Abstract

Background The gut microbiome has emerged as a promising source of biomarkers to enhance early detection of colorectal cancer (CRC). However, sex-specific differences in gut microbial profiles and their relationship to CRC risk remain underexplored.

Objective To investigate sex differences in screening-detected colorectal lesions and gut microbial profiles, as well as the potential for sex-specific associations between the gut microbiome and colorectal lesions.

Methods This cross-sectional study included 1,034 faecal immunochemical test-positive screening participants aged 55–77 years recruited from the Norwegian CRCbiome study. Shotgun metagenomic sequencing was used to generate taxonomic and functional profiles of the gut microbiome, which were integrated with clinicopathological, demographic, and lifestyle data. Associations between sex, colorectal lesions, and microbial characteristics – including α-diversity, β-diversity, and abundances of bacterial species and functions – were assessed, including their interactions.

Results Male participants had significantly higher odds of presenting with both non-advanced (OR: 1.50; 95% CI: 1.00–2.26) and advanced (OR: 1.46; 95% CI: 1.10–1.93) colorectal lesions compared to women. Gut microbial profiles differed markedly by sex, demonstrating compositional shifts and distinct bacterial profiles (19 taxa and 58 functions more abundant in men, 13 bacteria and 41 functions more abundant in women). In women, microbial α-and β-diversity varied across lesion subtypes, whereas no such differences were observed in men. Interaction analyses identified 5 bacteria and 6 functions that were differentially associated with colorectal lesions by sex.

Conclusion This study highlights sex-specific differences in the gut microbiome and their association with colorectal lesions, emphasising the need to take sex into account in future research aiming to enhance CRC prevention strategies and treatment.

Competing Interest Statement

The authors have declared no competing interest.

Clinical Trial

NCT01538550

Funding Statement

This project was made possible by funding from the Norwegian Cancer Society (grant nos. 190179 and 198048), the Norwegian Cancer Society's umbrella organization for cancer research (Kreftforeningens paraplystiftelse for kreftforskning), the Research Council of Norway (grant no. 280667), and the South-Eastern Norway Regional Health Authority (grant nos. 2022067 and 2020056). The BCSN trial study was funded by the Norwegian Parliament (Norwegian national budget from 2011). The bowel preparation used for colonoscopy was provided free of charge by Ferring Pharmaceuticals. The funders had no role in study design, data collection, analysis, interpretation, or the writing of this article.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The BCSN trial and the CRCbiome study have been approved by the Regional Committee for Medical and Health-related Research Ethics in Southeast Norway (REK ref: 2011/1272 and 63148, respectively. The BCSN trial is registered at clinicaltrials.gov (Clinical Trial (NCT) no.: 01538550).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as Clinicaltrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Footnotes

Sources of Support: This project was made possible by funding from the Norwegian Cancer Society (grant nos. 190179 and 198048), the Norwegian Cancer Society’s umbrella organization for cancer research (“Kreftforeningens paraplystiftelse for kreftforskning”), the Research Council of Norway (grant no. 280667), and the South-Eastern Norway Regional Health Authority (grant nos. 2022067 and 2020056). The BCSN trial study was funded by the Norwegian Parliament (Norwegian national budget from 2011). The bowel preparation used for colonoscopy was provided free of charge by Ferring Pharmaceuticals. The funders had no role in study design, data collection, analysis, interpretation, or the writing of this article.

Trial Registration: The BCSN is registered at clinicaltrials.gov (National clinical trial (NCT) no. 01538550).

AbbreviationsACMEAverage causal mediation effectADEAverage direct effectAICRAmerican Institute for Cancer ResearchANOVAAnalysis of varianceASVAmplicon sequence variantBCSNBowel Cancer Screening in NorwayBHBenjamini-HochbergBMIBody mass indexCIConfidence intervalCRCColorectal cancerFFQFood frequency questionnaireFITFecal immunochemical testGOGene ontologyKBSKostberegningssystemMaAsLinMicrobiome multivariable associations with linear modelsNCTNational clinical trialOROdds ratioPCoAPrincipal coordinate analysisPERMANOVAPermutational multivariate analysis of variancePPVPositive predictive valueSDStandard deviationTETotal effectTSSTotal sum scalingWCRFWorld Cancer Research Fund