Prevotella Contributing to the Individual Respons E of e of FOLFOX in Colon Cancer

Fengguo Xu (  fengguoxu@cpu.edu.cn ) Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of 6 Education), State Key Laboratory of Natural Medicine, China Pharmaceutical 7 University, Nanjing 210009, China 8 b https://orcid.org/0000-0001-9999-0128 Xiaoying Hou China Pharmaceutical University Weihua Chu China Pharmaceutical University Hongzhi Du Hubei University of Chinese Medicine Yiqiao Gao China Pharmaceutical University Ruiqi Sun China Pharmaceutical University Siyuan Qin China Pharmaceutical University Yuan Tian China Pharmaceutical University Pei Zhang China Pharmaceutical University Zunjian Zhang China Pharmaceutical University


Abstract
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 speci c gut bacteria and microbiota derived metabolites involved. As a result , signi cant variation of chemotherapy e cacy was observed in tumor bearing mice after FOLFOX administration. 16S rRNA gene sequencing analysis revealed the relative abundance of Staphylococcus , Jeotgalicoccus , Sphingomonas signi cantly increased in the FOLFOX sensitive group, whereas Prevotella was higher in the non sensitive individuals .
Meanwhile, veri cation study o n FOLFOX combined with bacteria colonization indicates that Prevotella could attenuate the anti cancer e cacy of FOLFOX in vivo . Furthermore, gut derived metabolite 3-Oxocholic acid (3-Oxo) identi ed by metabolomics approach was con rmed 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 e cacy, which provides novel predictive biomarkers for FOLFOX precise medicine as well as targets for colon cancer therapy.

Full-text
Due to technical limitations, full-text HTML conversion of this manuscript could not be completed. However, the manuscript can be downloaded and accessed as a PDF. There is no obvious difference on body weight ( e ) and tumor volume f ) in S and NS group before FOLFOX administration. RTV ( g ), inhibition rate h ) and Ki67 levels ( i ) of S (n=8) and NS (n=9) group at the end of the experiment (day12). Data was expressed as mean ± SD. The p values < 0.05 were considered statistically signi cant, * p <0.05, **p <0.01, ***p <0.001.    3-Oxo may be the key metabolite responsible for gut microbiota mediated FOLFOX e cacy. Relative abundance of indole 3-carboxylic acid (a ), 3-oxocholic acid b and phenylalanyl-asparaginec was signi cantly associated with the level of prevotella as measured by the Spearman's correlations analysis . ( d ) Concentrations of 3-Oxo in fecal samples from Model (n=20), ABX (n=20) and Prevotella (n=20) group, respectively. Data was expressed as mean ± SD. The p values < 0.05 were considered statistically signi cant, *p<0.05, **p<0.01.

Figure 6
Effects of 3-Oxo on CT 26 migration as well as on the anti cancer effect of FOLFOX. a, b ) The effect of 3-Oxo on CT 26 proliferation was evaluated by MTT (72 h) and colon formation assay (7 days). ( c, d ) 3-Oxo could attenuate the anti proliferation effect of FOLFOX (72h, 7days). ( e-f ) The effect of 3-Oxo on CT-26 migration was evaluated by wound healing assay and transwell chambers. ( g ) 3-Oxo could induce the secretion of IL-1β and TNF-α in macrophages. Data was expressed as mean ± SD of three independent experiments. The p values < 0.05 were considered statistically signi cant, *p<0.05, **p<0.01 , ***p<0.001.

Figure 7
Overview of the current study. Pharmacodynamic evaluation was used to identify individualized S and NS mice after FOLFOX treatment. Pharmacomicrobiomics was used integrated with pharmacometabolomics to identify biomarkers in fecal samples mediating FOLFOX e cacy. Prevotella and 3-Oxocholic acid were nally con rmed for contributing to individualized FOLFOX response.

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