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.

The liver is the most common site for colorectal cancer (CRC)–associated metastasis. There remain unsatisfactory medications in liver metastasis given the incomplete understanding of pathogenic mechanisms. Herein, with an orthotopic implantation model fed either regular or high-fat diets (HFD), more liver metastases were associated with an expansion of conjugated bile acids (BAs), particularly taurocholic acid (TCA) in the liver, and an increased gene expression of Na⁺–taurocholate cotransporting polypeptide (NTCP). Such hepatic BA change was more apparently shown in the HFD group. In the same model, TCA was proven to promote liver metastases and induce a tumor-favorable microenvironment in the liver, characterizing a high level of fibroblast activation and increased proportions of myeloid-derived immune cells. Hepatic stellate cells, a liver-residing source of fibroblasts, were dose-dependently activated by TCA, and their conditioned medium significantly enhanced the migration capability of CRC cells. Blocking hepatic BA uptake with NTCP neutralized antibody can effectively repress TCA–triggered liver metastases, with an evident suppression of tumor microenvironment niche formation. This study points to a new BA–driven mechanism of CRC–associated liver metastases, suggesting that a reduction of TCA overexposure by limiting liver uptake is a potential therapeutic option for CRC—associated liver metastasis.

Bile acids regulate Timp1 and CXCL5 expression,which associated with the disease-free survival of CRC

KEGG enrichment pathway of metastatic colorectal cancer

CPBAs promote liver metastasis in CRC mice induced by orthotopic implantation or intrasplenic injection