Association between gut microbial dysbiosis and clinical prognosis of advanced colorectal cancer

Abstract

BACKGROUND

Gut microbiota dysbiosis is involved in the progression of colorectal cancer, but its prognostic value in advanced colorectal cancer (aCRC) and correlation with chemotherapy response remain insufficiently clarified.

AIM

To investigate the association of gut microbial dysbiosis with clinicopathological features, first-line chemotherapy efficacy, and long-term prognosis in patients with aCRC.

METHODS

A total of 124 patients with stage IIIB-IV aCRC admitted from September 2020 to September 2025 were retrospectively enrolled in this study. The 16S rRNA high-throughput sequencing was performed to analyze gut microbiota and stratify patients into corresponding groups. Meanwhile, the levels of fecal short-chain fatty acids and secondary bile acids were detected, and clinical and pathological data of all subjects were collected. Differences in microbial diversity and species composition between groups were analyzed. Survival analysis was conducted using the Kaplan-Meier method, and prognostic factors were identified via univariate and multivariate Cox regression analysis. In addition, stratification analyses based on TNM staging and driver gene status were performed, and the efficacy of first-line chemotherapy was compared between the two groups.

RESULTS

There were no statistically significant differences in demographic characteristics, baseline tumor characteristics, or treatment regimens between the two groups (P > 0.05); the group with dysbiosis had a higher proportion of poorly differentiated tumors, stage IV disease, and vascular and nerve invasion (P < 0.05). In the microbiota dysbiosis group, all α-diversity indices were lower, and β-diversity showed significant intergroup divergence. The abundance of beneficial bacteria such as the Firmicutes phylum decreased, while that of pathogenic bacteria such as the Fusobacteria phylum increased, accompanied by decreased short-chain fatty acid levels and accumulation of secondary bile acids; all intergroup differences were statistically significant (P < 0.001). With a median follow-up of 32.5 months, both overall survival and disease-free survival were significantly shorter in the group with abnormal gut microbiota (P < 0.001); After adjusting for confounding factors such as age, carcinoembryonic antigen, and chemotherapy regimen in a multivariate Cox regression analysis, abnormal gut microbiota was an independent adverse prognostic factor for overall survival (hazard ratio =2.314, 95%CI: 1.258-4.259, P = 0.007). Stratified analysis revealed that the adverse prognostic effect of dysbiosis remained consistent across different TNM stages, with no significant interaction with tumor stage (P > 0.05). Among the 96 patients receiving first-line chemotherapy, the objective response rate and disease control rate were both higher in the group with normal microbiota (P < 0.05), and this difference in treatment efficacy was not influenced by the status of RAS/BRAF driver gene mutations.

CONCLUSION

Abnormalities in the gut microbiota are closely associated with increased tumor aggressiveness in aCRC, disruptions in microbial structure and metabolism, poor response to chemotherapy, and poor prognosis. They may serve as potential biomarkers for assessing patient prognosis and predicting the efficacy of chemotherapy, thereby providing a basis for clinical interventions targeting the gut microbiota.

Keywords: Advanced colorectal cancer; Gut microbial dysbiosis; Overall survival; Disease-free survival; Response to chemotherapy

Core Tip: This retrospective cohort study conducted a stratified analysis of patients with stage IIIB-IIIC and stage IV advanced colorectal cancer, confirming that gut microbiota dysbiosis – by modulating bile acid metabolism and the tumor immune microenvironment – is not only an independent adverse prognostic factor for overall survival but also significantly reduces the objective response rate to first-line chemotherapy.