Paired metabolomics identify associations between fecal and serum metabolites in cardiovascular-kidney-metabolic syndrome

Background Whether fecal metabolic alterations are associated with circulating metabolic changes in cardiovascular-kidney-metabolic (CKM) syndrome remains unclear. We compared serum and fecal metabolites between different CKM stages and investigated fecal-serum associations. Methods Forty-four participants participated in the cross-sectional study, including 19 subjects in CKM stages 1–2 and 25 subjects in CKM stages 3-4. All participants underwent untargeted serum and fecal metabolomics and fecal microbiome profiling. Exploratory serum proteomics was available for 35 participants. Candidate metabolites were selected according to group differences, annotation confidence and redundancy. CKM-adjusted partial Spearman correlations were calculated for paired metabolites. Bootstrap and leave-one-participant-out analyses assessed stability. Serum-fecal KEGG pathway scores and clinical associations were also examined. Results Serum analysis identified 470 annotated, non-exogenous features. Different features were involved in lipid-related, organic acid and steroid-related metabolites. Fecal analysis identified six features after Benjamini-Hochberg (BH) correction. Paired analysis of 17 fecal and 48 serum metabolites identified exploratory eight associations. Serum uridine was associated with fecal 1-palmitoyl lysophosphatidic acid, Asp Ala Phe and PE (16:0/0:0). Serum and fecal pyrimidine metabolism scores were positively correlated after adjustment for CKM group (partial rho = 0.429, P = 0.0041, BH-FDR = 0.0246). Selected metabolites were mainly associated with renal function indicators. The fecal microbiome showed greater genus-level dispersion in stages 3-4. Proteomic analysis identified 221 differential proteins enriched in complement and coagulation, inflammatory and lipid-related pathways. Conclusions Paired serum and fecal metabolomics identified a positive association between serum and fecal pyrimidine metabolism scores in CKM syndrome, accompanied by the uridine as an exploratory candidate associated with multiple fecal metabolites.