Butyrate protects against Klebsiella pneumoniae-induced oxidative stress in alveolar macrophages via p62-Keap1-Nrf2 pathway.

Klebsiella pneumoniae (K. pneumoniae)-induced pneumonia poses growing clinical challenges due to the emergence of hypervirulent and carbapenem-resistant strains. Butyrate contributes to antibacterial immunity while its role in pulmonary infections remains poorly understood. Here, we showed that K. pneumoniae infection caused alveolar macrophage depletion and concomitant inflammatory tissue damage, while butyrate administration preserved alveolar macrophage populations and attenuated pulmonary damage. Mechanistically, butyrate upregulated both the expression and phosphorylation of p62, and regulated the Keap1-Nrf2 signaling pathway to counter oxidative stress. Moreover, we demonstrated that K. pneumoniae infection triggered oxidative stress injury in critically ill pneumonia patients. Circulating monocytes exhibited elevated levels of 4-hydroxynonenal (4-HNE), a marker of oxidative stress, along with downregulated mRNA levels of SQSTM1 and NRF2, which were inversely correlated with 4-HNE levels. These findings establish butyrate as a dual modulator of the p62-Nrf2 antioxidant axis, highlighting its therapeutic potential for mitigating oxidative stress in K. pneumoniae-associated pneumonia.