Ketogenic diet alleviates septic lung injury via microbial gut-lung axis.

Sepsis is characterized by impaired immunity to infection, leading to multi-organ dysfunction, with the lung being the most vulnerable organ. Here, we show that ketogenic diet (KD) alleviates sepsis-induced lung injury through a microbial-gut-lung axis. KD alters the gut microbiota in mice and humans, enriching Limosilactobacillus reuteri and Lactiplantibacillus plantarum. Specific strains of these species produce a flavin-dependent monooxygenase (FMO) that converts oleic acid in KD into azelaic acid (AZA). During sepsis, AZA translocates to the lung, where it promotes neutrophil apoptosis and expands MerTK+ alveolar macrophages (AMs) via PPAR-γ activation, enhancing efferocytosis and resolution of lung injury. In patients with sepsis, elevated AZA correlates with improved clinical outcomes, including survival rates, ventilation-free days (VFDs), and pulmonary function, along with increased MerTK+ AMs and apoptotic neutrophils in patient lungs. These findings uncover a pathway of gut-lung crosstalk mediated by diet-microbiome interactions, highlighting the therapeutic potential of KD and microbiome modulation in sepsis.