Effects of SGLT2 Inhibitors on Modulating Protein-Bound Uremic Toxins and Gut Microbiota in Pre-Dialysis CKD Patients: A Matched Case-Control Study

Background:The intricate interplay between chronic kidney disease (CKD) and intestinal microbiota has gained increasing attention, with gut dysbiosis being implicated in uremic toxin accumulation and CKD progression. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are now transforming CKD management but pose uncertain effects on shaping gut microbiota. This study aimed to elucidate the impact of SGLT2 inhibitors on perturbations of gut microbial composition and metabolic responses in CKD patients.Methods:Analysis of fecal microbiota and targeted profiling of serum short-chain fatty acids (SCFAs) and gut-derived uremic toxins were conducted in a matched case-control study, including 60 CKD patients (treated: n=30; untreated: n=30) and 30 non-CKD controls.Results:Gut microbial composition differed significantly among three study groups. CKD patients receiving SGLT2 inhibitors 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 (IS) and p-cresyl sulfate (pCS), and several SCFAs (formic, acetic, propionic, valeric, and 2-methylbutanoic acid) in SGLT2 inhibitor-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 IS 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 SGLT2 inhibitors in CKD patients 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.