The Gut–Kidney Axis in Chronic Kidney Disease: Microbial Dysbiosis, Host–Microbial Metabolism, and Emerging Therapeutic Strategies

Chronic kidney disease (CKD) appears linked to changes in the gut microbiota, intestinal barrier defects, and microbiota-driven changes in metabolite profiles. Experimental evidence links gut microbiota disturbances to kidney injury through pathways such as microbial metabolism, inflammation, immune signals, and epithelial barrier dysfunction. Still, applying this knowledge in clinical practice for patients with CKD remains difficult. For instance, one study on indoxyl sulfate and p-cresyl sulfate levels in a patient showed that, beyond being synthesized by the intestinal microbiota, the host can also metabolize or alter these metabolites. In addition, they undergo impaired renal clearance and can be secreted by the tubules. Moreover, most human microbiome-related studies are observational, making it difficult to determine the causal role of bacterial dysbiosis. Disease, dietary factors, medication, and other comorbid conditions are major confounders. Microbiota-directed means of altering the composition of the microbiota, such as changing diet, using prebiotics, probiotics, synbiotics, oral adsorbents, and even fecal microbiota transplantation, have, to varying degrees, affected the composition of the gut microbiota, levels of uremic toxins, short-chain fatty acids, and markers of inflammation. They have also been connected to leaky gut syndrome. However, evidence that these actions delay eGFR decline or prevent kidney failure, cardiovascular events, hospitalization, or mortality remains limited. Postbiotics and microbiota-derived metabolites in pure form are distinct experimental therapies and need to be assessed independently. This article reviews the gut kidney axis at different levels of evidence and distinguishes preclinical mechanisms, human associations, surrogate biomarker responses, and clinical outcomes. It points out why impressive mechanistic and biomarker results have not translated into better kidney or cardiovascular outcomes. Future research should use standardized methodologies, provide more detail on microbial functions and host metabolite metabolism, and test microbiome-targeted therapies in sufficiently powered randomized controlled trials with meaningful endpoints.