Colorectal cancer-associated bacteria are broadly distributed in global microbiomes and drivers of precancerous change

Sep 21, 2026

Uploaded by Riley

Gut microbiome alterations are implicated in colorectal cancer (CRC), yet the full extent and membership of CRC- and health-associated gut bacteria across populations remains unclear. This study defines the scale of these bacteria using gene-level clustering and microbiome-CRC correlation analysis of ultra-deep shotgun metagenomic data from global surveys. About 23–40% of gut bacteria are linked to CRC or health, with predicted gene clusters validated in preclinical models. Results show microbiome-driven precancer states and senescence-related signatures.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Abstract

Microbiome involvement in colorectal cancer

Methods: gene-level correlation and clustering

Key findings: CRC/health-associated bacteria and CAGs

Validation in preclinical and organoid models

Implications for cancer prevention

[www. nature.com/scientificreports](www. nature.com/scientificreports) OPEN Colorectal cancer‑associated bacteria are broadly distributed in global microbiomes and drivers of precancerous change Samuel S. Minot 1,2, Naisi Li3, Harini Srinivasan4, Jessica L. Ayers 5, Ming Yu3, Sean T. Koester 3, Mary M. Stangis6, Jason A. Dominitz7,8, Richard B. Halberg6, William M. Grady 3,7 & Neelendu Dey2,3,5,7* The gut microbiome is implicated in the pathogenesis of colorectal cancer (CRC), but the full scope of this dialogue is unknown. Here we aimed to define the scale and membership of the body ofCRC‑ and health‑associated gut bacteria in global populations. We performed a microbiome‑CRC correlation analysis of published ultra‑deep shotgun metagenomic sequencing data from global microbiome surveys, utilizing a de novo (reference‑agnostic) gene‑level clustering approach to identify protein‑ coding co‑abundant gene (CAGs) clusters. We link an unprecedented ~ 23–40% of gut bacteria to CRC or health, split nearly evenly as CRC‑ or health‑associated. These microbes encode 2319 CAGs encompassing 427,261 bacterial genes significantly enriched or depleted in CRC. We identified many microbes that had not previously been linked toCRC, thus expanding the scope of“known unknowns” ofCRC‑associated microbes. We performed an agnostic CAG‑based screen of bacterial isolates and validated predicted effects of previously unimplicated bacteria in preclinical models, in which we observed differential induction of precancerous adenomas and field effects. Single‑cell RNA sequencing disclosed microbiome‑induced senescence‑associated gene expression signatures in discrete colonic populations including fibroblasts. In organoid co‑cultures, primary colon fibroblasts from mice with microbiomes promoted significantly greater growth than fibroblasts from microbiome‑ depleted mice. These results offer proof‑of‑principle for gene‑level metagenomic analysis enabling discovery of microbiome links to health and demonstrate that the microbiome can drive precancer states, thereby potentially revealing novel cancer prevention opportunities. Abbreviations CRCCAGs SEM GF SPFPERMANOVASASP FIT Colorectal cancer Co-abundant genes Standard error of the mean Germ-free Specific pathogen-free Permutational multivariate analysis of variance Senescence-associated secretory phenotype Fecal immunochemical testing Colorectal cancer (CRC) is a common cause of cancer death and suffering worldwide1. Epidemiological and disease cohort studies implicate the gut microbiome as a critical determinant of CRC risk2,3. However, while 1Data Core, Shared Resources, Fred Hutchinson Cancer Center, 1100 Fairview Ave North, Seattle 98109, WA, USA. 2Microbiome Research Initiative, Fred Hutchinson Cancer Center, Seattle, WA, USA. 3Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA. 4Genomics & Bioinformatics Core, Shared Resources, Fred Hutchinson Cancer Center, Seattle, WA, USA. 5Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA. 6University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA. 7Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, WA, USA. 8National Gastroenterology and Hepatology Program, U.S. Department of Veterans Affairs, Seattle, WA, USA. *email: [ndey@fredhutch.org](ndey@fredhutch.org) [www. nature.com/scientificreports/](www. nature.com/scientificreports/) several carcinogenic gut microbes have been identified (e.g. enterotoxigenic Bacteroides fragilis, colibactinproducing Escherichia coli, and Fusobacterium nucleatum), each appears to account for a minority ofCRC cases, and estimated effect sizes are modest3–7. Further, recent metagenomic studies of CRC microbiomes implicate increasing numbers ofCRC-associated bacteria and diverse bacterial communities3,8–

FAQs

What was the main goal of this study on colorectal cancer-associated bacteria?

To define the scale and membership of CRC- and health-associated gut bacteria across global populations.

How were bacteria linked to CRC or health in this research?

Through microbiome-CRC correlation analysis of ultra-deep shotgun metagenomic data using a de novo, reference-agnostic, gene-level clustering approach to identify co-abundant gene clusters.

What evidence supports that the microbiome can drive precancer states?

Preclinical validation showed differential induction of precancerous adenomas and field effects, while single-cell RNA sequencing and organoid co-cultures revealed microbiome-induced senescence-associated gene expression signatures and growth promotion by fibroblasts from microbiome-exposed mice.

Sep 21, 2026

Uploaded by Riley