Preoperative gut microbial network alterations and BCAA-Related metabolic disturbance in postoperative delirium after cardiac surgery: a prospective matched multi-omic study.

Postoperative delirium (POD) is a frequent neuropsychiatric complication after cardiac surgery, yet the biological basis of individual susceptibility remains unclear. In this prospective cohort study, 317 adults undergoing elective on-pump cardiac surgery were enrolled and followed for POD during the first 7 postoperative days. Thirty patients who developed POD were then matched 1:1 with 30 non-POD controls by age, sex, and primary diagnosis for multi-omic analyses. Preoperative fecal samples were collected from the first bowel movement after admission and before prophylactic antibiotic administration, and postoperative fecal samples were collected from the first postoperative bowel movement. Paired fecal samples underwent shotgun metagenomic sequencing, and perioperative serum samples underwent untargeted metabolomic profiling. Preoperatively, α- and β-diversity were comparable between groups, but patients who subsequently developed POD exhibited a less connected and less integrated microbial network structure. Postoperatively, gut microbial composition differed significantly between groups (PERMANOVA R² = 0.053, P < 0.001). Metagenomic profiling identified 35 differentially abundant species and 16 differentially enriched KEGG level 3 pathways, with POD-associated features showing inferred functional shifts toward amino-acid catabolism, including branched-chain amino acid (BCAA)-related pathways. Untargeted metabolomics demonstrated marked perioperative remodeling in both groups, but POD was associated with a 27-metabolite panel characterized predominantly by lower postoperative levels or impaired recovery, with pathway enrichment converging on valine, leucine, and isoleucine metabolism. Integrative analyses further linked POD-associated microbial taxa with amino-acid catabolic pathways and lower levels of BCAA-related serum metabolites. These findings suggest that POD is associated with preoperative alterations in microbial network organization and a postoperative microbiome-metabolome disturbance pattern centered on amino-acid metabolism, particularly the BCAA axis.