Ketogenic diet-mediated immunometabolic regulation improves airway clearance of Klebsiella pneumoniae 2253582

Introduction Multidrug-resistant Klebsiella pneumoniae (MDR Kp) is a global health threat, causing persistent, subacute airway infections that are often fatal in healthcare settings. The failure of antimicrobials underscores an urgent need for alternative host-targeted therapies. Kp evades airway immune responses by perturbing host metabolism, inducing mitochondrial oxidative phosphorylation (OXPHOS) and oxidative stress, thus establishing a disease-tolerant microenvironment. We hypothesized that a ketogenic diet (KD), which improves OXPHOS efficiency via ketone production, would restore immune control of Kp by enhancing the bioenergetics and function of innate immune cells. Methods C57BL/6 mice were fed a KD or control diet prior to intranasal Kp infection. Airway bacterial burden was enumerated and immunometabolic changes were assessed by scRNA-seq, flow cytometry, and spatial metabolomics. Results KD significantly enhanced Kp airway clearance and host survival. ScRNA-seq of lung tissue revealed markedly higher numbers of neutrophils and alveolar macrophages at day 2 post-infection in KD-fed mice, as well as an upregulation in phagolysosome signaling. By day 7 in the KD group, the neutrophil population contracted while B and T cells concomitantly expanded. Notably, IFN-γ-responsive genes were upregulated across all immune cell subsets. Exogenous ketones or drug-induced ketone accumulation bypassed the need for dietary intervention, likewise, conferring protection against Kp airway infection. Conclusion Ketones promote effective immunity to Kp by sustaining cellular energy production, thereby supporting immune cell survival and effector function. The ketone-enhanced innate immune response is followed by adaptive immune cell expansion and a broad IFN-γ transcriptional signature. Together, these findings suggest a novel therapeutic strategy for energetically demanding bacterial infections via diet-induced metabolic reprogramming.