Association between the gut microbiota and estimated glomerular filtration rate in two Swedish population-based cohorts

Evidence for gut–kidney interactions in early kidney disease is limited, particularly in community-dwelling adults with largely preserved kidney function. Here, we quantified links between gut microbiota and estimated glomerular filtration rate (eGFR) in two population-based Swedish cohorts. Deep shotgun metagenomics profiled fecal samples from 9788 adults in the Swedish CArdioPulmonary BioImage Study (SCAPIS) discovery cohort (mean age 58 ± 4 years; 52 % women) and 2080 adults in the Malmö Offspring Study (MOS) replication cohort (mean age 40 ± 14 years; 52 % women). Linear regression related the relative abundance of 494 metagenome-assembled species to the creatinine-based eGFR (by CKD-EPI equation), adjusting for demographics, albuminuria, cardiovascular risk factors and technical variables. Species passing false discovery rate under 0.05 in SCAPIS were tested in MOS for significant concordant direction. Functional enrichment linked eGFR-associated species to gut metabolic modules and plasma metabolites; partial Spearman correlations assessed metabolite/species/eGFR relationships. The alpha diversity showed a modest inverse association with eGFR across both cohorts. We identified 44 bacterial species consistently associated with eGFR in both cohorts, collectively explaining 7% of its variance. Enrichment analysis highlighted histidine and carnitine metabolism among the top three pathways involved. Their key products, trimethylamine N-oxide and imidazole propionate, were inversely related to eGFR, and a metabolite panel accounted for 51% of eGFR variation, underscoring metabolite-mediated microbial effects. Sensitivity analyses upheld these findings. Gut microbial diversity and 44 reproducible species are independently linked to kidney function in community dwelling adults. Enrichment of histidine and carnitine pathways, and their circulating metabolites implicates microbial metabolism as a contributor to eGFR variability, suggesting tractable targets for early kidney protection.