Dysbiosis of the Gut–Lung Axis and Its Immune Correlates During Pulmonary Cryptococcus neoformans Infection

<i>Cryptococcus neoformans</i> is a major fungal pathogen responsible for life-threatening meningitis, especially in immunocompromised individuals. Although the gut-lung axis is known to regulate immune responses in respiratory infections, its role in cryptococcosis remains unclear. This study aimed to define the dynamic changes in the gut and lung microbiota and their relationship with host immunity during <i>C. neoformans</i> infection. Using a mouse model, we found that pulmonary infection induced significant dysbiosis in both the lung and gut microbiota, marked by decreased beneficial commensals and increased opportunistic pathogens. Integrated analysis showed these microbial shifts were closely associated with distinct immune responses: lung dysbiosis correlated with a strong IL-17-mediated pulmonary inflammatory response, while gut dysbiosis was linked to systemic immune activation in the spleen. Functional metagenomic prediction further revealed widespread disruption in microbial metabolic pathways, including energy metabolism and biosynthesis, in both sites. Importantly, a positive correlation was observed between lung and gut dysbiosis, indicating an interconnected gut-lung axis during cryptococcosis. These findings demonstrate that <i>C. neoformans</i> infection causes coordinated disruptions in microbiota and immunity across the gut-lung axis, underscoring the microbiome as a critical modulator of host response and suggesting potential avenues for microbiome-targeted therapies.