Cross-kingdom microbiome interactions along the gut-lung axis: immune-microecological coordination, shared mechanisms, and disease-context dependence in respiratory disorders.

Cross-kingdom dysbiosis of the gut microbiome along the gut-lung axis has emerged as a key driver of chronic and acute respiratory diseases. Beyond bacteria, the intestinal mycobiome and virome, including bacteriophages, shape mucosal immunity and metabolism through partially overlapping but non-redundant pathways. In this Review, we synthesize rapidly expanding evidence that fungi, bacteria, and phages in the gut form an integrated network that may influence susceptibility, inflammatory tone, and therapeutic responsiveness across asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), and lung cancer via the gut-lung axis. We first summarize how cross-kingdom communities in the intestine are organized and interact, highlighting a tripartite framework centered on pathogen-associated molecular pattern-pattern recognition receptor (PAMP-PRR) circuits, the short-chain fatty acid (SCFA)-regulatory T-cell axis, and tryptophan-indole-aryl hydrocarbon receptor (AHR) signaling. We then compare how these shared axes are differentially perturbed across asthma, COPD, ARDS, and lung cancer, using these disorders as representative but non-sequential disease contexts along a conceptual gradient of immune-microecological disruption. Finally, we discuss how dietary modulation, pre-/pro-/postbiotics, mycobiome- and virome-targeted strategies, and phage-based approaches could be rationally combined to restore gut-derived immunometabolic circuits and improve respiratory outcomes. By integrating cross-kingdom ecology with mucosal immunology, this Review provides an integrative interpretive framework suggesting that gut microbiome-targeted strategies may help refine prevention, stratification, and adjunctive treatment approaches in selected respiratory disease contexts.