M. Wei, X. Yi, Z. Lin, J. Cai, S. Chen, F. Zhou, H. Cai, X. Lu, J. Tang, Y. Shi, L. Cui, L. Yang, X. Jing, Y. Zeng, R. Wu, T. Shu, Y. Li, F. Yang, Y. He, Z. Zhao, Y. Yang, W. Zhu, Q. Jiang, W. Zhang, X. Tan, Z. Ma, X. Fan, W. Ma, S. Li, W. Shu, H. Wei, Z. Xiang, JA. Gilbert, S. Gong, et al. (2026). Ketogenic diet alleviates septic lung injury via microbial gut-lung axis. Cell metabolism, 38(3), 493-511.e12. https://doi.org/10.1016/j.cmet.2026.01.005

PubMed 41643678

[Abstract]
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.