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Dietary fibre counters the oncogenic potential of colibactin-producing Escherichia coli in colorectal cancer

Nature Microbiology volume 10, pages 855–870 (2025)Cite this article

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Abstract

Diet, microbiome, inflammation and host genetics have been linked to colorectal cancer development; however, it is not clear whether and how these factors interact to promote carcinogenesis. Here we used Il10−/− mice colonized with bacteria previously associated with colorectal cancer: enterotoxigenic Bacteroides fragilis, Helicobacter hepaticus or colibactin-producing (polyketide synthase-positive (pks+)) Escherichia coli and fed either a low-carbohydrate (LC) diet deficient in soluble fibre, a high-fat and high-sugar diet, or a normal chow diet. Colonic polyposis was increased in mice colonized with pks+ E. coli and fed the LC diet. Mechanistically, mucosal inflammation was increased in the LC-diet-fed mice, leading to diminished colonic PPAR-γ signalling and increased luminal nitrate levels. This promoted both pks+ E. coli growth and colibactin-induced DNA damage. PPAR-γ agonists or supplementation with dietary soluble fibre in the form of inulin reverted inflammatory and polyposis phenotypes. The pks+ E. coli also induced more polyps in mismatch-repair-deficient mice by inducing a senescence-associated secretory phenotype. Moreover, oncogenic effects were further potentiated by inflammatory triggers in the mismatch-repair-deficient model. These data reveal that diet and host genetics influence the oncogenic potential of a common bacterium.

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Fig. 1: LC diet augments colibactin-mediated colon polyposis.
Fig. 2: LC diet augments NC101 colonization and colibactin-mediated DNA damage in the colon.
Fig. 3: The LC diet modulates the composition of faecal microbiota to enrich Enterobacteriaceae in Il10−/− mice.
Fig. 4: The effect of the LC diet on NC101 colonization and colonic tumorigenesis is dependent on colonic iNOS activity.
Fig. 5: Soluble-fibre-induced colonic PPAR-γ signalling limits NC101 colonization and tumorigenesis.
Fig. 6: MMR deficiency sensitizes mice to colibactin-induced senescence and CRC development.

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Data availability

The raw 16S sequencing data generated from mouse stool samples in this study have been submitted to the National Center for Biotechnology Information under BioProject ID PRJNA1198898. Silva database version 138.1 (https://github.com/BenKaehler/readytowear) was used for taxonomy assignment in microbiome analysis. The raw 16S genomic data from the GEM human cohort are publicly accessible under accession PRJNA685746. Requests for additional raw and analysed data should follow the instructions given at http://www.gemproject.ca/data-access/. All submissions will be reviewed by the CCC-GEM Project Operating Committee to ensure that the requested samples and data will not interfere in any way with the intended GEM Project analysis of the nested cohort as per the original GEM Project Study Design and is not a duplication of analysis already ongoing. Those proposals meeting this evaluation will be distributed to all members of the GEM Project Steering Committee (GPSC) for review and open discussion. This review will focus on the global scientific merit of the proposal and will assess the basic scientific merit and the availability of requested samples and data, ensuring that there is no compromise of the original intent of the GEM Project. It would be of value to contact a member of the GPSC who could help sponsor your application. Those projects achieving majority vote of approval at the GPSC will be informed that the GEM Project will provide a letter of support stating that the requested samples or data will be made available to the applicants once the applicant receives funding from a granting agency that applies an independent peer review process to the proposal. The criteria to be used for review of all submissions will include the ‘scientific relevance’ of the proposal and the judged availability of biological material requested. The budget to be requested from a funding agency must allow for any expenses in processing samples or in setting up the appropriate queries of the database. The intent is to allow sufficient time for applicants to consider submission for funding opportunities. Source data are provided with this paper.

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Acknowledgements

We thank D. Philpott and P. Poussier and the Martin laboratory for their helpful comments. We thank C. Sears (Johns Hopkins University, USA) for providing us the bacterial strain ETBF and A. Baumler (University of California, Davis, USA) for providing indicator strains EcN wild type and cydA napA narG narZ mutant, and plasmids pWSK29 and pWSK129. We also thank C. Gardner, J. Sonnenburg and E. Sonnenburg (Stanford University, USA) for providing us with the human stool samples from their DIETFITS study. This work was funded by the Canadian Institute of Health Research (PJT-173501). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the paper.

