Effects of Sodium-Glucose Cotransporter-2 Inhibitors on Modulating Protein-Bound Uremic Toxins and Gut Microbiota in Predialysis CKD Patients

Key Points A reduction of indoxyl sulfate, p-cresyl sulfate, and several short-chain fatty acids was seen in sodium-glucose cotransporter-2 inhibitor-treated CKD patients. Variations in gut microbiota composition are correlated with levels of gut-derived uremic toxins in sodium-glucose cotransporter-2 inhibitor-treated CKD patients. Background The intricate interplay between CKD and intestinal microbiota has gained increasing attention, with gut dysbiosis being implicated in uremic toxin accumulation and CKD progression. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are now transforming CKD management but pose uncertain effects on shaping gut microbiota. This study aimed to elucidate the effect of SGLT2i on perturbations of gut microbial composition and metabolic responses in patients with CKD. Methods Analysis of fecal microbiota and targeted profiling of serum short-chain fatty acids and gut-derived uremic toxins were conducted in a matched case-control study, including 60 patients with CKD (treated: n =30; untreated: n =30) and 30 non-CKD controls. Results Gut microbial composition differed significantly among the three study groups. Patients with CKD receiving SGLT2i exhibited distinctive taxonomic profiles, such as enrichment of Bacteroides stercoris and Bacteroides coprocola. Surveys of metabolomic profiles revealed a reduction of two uremic solutes, indoxyl sulfate and p-cresyl sulfate (pCS), and several short-chain fatty acids (formic, acetic, propionic, valeric, and 2-methylbutanoic acid) in SGLT2i-treated CKD patients. Co-occurrence analysis demonstrated a set of intestinal microbes that is positively or negatively correlated with the levels of pCS, and the abundance of these pCS-associated intestinal microorganisms was correlated with the levels of indoxyl sulfate and isovaleric acids in the same and opposite direction, respectively. Further functional prediction indicated attenuated pathways related to protein and carbohydrate metabolism. Conclusions Treatment with SGLT2i in patients with CKD is associated with distinct gut microbial composition and metabolite profiles, suggesting potential modulation of gut dysbiosis and metabolic pathways. Further studies are warranted to elucidate the clinical implications of these findings in CKD management.