Homeostasis of Gut Microbiota Protects against Susceptibility to Fungal Pneumonia

Abstract Fungal pneumonia is a serious disease with great harm and high prevalence, presenting significant challenges in diagnosis and treatment. The gut and respiratory microbiota play a critical role in protecting lung health against fungal pneumonia. Here, it is established fungal pneumonia by infection via the sinopulmonary route with Fusarium graminearum (F. graminearum) to investigate the influence of gut microbiota state on susceptibility to fungal pneumonia in BALB/c mice. This findings revealed that F. graminearum spore exposure not only impaired pulmonary clearance mechanisms but also significantly upregulated the expression of proinflammatory cytokines, including interleukin‐6 (IL‐6), interleukin‐1β (IL‐1β), and tumor necrosis factor‐α (TNF‐α). Moreover, spore invasion led to an increase in Staphylococcus abundance and activation of both triglyceride and galactose metabolic pathways. Antibiotic treatment disrupted the gut and respiratory microbiota, facilitating F. graminearum lung colonization, which is evidenced by elevated inflammatory markers in alveolar fluid and dysregulated lung metabolism. It is demonstrated that the gut microbiota influences susceptibility to fungal pneumonia by acting as an intermediary in the gut‐lung axis through the bloodstream, thereby modulating lung metabolism and inflammatory responses. These findings open avenues for novel therapeutic strategies, such as gut microbiota modulation, for the prevention and treatment of fungal pneumonia.