Author information

Authors and Affiliations

  1. Department of Immunology, University of Toronto, Toronto, Ontario, Canada

    Bhupesh Kumar Thakur, Yann Malaise, Saurav Roy Choudhury & Alberto Martin

  2. Division of Gastroenterology, Department of Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada

    Anna Neustaeter, Williams Turpin & Kenneth Croitoru

  3. Department of Laboratory Medicine, Unity Health Toronto, Toronto, Ontario, Canada

    Catherine Streutker

  4. Centre for the Analysis of Genome Evolution & Function, University of Toronto, Toronto, Ontario, Canada

    Julia Copeland & David S. Guttman

  5. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada

    Erin O. Y. Wong & William W. Navarre

  6. Department of Cell & Systems Biology, University of Toronto, Toronto, Ontario, Canada

    David S. Guttman

  7. Department of Infectious Diseases and Pathology, University of Florida College of Veterinary Medicine, Gainesville, FL, USA

    Christian Jobin

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Contributions

B.K.T. designed the experiments, performed the research and analysed the data. Y.M., S.R.C., A.N. and W.T. performed the research and analysed the data. C.S., E.O.Y.W. and J.C. performed the research. D.S.G., W.W.N., C.J., K.C. and A.M. supervised. B.K.T., C.J. and A.M. wrote the paper.

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Correspondence to Alberto Martin.

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Extended data

Extended Data Fig. 1 The LC diet potentiates NC101-mediated colon carcinogenesis in Il10−/− or C57BL/6J WT mice.

(a) Representative H&E-stained microscopic sections, displaying adenomas with dysplastic changes in the colon of mice infected with NC101 and fed LC diet (Related to Fig. 1f). Scale bar = 400 μm. The dashed line outline the adenoma with dysplastic lesions. (b) (left panels) Representative immunohistochemistry sections, displaying nuclear localization of β-catenin in dysplastic lesions and normal colonic tissues of mice infected with NC101 and fed the LC diet. Scale bar = 100 μm. The black dashed line indicates the adenoma with dysplastic lesions and the red arrows indicate the nuclear staining of β-catenin. (right panel) Nuclear β-catenin were quantified based on data in b. Percent of cells positive for nuclear β-catenin were calculated in four randomly chosen fields of view from both dysplastic lesions and normal regions of the tissue per mice. N = 6 in each group; **P = 0.0022. (c) Representative macroscopic colonic image displaying polyps from C57BL/6J wild-type mice orally inoculated with either PBS or the indicated NC101 strains, and fed with either NCD or LC diet for 16 weeks. (d, e) Four-week-old Il10−/− mice were orally inoculated with enterotoxigenic Bacteroides fragilis (ETBF) or H. hepaticus (H. hep) and fed with either NCD or LC diet. N = 6 (ETBF groups) and N = 5 (H. hep groups). Colonic polyp numbers were measured 8-week post-infection (d). Colonic polyps counted in d were graded according to their size (e). (f) Schematic illustrating the experimental design and timeline of infection and dietary intervention. Four-week-old Il10−/− mice were fed with NCD or LC diet for 4 weeks, followed by treatment with or without cefoxitin before infecting with NC101 or NC101ΔclbP, and fed NCD or LC diet for another 8 weeks. (g) Colonic polyp numbers were measured 8-week post-infection in mice treated as indicated in f. (+)Cef: N = 6 (NCD/ΔclbP and NCD/NC101) and N = 8 (LC diet/ΔclbP and LC diet/NC101); *P = 0.0308, ****P < 0.0001. (-)Cef: N = 7 (LC diet/ΔclbP) and N = 8 (LC diet/NC101); ***P = 0.0005. (h) Colonic polyps counted in g were graded according to their size. (i) Number of adenomas with different grades of dysplasia were assessed based on histopathological features in H&E-stained colonic sections of mice used in Fig. 1j. (j, k) Four-week-old Il10−/− mice were orally inoculated with NC101 or NC101ΔclbP, and fed either NCD or Low-Kcal LC diet for 8 weeks. Colonic polyp numbers were measured 8-weeks post-infection (j). NCD: N = 4 (PBS), N = 4 (NC101) and N = 3 (ΔclbP); Low-Kcal LC diet: N = 7 (PBS), N = 8 (NC101) and N = 8 (ΔclbP). **P = 0.0023, ***P = 0.0002, ****P < 0.0001. Colonic polyps counted in j were graded according to their size (k). Data are presented as mean values ± s.e.m. of one to three independent experiments and were analyzed with one-way ANOVA with Sidak’s multiple comparison test (d,g,j) or two-sided Mann-Whitney test (b,right panel of g,i). ns, not significant.

