Jianpi Huayu Decoction enhances the effect of sorafenib and alleviates adverse events in hepatocellular carcinoma by remodeling the gut microbiota

Abstract

BackgroundThere is an urgent need for effective treatment for advanced hepatocellular carcinoma (HCC). Sorafenib, a multi-kinase inhibitor, is the first-line treatment for advanced HCC, which has a modest efficacy due to severe adverse effects (AEs), acquired resistance, and others. Jianpi Huayu Decoction (JHD) is a traditional Chinese medicine formulation, effective as an alternative and complementary therapy of HCC. Combined sorafenib with JHD is a potential approach to overcome sorafenib resistance. MethodsEffect and AEs of clinical-dose sorafenib combined JHD were evaluated in a subcutaneous model. Diarrhea, the most frequently reported AEs, was evaluated by diarrhea score. Illumina NovaSeq analyzed the gut microbiota (GM) composition of the mice. ResultsJHD administration enhanced anti-tumor response to sorafenib and prevented the occurrence of sorafenib-induced diarrhea and body weight loss. Proinflammatory GM Helicobacter positively correlated with sorafenib treatment while anti-inflammatory GM, Muribaculum, Fusicatenibacter, and Dorea positively correlated with JHD treatment. In addition, JHD decreased the infiltration of inflammatory cells and downregulated signaling of interleukin 6/signal transducer and activator of the transcription-3 pathway. ConclusionsOur finding suggested that JHD with microbiota modulation properties could significantly potentiate sorafenib and provide a promising treatment for advanced HCC.