Integrated analysis of fecal metabolome, lipidome and pseudo-germ-free model reveals the mechanisms of Qikui granules in the treatment of diabetic kidney disease.

Diabetic kidney disease (DKD) has a complex and multifactorial pathogenesis, and highly effective pharmacotherapies for this condition remain limited. Qikui granules (QKG), a compound traditional Chinese medicine preparation, has shown favorable therapeutic efficacy against DKD in clinical studies. Our prior work, based on integrated network pharmacology, 16S rRNA gene sequencing, and lipidomic profiling of serum and kidney tissues, demonstrated that QKG ameliorates DKD in db/db mice by enriching Candidatus Arthromitus and modulating lipid homeostasis. As a follow-up validation of our earlier findings, the present study adopts an integrated multi-omics strategy combining fecal metabolomics, lipidomics, and 16S rRNA sequencing, coupled with a pseudo-germ-free mouse model, to further elucidate the therapeutic efficacy of QKG against DKD and the pivotal role of gut microbiota in its renoprotective effects. Firstly, fecal metabolomic and lipidomic profiling was performed to explore the pharmacological mechanisms of QKG against DKD. Subsequently, a pseudo-germ-free mouse model established via antibiotic administration was used to verify the microbiota-mediated mechanism of QKG. Metabolomic and lipidomic analysis revealed that QKG significantly reversed the upregulation of 24 special potential biomarkers (SPBs) in feces, including phosphatidylcholines (PC), phosphatidylethanolamines (PE) and unsaturated fatty acids (UFA); glycerophospholipid metabolism and arachidonic acid metabolism were identified as the most relevant pathways. The pseudo-germ-free mouse model validated the microbiota-dependent therapeutic effect of QKG on DKD from both pharmacodynamic and gut microbiota composition perspectives. Furthermore, correlation analysis showed that the 24 SPBs associated with the anti-DKD efficacy of QKG were negatively correlated with the relative abundance of Candidatus Arthromitus. Collectively, our findings suggest that QKG exerts microbiota-dependent efficacy against DKD-related metabolic disorders and inflammation, mainly by increasing the abundance of Candidatus Arthromitus and thereby reducing the levels of PC, PE, and UFA.