmonary immunity. In asthma, gut dysbiosis-characterized by reduced microbial diversity, depletion of short-chain fatty acid (SCFA)-producing taxa, and expansion of pro-inflammatory pathobionts-has been consistently associated with disease severity and type 2 inflammation. While the axis is conceptually bidirectional, the vast majority of mechanistic evidence to date describes unidirectional gut to lung regulation. This review critically synthesizes evidence on the gut-lung axis in asthma. We evaluate multi-kingdom microbial ecology, evaluating contributions from bacterial, fungal, protozoan, and phage. We examine metabolite-specific immune reprogramming via SCFAs, bile acids, and tryptophan derivatives, explicitly acknowledging unresolved controversies including the SCFA concentration paradox. We integrate causal inference frameworks that combine Mendelian randomization, gnotobiotic models, and experimental triangulation. We also present precision therapeutic pipelines with evidence-based grading of interventions ranging from probiotics to engineered live biotherapeutics. We propose that targeting the gut-lung axis represents a foundational strategy for asthma modification and outline a roadmap from multi-omics discovery to biomarker-guided clinical trials. Distinguishing this review from prior work, we explicitly separate established mechanisms from speculative pathways and provide actionable criteria for clinical translation. We also critically identify the reverse (lung to gut) pathway as a major knowledge gap requiring urgent investigation.