Source data

Extended Data Fig. 2 Effect of specific diets on the gut colonization of CRC-associated bacteria, mucus, and DNA damage in the colon of Il10−/− or C57BL/6J WT mice.

(a, b) Four-week-old Il10−/− mice were infected orally with ETBF or H. hep and fed with either the NCD or LC diet. B. fragilis (a) and H. hep (b) ΔCt relative to total bacteria was calculated by 16S rRNA qPCR using genomic DNA extracted from faeces collected at 6 weeks post-infection from these mice. N = 5-6 mice in each group. (c) Gut colonization of NC101 was determined by quantifying their numbers in faeces collected at indicated times from C57BL/6J WT mice indicated in Fig. 1g. Data are presented as CFU/g faeces after considering their dilution factors and samples with undetected CFU count are plotted as detection limit. ***P = 0.0004. (d) Transcript level of Muc2 in colonic tissues of mice from Fig. 1b was quantified by qPCR. N = 6 in each group. ***P = 0.0008 (NCD vs. LC diet), ***P = 0.0010 (NCD/NC101 vs. WSD/NC101), ****P < 0.0001. (e) Representative images displaying γH2AX immunofluorescence in colonic sections from Il10−/− mice inoculated with either PBS or NC101 and fed with WSD for 8 weeks. Scale bar = 20 μm. (f) Number of γH2AX-positive cells in the colon of mice indicated in e were counted in two crypts per FOV and four FOV per mice. One dot represents the mean γH2AX-positive cells from eight crypts per mice. N = 3 in each group. Data are presented as mean values ± s.e.m. of one to three independent experiments and were analyzed with either one-way ANOVA with Sidak’s multiple comparison test (d) or two-way ANOVA with Sidak’s multiple comparison test (c) or two-sided Mann-Whitney test (a,b,f). ns, not significant.

Source data

Extended Data Fig. 3 Mice fed the LC diet develop signs of chronic mucosal inflammation.

(a, b) Four-week-old Il10−/− mice were inoculated with either PBS, NC101 or NC101ΔclbP, and fed with either the NCD, LC diet or WSD for 8 weeks. Caecum weight (a) and colon length (b) were measured 8-week post-infection from mice on indicated treatments. NCD: N = 6 (PBS), N = 6 (NC101) and N = 4 (ΔclbP); LC diet: N = 10 (PBS), N = 13 (NC101) and N = 9 (ΔclbP); WSD: N = 9 (PBS), N = 9 (NC101) and N = 5 (ΔclbP). ****P < 0.0001. (c) Colon image displaying the gross macroscopic appearance (Red circle highlights the inflamed proximal colon). (d, e) Four-week-old C57BL/6J WT mice were orally inoculated with either PBS or the indicated NC101 strains, and fed with either NCD or LC diet for 16 weeks. Caecum weight (d) and colon length (e) were measured 16-week post-infection from mice on indicated treatments. NCD: N = 4 (PBS), N = 5 (NC101) and N = 5 (ΔclbP); LC diet: N = 8 (PBS), N = 10 (NC101) and N = 8 (ΔclbP). *P = 0.0338 (NCD/PBS vs. LC diet/PBS), *P = 0.0297 (NCD/PBS vs. LC diet/NC101). (f) Representative H&E-stained colonic sections displaying microscopic features. Scale bar = 200 μm. (g) Transcript level of indicated inflammatory cytokines were quantified by qPCR in the colon of Il10−/− mice orally inoculated with either PBS or NC101 and fed the indicated diets. Relative mRNA expression in comparison to PBS-treated, NCD-fed control mice is presented (set as 1). N = 6 in each group. TNFα: *P = 0.0241 (NCD vs LC diet), **P = 0.0056 (NCD vs. WSD), *P = 0.0361 (NCD vs LC diet/NC101), *P = 0.0371 (NCD vs. WSD/NC101), *P = 0.0357 (NCD/NC101 vs LC diet/NC101), *P = 0.0366 (NCD/NC101 vs. WSD/NC101); IL-1β: **P = 0.0060 (NCD vs. WSD), *P = 0.0486 (NCD vs LC diet/NC101), *P = 0.0423 (NCD vs. WSD/NC101), *P = 0.0377 (NCD/NC101 vs LC diet/NC101), *P = 0.0327 (NCD/NC101 vs. WSD/NC101); IFNγ: *P = 0.0184 (NCD vs LC diet), **P = 0.0048 (NCD vs. WSD), **P = 0.0069 (NCD vs LC diet/NC101), **P = 0.0082 (NCD vs. WSD/NC101), **P = 0.0042 (NCD/NC101 vs LC diet/NC101), **P = 0.0050 (NCD/NC101 vs. WSD/NC101). (h) (left panels) Macrophage (F4/80) in colonic sections of NC101-infected mice fed with the indicated diets. Scale bar = 200 μm. (right panel) Macrophage (F4/80) are quantified based on data in h. N = 3 (NCD), N = 5 (LC diet) and N = 4 (WSD); P = 0.529 (NCD/NC101 vs.LC diet/NC101), P = 0.7871 (NCD/NC101 vs. WSD/NC101). Data are presented as mean values ± s.e.m. of one to three independent experiments and were analyzed with one-way ANOVA with Sidak’s multiple comparison test (a,b,d,e,g,h). ns, not significant.

