Synergistic Sorafenib with Jianpi Huayu Decoction Resulted in Tumor Regression and Prevented Adverse Events in Hepatocellular Carcinoma by Remodeling the Gut Microbiota

Abstract Background: There is an urgent need for effective treatments for hepatocellular carcinoma (HCC). Sorafenib is first-line treatment for HCC, which has a modest efficacy due to severe adverse effects(AE), acquired resistance and others. Combination therapy may be able to overcome this limitation. Jianpi Huayu Decoction (JHD) is a traditional Chinese medicine formulation, which has been shown to be effective as an alternative and complementary therapy of HCC. We investigated the synergistic effect of JHD with sorafenib by a xenograft model.Methods: Growth of mouse-derived HCC cells and adverse events(AE) of treatment were evaluated in a subcutaneous model with JHD and clinical-dose sorafenib combination treatment. Diarrhea, the most frequently reported AE, was evaluated by diarrhea score. The gut microbiota(GM) composition of the mice was analyzed by Illumina NovaSeq. Results: JHD administration in mice synergistically enhanced the anti-tumor response, thereby suppressing HCC, and prevented occurrence of the most common AEs(diarrhea and body weight loss) of sorafenib. Sorafenib induced increased proinflammatory GM(Helicobacter) which promoted the progression of HCC and against anti-tumor treatment. JHD reduced the abundance of anti-inflammatory microbiota Muribaculum, Fusicatenibacter, and Dorea. Following the modulation of GM, the proinflammatory signaling interleukin 6/signal transducer and activator of transcription-3 pathway was downregulated by JHD.Conclusions: Our finding suggested that differences in the microbial gut flora may modulate resistance to sorafenib through IL-6/STAT3 signaling. JHD with microbiota modulation properties could potentiate sorafenib and provided a promising approach for HCC treatment.