Crosstalk between the microbiome and the mucosal immunoglobulin A system in the lung, in health and disease

The lung, and more specifically the airway epithelium, is continuously exposed to a wide range of inhaled environmental agents. Acting as a frontline physical and biochemical barrier, the airway epithelium orchestrates early host defense mechanisms, among which immunoglobulin A (IgA) plays a central role. Long considered sterile, the healthy lung is now recognized as a complex mucosal ecosystem harboring diverse and dynamic microbial communities, including bacteria, fungi, viruses, and archaea. Although the lung microbiome is generally transient and low in biomass, accumulating evidence suggests that it contributes to pulmonary homeostasis by supporting immune system maturation, preserving structural tissue integrity, and limiting pathogen colonization. How immune homeostasis is maintained in this constantly challenged environment remains however a central and largely unanswered question. This review synthesizes current state-of-the-art knowledge on the origin, composition, and functional determinants of the lung microbiome, with a specific focus on its bidirectional interplay with secretory IgA. We discuss microbiota-specific IgA responses, factors influencing IgA-microbiome interactions, and how these processes are disrupted in chronic and inflammatory lung diseases. Finally, we highlight major knowledge gaps and explore emerging therapeutic perspectives targeting IgA-microbiome crosstalk to restore pulmonary immune homeostasis.