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Extended Data Fig. 4 LC diet-induced iNOS regulates colon carcinogenesis but not mucosal inflammation.

(a) Nos2 mRNA expression was quantified by qPCR in the colonic epithelial cells (CECs) of mice inoculated with a single dose of either PBS or NC101 and fed the NCD or LC diet for 8 weeks. N = 3 in each group; **P = 0.0030, ***P = 0.0005. (b) Immunofluorescence for iNOS and Epithelial Cell Adhesion Molecule (EpCAM) in colonic sections of mice fed the indicated diets. Scale bar = 50 μm. (c, d) Caecum weight (c) and colon length (d) were measured from mice orally inoculated with either PBS or NC101 and fed on LC diet with or without L-Nil for 8 weeks. N = 7 (LC diet), N = 6 (LC diet/L-Nil), N = 9 (LC diet/NC101) and N = 5 (LC diet/NC101/L-Nil). (e) Transcript level of indicated inflammatory cytokines were quantified by qPCR in the colon of mice treated as indicated above. Relative mRNA expression in comparison to PBS-treated, NCD-fed control mice is presented (set as 1).TNFα: *P = 0.0395 (NCD vs. LC diet), *P = 0.0198 (NCD vs. LC diet/NC101); IL-1β: **P = 0.0030 (NCD vs. LC diet), *P = 0.0429 (NCD vs. LC diet/NC101); IFNγ: P = 0.0521 (NCD vs. LC diet), P = 0.0248 (NCD vs. LC diet/NC101); IL-6: *P = 0.0457 (NCD vs. LC diet), *P = 0.0350 (NCD vs. LC diet/NC101); IL-17: **P = 0.0089 (NCD vs. LC diet), **P = 0.0029 (NCD vs. LC diet/NC101); IL-22: ***P = 0.0004 (NCD vs. LC diet), ***P = 0.0004 (NCD vs. LC diet/NC101). (f) Colonic polyps counted in Fig. 4k were graded according to their size. Data are presented as mean values ± s.e.m. from two independent experiments and were analyzed with one-way ANOVA with Sidak’s multiple comparison test (a,c,d,e). ns, not significant.

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Extended Data Fig. 5 LC diet abrogates epithelial PPAR-γ signaling to induce colonic nitrates and tumorigenesis.

