Integrating lung microbiome, amino acid metabolism, and host immune response in elderly patients for severe lower respiratory Infections diagnosis: a multi-omics study.

BACKGROUND

Lower respiratory infections (LRIs) cause significant morbidity and mortality in elderly individuals, but the mechanisms driving severe deterioration remain unclear.

METHODS

This prospective study enrolled 105 patients aged ≥60 with suspected LRIs between October 2024 and April 2025. Bronchoalveolar lavage fluid (BALF) was analyzed using 16S rRNA sequencing, metagenomics, untargeted metabolomics, and cytokine profiling. Multi-omics data were integrated into a tripartite network, and severity-associated signatures were identified via PLS-DA, logistic regression, and ROC analysis.

RESULTS

The cohort included 40 severe (sLRIs) and 65 mild (mLRIs) cases. sLRIs exhibited reduced microbial diversity, shifting from commensal genera to opportunistic pathogens (Klebsiella, Corynebacterium, Elizabethkingia), with Klebsiella pneumoniae as a major bacterial hub. Metabolomics revealed 180 differential metabolites. Phenylalanine and beta-Alanine metabolism emerged as key severity-associated pathways. sLRIs showed accumulation of pro-inflammatory metabolites L-phenylalanine and phenylpyruvic acid. L-3-phenyllactic acid (PLA) served as the central metabolic hub. Cytokine profiling revealed local hyperinflammation (elevated IL-1β, IL-6, IL-8, TNF-α, IFN-γ), with IL-6 as central hubs. Multivariate analysis identified PLA and IL-8 as independently associated with severe status. Combined metabolic-immune signatures achieved high diagnostic accuracy (AUC: 0.858-0.882).

CONCLUSIONS

sLRIs in elderly patients are characterized by microbial dysbiosis, opportunistic pathogen enrichment, and remodeled Phenylalanine and beta-Alanine metabolism that correlates with hyperinflammation. BALF PLA and IL-8 represent promising metabolic-immune biomarkers for severity stratification.