Longitudinal profiling of host response and oropharyngeal respiratory microbiome reveals dynamic alterations during recovery from community-acquired pneumonia.

Community-acquired pneumonia (CAP) is a major global health concern, with limited understanding of longitudinal changes in host gene expression and respiratory microbiome throughout disease progression and recovery. To address this gap, we longitudinally collected CAP patients' peripheral blood for transcriptome and oropharyngeal swabs for microbiome analysis from admission to 4 months post infection. Age- and sex-matched volunteers were recruited as controls. We observed CAP patients mounted rapid, effective, and moderate immune responses against infection. Coagulation activation and mitochondrial dysfunction were the striking pathways showing distinct difference in CAP patients compared to controls, and the latter was validated by lower adenosine triphosphate (ATP) levels in the peripheral blood mononuclear cells (PBMCs) of CAP patients. Although transcriptional perturbations gradually decreased, they did not fully recover during the follow-up period. Similarly, persisting oropharyngeal microbiome dysbiosis was observed, characterized by significantly lower alpha diversity and altered taxonomy distribution ( < 0.05). CAP increased the relative abundance of , and , while decreasing that of , , and . Integrated analysis of host response and oropharyngeal microbiome revealed that the relative abundance of , , , and were positively related to mitochondrial structure and function pathways, whereas the relative abundance of declined over time in patients and positively correlated with anti-pathogen and interferon signaling pathways. These results underscore the persistent impact of CAP on both host immunity and oropharyngeal microbiome, even months after infection, emphasizing the need for long-term follow-up and targeted strategies to facilitate full recovery and restore homeostasis.