Some components of Zexie（Alismatis Rhizoma）are nephrotoxic and may cause kidney injury through intestinal flora. In the combination of Liuwei Dihuang Pills（六味地黄丸），the pharmacological effects of the other medicinal materials may reduce or offset the nephrotoxicity of Zexie（Alismatis Rhizoma），thereby exerting an overall kidney protective effect. Therefore，it is necessary to explore the mechanism of drug-induced kidney injury caused by Zexie（Alismatis Rhizoma）and the protective mechanism of Liuwei Dihuang Pills on kidney disease from the perspective of the “gut-kidney axis”.

In this study，the potential target of kidney injury induced by Zexie（Alismatis Rhizoma）was screened by network toxicology，and the potential target of Liuwei Dihuang Pills for protecting kidney injury was screened by network pharmacology. In addition，Mendelian randomization method was used to conduct the causal inference analysis between microbiota and kidney injury diseases. Relevant genes adjacent to significant single nucleotide polymorphisms（SNPs）were searched on NCBI and 3DSNP websites. Finally，protein-protein interaction（PPI）network was constructed with potential drug targets to explore the mechanism of reducing kidney injury caused by Zexie（Alismatis Rhizoma）combined with Liuwei Dihuang Pills.

After screening on the traditional Chinese medicine system toxicology database（TCMSTD）platform，15 toxic components were obtained，and the overlap target of toxic components of Zexie（Alismatis Rhizoma）with intestinal flora dysregulation syndrome and kidney injury was HSPA5. In addition，66 active components of Liuwei Dihuang Pills were obtained from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform（TCMSP），and 27 common targets were obtained with intestinal flora dysregulation syndrome and kidney injury. Through Mendelian randomization，the causal relationship of intestinal flora induced kidney injury was investigated. Marvinbryantia，Lachnospiraceae，Porphyromonadaceae and Coprococcus1（OR>1）were found to cause kidney injury. The gene HSPA5 located in the significant SNP of the flora in the PPI network had protein interaction with the target of kidney injury caused by Zexie（Alismatis Rhizoma），indicating that Zexie（Alismatis Rhizoma）may cause kidney injury by regulating such intestinal flora. The causal relationship between intestinal flora and kidney injury was investigated by Mendelian randomization. Among the intestinal flora that had protective effects on kidney injury，there were 15 types of flora that had protective effects on kidney injury（OR<1）. In the PPI network，the gene with significant bacterial SNPS had the highest TNF degree，which had protein interaction with the target of Liuwei Dihuang Pill protective effect on kidney injury.

From the perspective of the “gut-kidney axis”，Zexie（Alismatis Rhizoma）has the mechanism of drug-induced kidney injury through regulation of HSPA5，but Liuwei Dihuang Pills have a protective effect on kidney through regulation of TNF through combination，which illustrates the efficacy and safety mechanism of Liuwei Dihuang Pills.