Shen-Bai-Jie-Du decoction inhibits colorectal tumorigenesis by attenuating the malignancy of cancer stem cells via the gut microbiota-bile acid-FXR axis

Abstract

Background: Shen-Bai-Jie-Du decoction (SBJDD), a traditional Chinese herbal formula grounded in evidence-based medicine, demonstrates efficacy in reducing the recurrence and carcinogenesis of colorectal adenoma (CRA). However, the mechanism by which SBJDD inhibits CRA carcinogenesis remains unclear.

Purpose: This study aimed to elucidate the mechanism through which SBJDD suppresses colorectal cancer stem cell (CSC) aggressiveness by modulating the gut microbiota-bile acid (BA)-Farnesoid X receptor (FXR) signaling axis.

Methods: The APC^min/+ mouse model and subcutaneously tumor-bearing mouse model were established to investigate the efficacy and underlying mechanisms of SBJDD in CRA carcinogenesis. Multi-omics analyses were conducted using 16S rRNA, metabolomics, and transcriptome sequencing. The pharmacological effects and mechanisms of SBJDD were evaluated through RT-qPCR, immunohistochemical staining, molecular docking, Western blot, immunofluorescence staining, and flow cytometry assay. Moreover, paired fecal samples and adenoma tissues were collected from CRA patients to further validate the findings.

Results: Our findings demonstrated that SBJDD can protect the integrity of the intestinal mucosal barrier, thereby inhibiting colorectal tumorigenesis. Mechanistically, our study revealed that SBJDD can reduce the fecal abundance of BA-producing gut microbiota. Meanwhile, we confirmed that the BA receptor FXR and its downstream target genes were significantly upregulated following SBJDD administration, and molecular docking analyses demonstrated that the bioactive components of SBJDD can bind to FXR. Moreover, we showed that SBJDD can downregulate CSC marker genes by regulating FXR signaling pathways.

Conclusion: Our study objectively verified that SBJDD can alleviate the malignancy of CSCs by modulating the gut microbiota-bile acid-FXR axis, ultimately suppressing the progression from colorectal adenoma to carcinoma.

Keywords: Bile acid; Cancer stem cells; Colorectal adenoma; Farnesoid X receptor; Gut microbiota; Shen-Bai-Jie-Du decoction.