(a) PPAR-γ and Angptl4 mRNA expression as quantified by qPCR in colonic epithelial cells (CECs) of mice orally inoculated with either PBS or NC101 and fed with NCD or LC diet for 8 weeks. N = 3 in each group. PPAR-γ: **P = 0.0022 (NCD vs. LC diet), **P = 0.0036 (NCD vs. LC diet/NC101), *P = 0.0118 (NCD/NC101 vs. LC diet/NC101); Angptl4: **P = 0.0037 (NCD vs. LC diet), **P = 0.0079 (NCD vs. LC diet/NC101), *P = 0.0153 (NCD/NC101 vs. LC diet/NC101). (b) PPAR-γ and Nos2 mRNA expression quantified by qPCR in colon of mice inoculated with either PBS or NC101 and fed the LC diet with or without rosiglitazone (Rosi) for 8 weeks. PPAR-γ: N = 6 (NCD and LC diet) and N = 8 (LC diet/Rosi, LC diet/NC101 and LC diet/NC101/Rosi); P < 0.0001. Nos2: N = 6 (NCD and LC diet), N = 8 (LC diet/Rosi and LC diet/NC101) and N = 7 (LC diet/NC101/Rosi); ***P = 0.0002, P < 0.0001, **P = 0.0019 (LC diet vs. LC diet/Rosi), **P = 0.0037 (LC diet/NC101 vs. LC diet/NC101/Rosi). (c) Colonic transcript levels of indicated inflammatory cytokines from indicated treatment groups were quantified by qPCR. Relative mRNA expression in comparison to PBS-treated, NCD-fed control mice (set as 1) is presented. TNFα: ****P < 0.0001, **P = 0.0035 (LC diet vs. LC diet/Rosi), ***P = 0.0008 (LC diet/NC101 vs. LC diet/NC101/Rosi); IL-1β: **P = 0.0011 (NCD vs. LC diet), ***P = 0.0007 (NCD vs. LC diet/NC101), **P = 0.0061 (LC diet vs. LC diet/Rosi), **P = 0.0100 (LC diet/NC101 vs. LC diet/NC101/Rosi); IFNγ: **P = 0.0019 (NCD vs. LC diet), *P = 0.0121 (NCD vs. LC diet/NC101), *P = 0.0239 (LC diet vs. LC diet/Rosi), P = 0.0584 (LC diet/NC101 vs. LC diet/NC101/Rosi); IL-6: ***P = 0.0010 (NCD vs. LC diet), **P = 0.0100 (NCD vs. LC diet/NC101), **P = 0.0012 (LC diet vs. LC diet/Rosi), P = 0.0552 (LC diet/NC101 vs. LC diet/NC101/Rosi); IL-17: **P = 0.0062 (NCD vs. LC diet), ****P < 0.0001 (NCD vs. LC diet/NC101), *P = 0.0462 (LC diet vs. LC diet/Rosi), **P = 0.0031 (LC diet/NC101 vs. LC diet/NC101/Rosi); IL-22: ****P < 0.0001, ***P = 0.0005 (LC diet vs. LC diet/Rosi), **P = 0.0024 (LC diet/NC101 vs. LC diet/NC101/Rosi). (d) Colonic polyps counted in Fig. 5e were graded according to their size. Data are presented as mean values ± s.e.m. of two independent experiments and were analyzed with one-way ANOVA with Sidak’s multiple comparison test (a,b,c). ns, not significant.

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Extended Data Fig. 6 Inulin supplementation rescues LC diet-mediated effects on colonic inflammation and CRC development.

(a) Transcript level of Nos2 was quantified by qPCR in the colonic tissues of mice fed either the NCD or LC diet with or without inulin for 8 weeks. Relative mRNA expression in comparison to PBS-treated, NCD-fed control mice (set as 1) is presented. N = 6 (NCD), N = 4 (NCD/inulin), N = 5 (LC diet), N = 6 (LC diet/inulin); ***P = 0.0004, **P = 0.0076. (b, c) Caecum weight (b) and colon length (c) were measured in mice orally inoculated with PBS or NC101 and fed either the NCD or LC diet with or without inulin for 8 weeks. N = 6 (NCD), N = 4 (NCD/inulin), N = 5 (LC diet), N = 11 (LC diet/inulin), N = 6 (LC diet/NC101) and N = 10 (LC diet/NC101/inulin). **P = 0.0041, *P = 0.0280 (b) and *P = 0.0141 (c). (d) Colonic transcript levels of indicated inflammatory cytokines from indicated treatment groups in a were quantified by qPCR. Relative mRNA expression in comparison to PBS-treated, NCD-fed control mice (set as 1) is presented. TNFα: *P = 0.0173; IL-1β: **P = 0.0023; IFNγ: ***P = 0.0005; IL-6: **P = 0.0075; IL-17: *P = 0.0402; IL-22: ****P < 0.0001, **P = 0.0010. (e, f) Faecal samples at 6-weeks from indicated group of mice used in Fig. 5i were collected and processed for microbiota analysis by 16S rRNA gene sequencing. N = 5 (LC diet) and N = 6 (LC diet/inulin, LC diet/NC101, LC diet/NC101/inulin). Bray-Curtis PCoA plot for beta diversity (e) and taxonomic composition (f) of faecal microbiota of mice with indicated treatments were shown. (g) Colonic polyps counted in Fig. 5i were graded according to their size. Data are presented as mean values ± s.e.m. of two independent experiments and were analyzed with one-way ANOVA with Sidak’s multiple comparison test (a,b,c,d) or ADONIS2 (e). ns, not significant.

