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However, the causal relationship between gut microbiota and chronic kidney disease (CKD) or related kidney function, and whether cytokines and immune cells act as mediators, remains unclear. Using genome-wide association studies (GWAS) data for CKD, estimated glomerular filtration rate (eGFR) and UACR (urinary albumin to creatinine) from the CKDGen consortium, microbiome data from the MiBioGen consortium and the Dutch Microbiome Project (DMP), 41 cytokine and 731 immune cell traits were identified from large-scale GWAS summary data. We performed two-sample Mendelian randomization (MR) analysis to analyses the causal relationships between gut microbiome, circulating cytokines, immune cells and CKD, eGFR and UACR. In addition, we investigated whether cytokines and immune cells are the mediating factor in the pathway from gut microbiome to CKD, eGFR and UACR. We demonstrated the causal relationships between 8 gut microbiotas in MiBioGen and 8 gut microbiota and 6 metabolism pathways in DMP with CKD, 7 gut microbiotas in MiBioGen and 7 gut microbiota and 3 metabolism pathways with eGFR and 4 gut microbiotas in MiBioGen and 10 gut microbiota and 3 metabolism pathways in DMP with UACR. Additionally, we identified 25 cytokine and immune cell characteristics associated with CKD, 18 with eGFR and 22 with UACR. Importantly, we identified no cytokine, but several immune cell properties that mediate the effects of microbiome on CKD, eGFR and UACR through mediation MR analysis. For instance, <jats:italic>Alistipes indistinctus<\/jats:italic> and <jats:italic>Alistipes putredinis<\/jats:italic> affects CKD via CD28\u2009+\u2009CD45RA\u2009+\u2009CD8\u2009+\u2009T cell. The mediation effects highlighted the intricate relationship between gut microbiome exposure, immune cell activity, and their combined influence on CKD. This data supports a causal effect of the gut microbiome on CKD, eGFR and UACR and underscores the value of MR in clarifying causal relationships identified in microbiome-wide association studies. Circulating immune cells may act as mediators in the pathway linking gut microbiota to CKD progression.<\/jats:p>","DOI":"10.1038\/s41598-025-05941-x","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T18:29:35Z","timestamp":1751394575000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Mendelian randomization study revealed a gut microbiota-immune system-kidney junction axis in chronic kidney disease"],"prefix":"10.1038","volume":"15","author":[{"given":"Junjie","family":"Tan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhile","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengyou","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"key":"5941_CR1","doi-asserted-by":"publisher","first-page":"1229636","DOI":"10.3389\/fimmu.2023.1229636","volume":"14","author":"H Li","year":"2023","unstructured":"Li, H. et al. 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