Intratumoral microbiota in colorectal cancer: an independent prognostic indicator?
A prospective cohort study involving 937 patients suggests that the microbiota present within colorectal tumor tissues is associated with prognosis, independently of established clinical and molecular factors.
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About this article
Colorectal cancer is the second leading cause of cancer-related death worldwide.
9,3 % Representing 9.3% of the total cancer mortality in 2022 ¹.
47 582 In France, 47,582 new cases were diagnosed in 2023 – 95% of which occurred in people over the age of 50, with men accounting for 55% of cases and women 45% ².
Benchmark methodology: Next-Generation Sequencing (NGS) on 937 patients
Shi et al. 3 analyzed whole-genome sequencing data from 1,412 tissue samples:
- 937 tumors and 475 normal adjacent tissues (NAT)
- and 462 blood samples from 937 treatment-naive patients recruited from the prospective U-CAN cohort (Uppsala-Umeå, Sweden).
Validation was performed using an independent external cohort (AC-ICAM, n = 246). To address recent methodological controversies in this field, a rigorous bioinformatics pipeline was developed to detect and quantify bacteria present in tumor tissues, prioritizing specificity over sensitivity.
Molecular subtypes of colorectal cancer (CMS1–4)
Colorectal cancer is not a homogeneous group. The international CMS (Consensus Molecular Subtypes) classification distinguishes four subtypes based on the tumor’s molecular profile 4.
This classification is central to the interpretation of the results by Shi et al.
Characteristics:
- hypermutated tumors,
- strong immune response,
- ascending colon.
Microbial correlation in the study by Shi et al., 2025: relative abundance: enrichment in Fusobacterium (Fn. animalis C2, Fn. nucleatum, Fn. vincentii and Fn. polymorphum), and oral bacteria (Parvimonas, Peptostreptococcus, Treponema) compared to other CMSs. No pks+ prognostic correlation specific to this subtype.
Characteristics:
- most common (37%),
- activation of the WNT and MYC pathways.
Microbial correlation in the study by Shi et al., 2025: specific pks+/Enterobacteriaceae prognostic correlation→ poor prognosis.
Characteristics:
- metabolic abnormalities
- frequent KRAS mutation.
Microbial correlation in the study by Shi et al., 2025: no specific pks+ prognostic correlation identified in this study.
Characteristics:
- mesenchymal transformation
- high risk of metastasis.
Microbial correlation in the study by Shi et al., 2025: prognostic correlation with an enrichment in Fn. animalis C2, Fn. nucleatum, and Fn. polymorphum, linked to reduced survival via specific immunometabolic pathways.
While the prognostic correlation of pks+/Enterobacteriaceae with patient outcome is specific to CMS2, CMS1 and CMS4 exhibit distinct microbial signatures with no such pks+ prognostic association.
361 species identified and a validated microbial risk score
The authors identified 249 genera and 361 bacterial species common to both tumors and NATs, including:
- Fusobacterium nucleatum,
- various Enterobacteriaceae (E. coli),
- Akkermansia muciniphila,
- Firmicutes, and species belonging to the genus Treponema.
Microbial signatures varied according to anatomical location, tumor stage, and consensus molecular subtypes (CMS1–4).
17.4% of tumors tested positive for the pks genomic island, which is carried by certain genotoxic E. coli strains that affect colorectal cancer cells via the toxin colibactin. The presence of pks+ and a high abundance of Enterobacteriaceae were specifically associated with a poor prognosis in the CMS2 subtype.
Intestinal microbiota modulates tumour response in cancer patients
Two microbial risk scores – MRS-T (tumor) and MRS-N (NAT) – were developed and validated across the three cohorts. These scores were able to predict overall survival independently of conventional clinicopathological factors, thereby improving the discriminatory power of the prognostic model compared with models based on host factors alone.
The unfavorable taxa were associated with the activation of pro-inflammatory pathways (hypoxia, MAPK1/3, IL-6) and the modulation of the tumor immune system.
Clinical implications and limitations
The intratissue microbiota of colorectal cancer constitutes an independent source of prognostic information, that could complement current molecular markers. The specificity of the correlation between the presence of pks/Enterobacteriaceae and poor prognosis in the CMS2 subtype suggests that molecular subtyping must be incorporated when interpreting the role of the microbiome.
Limitations to note include:
- observational study design,
- the inclusion of treatment-naive patients only,
- and the fact that WGS is not yet feasible for routine clinical use at this stage.
Mechanistic and prospective studies remain necessary before these findings can have any clinical application.
1. PAHO-Bilan mondial du cancer.
2. Ameli-Cancer colorectal.
3. Shi Z. et al. Tissue-resident microbiota impacts colorectal cancer progression and prognosis. Nature Communications, 2026, 17:346. https://doi.org/10.1038/s41467-025-67047-2.
4. Guinney J. et al. The consensus molecular subtypes of colorectal cancer. Nature Medicine, 2015, 21(11), 1350–1356. https://doi.org/10.1038/nm.3967.
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