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Extended Data Fig. 7 Dietary pattern low in carbohydrates promotes colonic inflammation and E. coli abundance in human cohort.

Total dietary energy (a), total dietary fat (b), total dietary protein (c), total dietary carbohydrate (d), and total dietary fiber (e) intake was calculated by food-intake assessment of subjects on ad libitum diet lower in carbohydrate in the DIETFITS study at baseline, 3 months, and 12 months. N = 20. ***P = 0.0007, **P = 0.0056 (a); ****P < 0.0001 (d); ***P = 0.0001, *P = 0.0484 (e). (f, g) Faecal calprotectin was quantified by ELISA (f), and E. coli enrichment was measured by qPCR (g) in stool samples of these subjects. **P = 0.0083, *P = 0.0296 (f); **P = 0.0073 (g). Data were analyzed using two-tailed Wilcoxon matched-pairs signed rank test. (h) Fiber intake was obtained from StatsCan data of items within a food frequency questionnaire, and intestinal inflammation was measured via stool-derived faecal calprotectin (log10 transformation). N = 4,143 CCC-GEM participants. A Pearson correlation was performed, R represents the correlation coefficient, and the P value is for the statistical test to reject the hypothesis of lack of correlation (R = 0). A generalized estimating equation general linear model was also performed, the effect (beta) of dietary fiber was -0.0186, P = 0.00036, while the effect (beta) of dietary fiber was -0.0193, P = 0.000022 when adjusted for age, sex, and familial cluster. The Pearson coefficient of determination (R2) was -0.002809. (i) The relative abundance of E. coli (cube root transformed) was obtained from shotgun sequencing of stool microbiome, and intestinal inflammation was measured via stool-derived faecal calprotectin (log10 transformation). N = 286 CCC-GEM participants. A Pearson correlation was performed, R represents the correlation coefficient, and the P value is for the statistical test to reject the hypothesis of lack of correlation (R = 0). A generalized estimating equation general linear model was also performed, the effect (beta) of faecal calprotectin was 0.167, P = 0.015, while the effect (beta) of faecal calprotectin was 0.167, P = 0.015, when adjusted for age, sex, and familial cluster. The Pearson coefficient of determination (R2) was 0.042436. (j) The ratio of arginine to citrulline was derived from stool-based metabolomics data, and intestinal inflammation was measured via stool-derived faecal calprotectin (log10 transformation). N = 83 CCC-GEM participants. A Pearson correlation was performed, R represents the correlation coefficient, and the P value is for the statistical test to reject the hypothesis of lack of correlation (R = 0). A beta regression was also performed, the effect (beta) of faecal calprotectin was -0.435, P = 0.0379, while the effect (beta) of faecal calprotectin was -0.414, P = 0.0454 when adjusted for age and sex. The Pearson coefficient of determination (R2) was -0.047961. ns, not significant.

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Extended Data Fig. 8 Specific DNA repair-deficiencies in susceptibility to colibactin-induced CRC development.

(a-c) Four-week-old APCmin mice with Msh2-proficiency or -deficiency in their intestinal epithelial cells were orally inoculated with either PBS, H. hepaticus or CDT-mutant H. hepaticus (ΔCDT). Colonic (a) and small intestinal (SI) (b) polyp numbers were measured 8-week post-infection. Msh2fl/fl/Msh2fl/+ Villin-Cre APCmin mice: N = 5 (PBS), N = 5 (NC101) and N = 3 (ΔclbP); Msh2fl/fl Villin-Cre APCmin mice: N = 8 (PBS), N = 9 (NC101) and N = 6 (ΔclbP). (c) Colonic polyps counted in a were graded according to their size. (d-f) Same as (a-c), except that four-week-old 53BP1-proficient or -deficient mice with APCmin background were used, and polyp numbers were measured 8-week post-infection. 53BP+/+ APCmin mice: N = 7 (PBS), N = 10 (NC101) and N = 8 (ΔclbP); 53BP−/− APCmin mice: N = 8 (PBS), N = 10 (NC101) and N = 8 (ΔclbP). (g-i) Same as (a-c), except that four-week-old FancC-proficient or -deficient mice with APCmin background were used. FancC+/− APCmin mice: N = 10 (PBS), N = 8 (NC101) and N = 9 (ΔclbP); FancC−/− APCmin mice: N = 4 (PBS), N = 4 (NC101) and N = 4 (ΔclbP). Data are presented as mean values from at least two independent experiments and were analyzed with two-way ANOVA with Dunnett’s multiple comparison test (a,b,d,e,g,h). ns, not significant.

