Gut Microbiota–Mediated Bile Acid Metabolism Regulates Colorectal Cancer Liver Metastasis by Altering Neutrophil Recruitment

The gut microbiome is frequently dysregulated in colorectal cancer. Gut microbiota can modify bile acids (BA), which is a group of metabolites that have been linked to tumorigenesis and progression. In this study, we observed a significant deficiency in gut bacteria with bile salt hydrolase (BSH) activity in patients with liver metastatic colorectal cancer (CRLM). These patients exhibited elevated levels of conjugated primary BAs (CPBA) and decreased levels of unconjugated BAs (UBA) in their circulation. The changes in bacterial BSH activity and CPBA levels were more pronounced in male patients with CRLM. Microbial manipulation in mouse colorectal cancer models to create a BSH-deficient state increased CPBAs, reduced UBAs, and promoted liver metastasis. Specifically, taurocholic acid (TCA), a CPBA, promoted CRLM through a neutrophil-dependent mechanism. TCA upregulated TIMP1 in colorectal cancer cells, which in turn stimulated CXCL5/CXCR2-mediated neutrophil recruitment and CRLM. Alternatively, unconjugated primary and secondary BAs counteracted neutrophil migration induced by TCA in vitro and abolished TCA-promoted neutrophil recruitment and liver metastasis in vivo. Together, these findings elucidate a mechanistic role of the dysregulated gut microbiota-BA axis in CRLM, suggesting that manipulating the balance between conjugated and UBAs could be a potential therapeutic strategy to suppress colorectal cancer metastasis. SIGNIFICANCE: In colorectal cancer, enrichment of bile salt hydrolase-deficient gut microbiota elevates conjugated primary bile acids that promote liver metastasis by inducing TIMP1-mediated neutrophil recruitment, which can be reversed by supplementing with unconjugated bile acids.