Metabolites Mediate the Causal Associations Between Gut Microbiota and Chronic Kidney Disease: A Mendelian Randomization Study and Therapeutical Strategy from Traditional Chinese Medicine Perspective

Background:In chronic kidney disease (CKD), patients often suffer from intestinal barrier damage and gut microbiota disorders, characterized by reduced beneficial bacteria, increased harmful bacteria, and production of neurotoxins that worsen kidney damage. While associations between gut microbiota, plasma metabolites, and CKD have been observed, the causal relationships remain unclear and may be confounded by other factors. To address this, we used Mendelian randomization (MR) to investigate the causal effects of gut microbiota and plasma metabolites on CKD. Simultaneously, we explored the strategy of Traditional Chinese medicine to regulate the influence of gut microbiota mediated by serum metabolites on CKD. Methods:A two-sample MR study was conducted to evaluate the potential causal connections among gut microbiota, plasma metabolites, and CKD susceptibility. Gut microbiota data were obtained from the genome-wide association studies (GWASs) of gut microbiome composition by the Dutch Microbiome Project. CKD data were procured from the FinnGen biobank analysis, while comprehensive GWAS summary statistics for plasma metabolites were derived from the NHGRI-EBI GWAS Catalog. Fluctuations in gut microbiota and plasma metabolites in patients with CKD were evaluated using the weighted mode method. Additionally, pleiotropic and heterogeneity analyses were conducted to assess the reliability of the findings. Results:Twelve taxonomic and bacterial pathways and sixteen metabolites were found to be significantly associated with CKD. MR analysis revealed four causal relationships. Mediation analysis showed that arachidonoylcholine levels mediated the causal relationship between the enterobacterial common antigen biosynthesis pathway (ECASYN.PWY) and the risk of CKD, with a mediation proportion of 24.8%. X-12007 levels mediated the causal relationship between the aspartate superpathway (PWY0.781) and the risk of CKD, with a mediation proportion of 15.6%. N-acetyl-2-aminooctanoate levels mediated the relationship between tetrapyrrole biosynthesis II from glycine pathway (PWY.5189) and the risk of CKD, with a mediation proportion of 7.7%. X-22776 levels mediated the causal relationship between the superpathway of pyrimidine deoxyribonucleotides de novo Biosynthesis (PWY.7211) and the risk of CKD, with a mediation proportion of 23.8%. Conclusion:The current MR study provides evidence supporting potential causal relationships among specific gut microbiota taxa and pathways, plasma metabolite, and CKD. These findings offer novel perspectives for future research and the development of treatment and prevention strategies for CKD, as well as a scientific basis for traditional Chinese medicine intervention in the gut microbiota.