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Objective. To explore the effect and underlying mechanism of Zengye decoction (ZYD), a traditional formula from China, on the severe acute pancreatitis (SAP) rat model with acute kidney injury (AKI). Methods. The SAP-AKI model was induced by 3.5% sodium taurocholate. Rats were treated with normal saline or ZYD twice and sacrificed at 36 h after modeling. Amylase, lipase, creatinine, blood urea nitrogen, kidney injury molecule 1(KIM-1), and multiple organs' pathological examinations were used to assess the protective effect of ZYD. Gut microbiome detected by 16S rRNA sequencing analysis and serum amino acid metabolome analyzed by liquid chromatography-mass spectrometry explained the underlying mechanism. The Spearman correlation analysis presented the relationship between microflora and metabolites. Results. ZYD significantly decreased KIM-1(P < 0.05) and the pathological score of the pancreas (P < 0.05), colon (P < 0.05), and kidney (P < 0.05). Meanwhile, ZYD shifted the overall gut microbial structure (β-diversity, ANOSIM R = 0.14, P = 0.025) and altered the microbial compositions. Notably, ZYD reduced the potentially pathogenic bacteria—Bacteroidetes, Clostridiales vadin BB60 group, and uncultured_Clostridiales_bacterium, but promoted the short-chain fatty acid (SCFA) producers—Erysipelotrichaceae, Bifidobacterium, Lactobacillus, and Moryella (all P < 0.05). Moreover, principal component analysis (PCA), partial least squares-discriminant analysis (PLS-DA), and hierarchical clustering analysis (HCA) presented a remarkable change in amino acid metabolome after SAP-AKI induction and an apparent regulation by ZYD treatment (R2Y 0.878, P = 0.01 ; Q2 0.531, P = 0.01). Spearman's correlation analysis suggested that gut bacteria likely influenced serum metabolites levels (absolute r > 0.4 and FDR P < 0.02). Conclusions. ZYD attenuated SAP-AKI by modulating the gut microbiome and serum amino acid metabolome, which may be a promising adjuvant treatment. [ABSTRACT FROM AUTHOR]