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Extended Data Fig. 9 MMR-deficiency increases susceptibility to colibactin-induced CRC development.

(a) Relative γH2AX intensity is presented for colonic sections counted for γH2AX-positive cells in Fig. 6d. N = 4 in each group. The mean fluorescence intensity (MFI) of γH2AX and the number of cells per FOV was calculated using ImageJ. MFI of γH2AX/cell was calculated by dividing MFI with number of cells/FOV. Relative γH2AX intensity in comparison to PBS-treated, Msh2-proficient control mice is presented (set as 1). *P = 0.0117. (b, c) Four-week-old APCmin mice with Msh2-proficiency or -deficiency in their intestinal epithelial cells were orally inoculated with either PBS, NC101 or NC101ΔclbP (indicated groups from mice used in Fig. 6a). Colon (b) and caecum weight (c) were measured 8-week post-infection. Msh2fl/fl APCmin mice: N = 5 (PBS), N = 7 (NC101) and N = 4 (ΔclbP); Msh2fl/fl Villin-Cre APCmin mice: N = 8 (PBS), N = 11 (NC101) and N = 7 (ΔclbP). (d, e) Colonic transcript levels of indicated inflammatory cytokines 2-week (d) and 8-week (e) post-infection were quantified by qPCR in mice as indicated. Relative mRNA expression in comparison to PBS-treated, Msh2-proficient control mice is presented (set as 1). 2-week: N = 4 in each group; TNFα: *P = 0.0168 (PBS vs. NC101), *P = 0.0150 (PBS vs. ΔclbP); IL-6: *P = 0.0231 (PBS vs. NC101), *P = 0.0283 (PBS vs. ΔclbP); CXCL1: Msh2fl/fl APCmin mice ***P = 0.0008 (PBS vs. NC101), ***P = 0.0003 (PBS vs. ΔclbP); CXCL1: Msh2fl/fl Villin-Cre APCmin mice *P = 0.0156 (PBS vs. NC101), **P = 0.0031 (PBS vs. ΔclbP). 8-week: Msh2fl/fl APCmin mice: N = 5 (PBS), N = 5 (NC101) and N = 4 (ΔclbP); Msh2fl/fl Villin-Cre APCmin mice: N = 4 (PBS), N = 7 (NC101) and N = 7 (ΔclbP); TNFα: *P = 0.0196; IL-6: *P = 0.0155; CXCL1: *P = 0.0170; IL-1β: *P = 0.0478. (f) Representative images for cleaved caspase-3 immunofluorescence in colonic sections of indicated groups of mice. Scale bar = 50 μm. (g) Colonic transcript levels of p16INK4A 8-week post-infection were quantified by qPCR. Relative mRNA expression in comparison to PBS-treated, Msh2-proficient control mice is presented (set as 1). Msh2fl/fl APCmin mice: N = 5 (PBS), N = 5 (NC101) and N = 4 (ΔclbP); Msh2fl/fl Villin-Cre APCmin mice: N = 4 (PBS), N = 7 (NC101) and N = 6 (ΔclbP); **P = 0.0012. (h) Schematic illustrating the experimental design and timeline of infection and senolytic (Fisetin) treatment. (i) Representative macroscopic colonic image displaying polyps. (j) Colonic polyps counted in Fig. 6g were graded according to their size. (k) Colonic polyps counted in Fig. 6h were graded according to their size. (l) Colonic polyps counted in Fig. 6i were graded according to their size. Data are presented as mean values ± s.e.m. from at least two independent experiments and were analyzed with two-way ANOVA with Tukey’s multiple comparison test (a) or Dunnett’s multiple comparison test (b,c,d,e,g). ns, not significant.

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Thakur, B.K., Malaise, Y., Choudhury, S.R. et al. Dietary fibre counters the oncogenic potential of colibactin-producing Escherichia coli in colorectal cancer. Nat Microbiol 10, 855–870 (2025). https://doi.org/10.1038/s41564-025-01938-4

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