The study, published in the journal Biology of Sex Differences, drew on the CRCbiome study, an offshoot of the Bowel Cancer Screening in Norway (BCSN) trial. The research team, led by Cecilie Bucher-Johannessen and Ane Sørlie Kvaerner of the Cancer Registry of Norway and the University of Oslo, focused on 1,034 men and women aged 55 to 77 who had tested positive on a fecal immunochemical test, or FIT, the standard first-line screening tool that detects hidden blood in stool. Because all participants had already flagged a possible abnormality, the cohort offered a uniquely informative window into how the gut microbial landscape varies across the full spectrum of colorectal lesions, from benign polyps to advanced adenomas and outright cancer.

To characterize the microbial communities, the researchers turned to shotgun metagenomic sequencing, a technique that reads the genetic material of every microorganism present in a stool sample rather than targeting a single marker gene. This approach yields both taxonomic profiles, essentially a census of which bacterial species are present and in what abundance, and functional profiles, which reveal what metabolic pathways and genes those microbes are actively carrying. The team then integrated these microbial data with clinicopathological information from colonoscopy, along with demographic and lifestyle variables, allowing them to ask not only whether men and women harbor different gut communities, but whether the relationship between those communities and colorectal lesions itself differs by sex.

The first major finding concerned who actually develops lesions. Men in the FIT-positive cohort had significantly higher odds of harboring colorectal lesions of every grade. Compared with women, men showed roughly 50 percent higher odds of presenting with non-advanced lesions, with an odds ratio of 1.50 and a 95 percent confidence interval of 1.00 to 2.26, and 46 percent higher odds of advanced lesions, with an odds ratio of 1.46 and a confidence interval of 1.10 to 1.93. This aligns with the long-standing epidemiological observation that colorectal cancer incidence is higher in men, but the study went further by embedding that risk difference within a rich microbial context drawn from the same screening population.

When the researchers compared the gut microbiomes of men and women, the differences were marked. In total, 32 bacterial taxa and 99 functional pathways differed significantly between the sexes, with 13 bacterial species and 41 functions more abundant in women and 19 taxa and 58 functions more abundant in men. These were not subtle shifts confined to rare organisms; they represented compositional and functional divergence across the community, visible in both alpha-diversity measures, which capture diversity within a single individual’s gut, and beta-diversity measures, which capture differences between individuals. The results confirm that sex is one of the strongest determinants of gut microbial composition, comparable in influence to diet, age, and medication use.

The most provocative result, however, emerged when the team examined how microbial diversity tracked with disease status. In women, both alpha- and beta-diversity varied significantly across colorectal lesion subtypes, meaning that the structure of the gut microbial community shifted measurably as lesions progressed from non-advanced to advanced forms. In men, no such pattern was observed. In other words, the microbiome of a woman with an advanced lesion looked measurably different from that of a woman with a benign finding, while the microbiome of a man offered no comparable signal. This is the basis for the study’s central conclusion: microbiome signatures of colorectal cancer development are more pronounced in women than in men.

Formal interaction analyses sharpened the picture further. The researchers identified five bacterial species and nine microbial functions whose associations with colorectal lesions differed significantly between the sexes, suggesting that the same organism can play different roles, or be interpreted differently, depending on the host’s sex. Among the known colorectal cancer-associated bacteria, most showed broadly similar profiles in women and men, but one notable exception stood out. pks-positive Escherichia coli, a strain carrying the polyketide synthase island that produces colibactin, a genotoxic compound capable of damaging the DNA of colonic cells, was associated with colorectal cancer in women only. Given the growing interest in pks-positive E. coli as a mechanistic driver of colorectal carcinogenesis, its sex-specific association raises questions about whether hormonal, immunological, or anatomical differences modulate the bacterium’s interaction with the colonic epithelium.

The technical rigor of the analysis deserves emphasis. By using shotgun metagenomics rather than 16S ribosomal RNA amplicon sequencing, the team could resolve bacteria to the species level and even assess strain-level features such as the presence of the pks island, something amplicon approaches cannot do. Statistical models adjusted for confounders including age, body mass index, diet, and medication use, and the researchers applied multiple-testing corrections to guard against spurious associations. The cross-sectional design, however, means the data capture a single moment in time; they show that microbial profiles differ across lesion categories but cannot establish whether the microbiome drives lesion development, responds to it, or both. Longitudinal follow-up of screening cohorts will be needed to disentangle cause from consequence.

The implications for screening and prevention are substantial. Microbiome-based colorectal cancer tests are under active development around the world, with several companies and academic groups pursuing stool-based microbial biomarkers as complements or alternatives to FIT. If the microbial signals of neoplasia differ between women and men, as this study suggests, then a single one-size-fits-all diagnostic model may perform unevenly across the population. Sex-stratified reference ranges, sex-aware machine learning classifiers, or even sex-specific biomarker panels could improve sensitivity and specificity, particularly for women, whose lesion-associated microbial signals appear richer and potentially more informative. The findings also echo a broader movement in precision medicine to treat sex as a biological variable rather than a nuisance confounder, a principle now mandated by major funding agencies for clinical trial design.

The authors caution that their cohort consisted exclusively of FIT-positive individuals, a group enriched for lesions compared with the general screening population, and that results should be validated in FIT-negative and unscreened populations before being generalized. Still, the study stands as one of the clearest demonstrations to date that the gut microbiome’s relationship with colorectal cancer is not sex-neutral. As microbiome science moves from association toward clinical application, the message from the Norwegian screening cohort is unambiguous: to read the microbial signatures of colorectal cancer accurately, researchers and clinicians must first ask whether they are reading a woman’s gut or a man’s.

Subject of Research: Sex-specific gut microbiome signatures associated with colorectal cancer development in a population-based screening cohort

Article Title: Gut microbiome signatures of colorectal cancer development are more pronounced in women compared to men in a population-based screening cohort

Article References: Bucher-Johannessen, C., Kvaerner, A. S., Birkeland, E., Botteri, E., Avershina, E., Bemanian, V., Hoff, G., Randel, K. R., Hovig, E., Berstad, P., & Rounge, T. B. (2026). Gut microbiome signatures of colorectal cancer development are more pronounced in women compared to men in a population-based screening cohort. Biology of Sex Differences. https://doi.org/10.1186/s13293-026-00985-8

Image Credits: AI Generated

DOI: 10.1186/s13293-026-00985-8

Keywords: gut microbiome, colorectal cancer, colorectal lesions, sex differences, shotgun metagenomics, fecal immunochemical test, pks-positive E. coli, cancer screening, microbiome biomarkers, alpha-diversity, beta-diversity, Norway