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While FOLFOX has been the preferred chemotherapeutic strategy in colon cancer treatment, the limited response rate has seriously restricted its application in clinic. The underlying mechanisms of the individual response of FOLFOX remain to be elucidated. In this study, pharmacomicrobiomics integrated with pharmacometabolomics was applied to disentangle the key role of specific gut bacteria and microbiota derived metabolites involved. As a result , significant variation of chemotherapy efficacy was observed in tumor bearing mice after FOLFOX administration. 16S rRNA gene sequencing analysis revealed the relative abundance of Staphylococcus , Jeotgalicoccus , Sphingomonas significantly increased in the FOLFOX sensitive group, whereas Prevotella was higher in the non sensitive individuals . Meanwhile, verification study o n FOLFOX combined with bacteria colonization indicates that Prevotella could attenuate the anti cancer efficacy of FOLFOX in vivo . Furthermore, gut derived metabolite 3-Oxocholic acid (3-Oxo) identified by metabolomics approach was confirmed to associate with Prevotella in fecal samples. In addition, preliminary functional exploration suggested that 3-Oxo could reverse the anti cancer effect of FOLFOX and promote malignant progression Taken together, integrated pharmacomicrobiomics and pharmacometabolomics revealed that Prevotella and related metabolite 3-Oxo may be responsible for individualized FOLFOX efficacy, which provides novel predictive biomarkers for FOLFOX precise medicine as well as targets for colon cancer therapy.

Radix Bupleuri is a hepatoprotective traditional Chinese medicine (TCM) used for thousands of years in clinical, which was reported to be linked with liver damage. Previous studies have revealed that saikosaponins are the major types of components that contribute to the hepatotoxicity of Radix Bupleuri. However the underlying molecular mechanism is far from being understood. In order to clarify whether these structural analogues exert toxicity effects through the same molecular targets, a systematic comparison study was done in this paper. The effects of SSa, b2, c, and d on isolated rat liver mitochondria and human hepatocyte L02 cells were explored, respectively. The collective results indicated that although saikosaponins share the similar structures but they have quite different mechanisms. SSb2 and SSd showed most serious damage on the function of mitochondria and survival rate of cell, respectively. SSb2 could cause mitochondrial permeability transition pore (mPTP) opening and collapse of mitochondrial membrane potential ({\Delta}{\Psi}m) by impairing the mitochondrial respiratory chain complex III. While SSd destroyed plasma membrane and led to the release of lactate dehydrogenase (LDH) mainly through activating caspase-1. Furthermore, the combine index (CI) demonstrated that the combined hepatotoxicity of SSb2 and SSd could be additive. This finding might yield more in depth understanding of hepatotoxicity of Radix Bupleuri possess many different saikosaponins.