Gut microbiota pathways linking primary sclerosing cholangitis to colorectal cancer: the Lachnospiraceae family and PCBP1.

BACKGROUND

Colorectal cancer (CRC) remains a leading cause of cancer-related death worldwide. Primary sclerosing cholangitis (PSC) increases the risk of CRC, but the biological link is not well understood. Changes in the gut-liver axis, including gut microbiota and microbial metabolites, may contribute to CRC development in PSC.

OBJECTIVE

To explore pathways connecting PSC with CRC through gut microbiota signals, and to identify candidate host genes for follow-up analyses.

METHODS

Mendelian randomization (MR) was used to estimate the causal effect of genetically predicted PSC on CRC risk and to test associations between PSC liability and gut microbial traits. Mediation analyses were performed to assess whether specific microbial features may contribute to the PSC-CRC association. Single-cell RNA sequencing (scRNA-seq) data from PSC and CRC were integrated to screen candidate host genes, which were further evaluated using survival analyses and immunohistochemistry.

RESULTS

MR supported a causal association between PSC and higher CRC risk (OR = 1.172, 95% CI: 1.033-1.329, P = 0.014). Genetically predicted PSC was associated with changes in gut microbial composition, with the family Lachnospiraceae emerging as a notable feature. Within these signals, the genus Lachnospiraceae FCS020 group was associated with CRC risk (OR = 1.237, 95% CI: 1.004-1.523, P = 0.045) and partially mediated the PSC-CRC association (mediating proportion 13.7%, 95% CI: 1.0%-68.1%; indirect effect 0.021, 95% CI: 0.000-0.054). In scRNA-seq analyses, PCBP1 emerged as a shared signal across PSC and CRC programs and was linked to butyrate related gene signatures. Higher PCBP1 expression was associated with poorer overall survival (OS) and recurrence-free survival (RFS) in CRC, and PCBP1 showed a positive association with PD-L1 by immunohistochemistry in an exploratory analysis.

CONCLUSION

These findings provide supportive evidence that gut microbiota changes and host gene signals are linked to the PSC-CRC association. Lachnospiraceae related microbial features and PCBP1 warrant further validation. Studies in independent cohorts and mechanistic models will be important to clarify functional specificity and clinical utility.