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Speeckaert,  \nGhent University Hospital, Belgium  \nREVIEWED BY  \nİsmail Mert Vural,  \nUniversity of Health Sciences (Turkey), Türkiye Xiangyu Zou,  \nShanghai Children’s Hospital, China  \n*CORRESPONDENCE  \nSami Alobaidi  \n [salobaidi@uj.edu.sa](salobaidi@uj.edu.sa)  \nRECEIVED 29 July 2025  \nREVISED 02 December 2025  \nACCEPTED 04 December 2025  \nPUBLISHED 23 December 2025  \nCITATION  \nAlobaidi S (2025) The gut–kidney axis in chronic kidney disease: mechanisms, microbial metabolites, and microbiome-targeted therapeutics.  \nFront. Med. 12:1675458 .  \ndoi: 10.3389/fmed.2025.1675458  \nCOPYRIGHT  \n© 2025 Alobaidi. This is an open-access article distributed under the terms of the  \nCreative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.  \nTYPE Review  \nPUBLISHED 23 December 2025 DOI 10.3389/fmed.2025.1675458  \nThe gut–kidney axis in chronic kidney disease: mechanisms, microbial metabolites, and microbiome-targeted therapeutics  \nSami Alobaidi*  \nDepartment of Internal Medicine, University of Jeddah, Jeddah, Saudi Arabia  \nChronic kidney disease (CKD) remains a major global health issue, affecting millions and presenting persistent diagnostic and therapeutic challenges. Conventional biomarkers such as serum creatinine and estimated glomerular filtration rate have well-recognized limitations, underscoring the need for novel diagnostic tools and interventions. Emerging evidence highlights the gut–kidney axis as a central contributor to CKD pathogenesis, shaped by microbial dysbiosis and altered metabolite production. Harmful metabolites such as indoxyl sulfate, p-cresyl sulfate, and trimethylamine-N-oxide promote inflammation, endothelial dysfunction, and fibrosis, while loss of protective short-chain fatty acids impairs barrier integrity and immune regulation. This review integrates mechanistic, translational, clinical, and therapeutic perspectives, offering a comprehensive and distinctive synthesis of current knowledge. We emphasize both harmful and protective microbial metabolites, incorporate the often-overlooked oral–gut–kidney axis, and highlight advances in multi-omics and computational approaches for biomarker discovery. Microbiome-targeted interventions—including dietary strategies, prebiotics, probiotics, synbiotics, oral adsorbents, and fecal microbiota transplantation—are critically evaluated with respect to efficacy, safety, and translational readiness. By bridging basic science, clinical evidence, and therapeutic implications, this review provides a forward-looking framework for integrating microbiome insights into CKD diagnosis and management. Our synthesis complements existing literature while highlighting unmet needs, thereby informing future research priorities and guiding the development of clinically relevant microbiome-based strategies.  \nKEYWORDS  \nchronic kidney disease, dysbiosis, fecal microbiota transplantation, gut microbiota, gut– kidney axis, microbiome-targeted therapy, trimethylamine N-oxide, uremic toxins  \n1 Introduction and rationale  \nChronic kidney disease (CKD) is a significant global health concern, currently affecting approximately 9.1% of the global population, corresponding to approximately 697 million individuals, with substantial contributions to morbidity, mortality, and healthcare costs ( 1). Early detection of CKD remains difficult due to limitations of conventional diagnostic tools. Serum creatinine and estimated glomerular filtration rate (eGFR), common indicators of kidney function, are significantly influenced by age, sex, and muscle mass, thereby reducing their accuracy, especially during CKD’s initial stages (2, 3). These limitat","cbCaiq8T1D5QBLTC","https://ap.wps.com/l/cbCaiq8T1D5QBLTC","pdf",1587719,"English","# 1 Introduction and rationale\n## Gut–kidney axis and uremic metabolites\n## Dysbiosis across pediatric and adult CKD\n## Microbiome-targeted therapies and clinical variability","[{\"question\":\"Why are conventional CKD biomarkers such as serum creatinine and eGFR limited?\",\"answer\":\"They are influenced by age, sex, and muscle mass, which reduces accuracy, particularly in early CKD. The review highlights the resulting need for better biomarkers and advanced diagnostic methods.\"},{\"question\":\"How does the gut–kidney axis contribute to CKD progression?\",\"answer\":\"CKD-associated uremia disrupts intestinal balance, while gut-derived microbial metabolites further drive kidney damage, inflammation, and fibrosis. Dysbiosis increases toxin-producing bacteria and raises uremic toxins such as indoxyl sulfate, p-cresyl sulfate, and TMAO.\"},{\"question\":\"What microbiome-targeted interventions are discussed, and how is their effectiveness evaluated?\",\"answer\":\"The review evaluates dietary strategies, prebiotics, probiotics, synbiotics, oral adsorbents, and fecal microbiota transplantation. It emphasizes assessing efficacy, safety, and translational readiness, noting that outcomes can vary across interventions.\"}]","The gut–kidney axis in chronic kidney disease: mechanisms, microbial metabolites, and microbiome-targeted therapeutics | PDF",1790704945,45]