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Approaches to improve disease\u2010free survival (DFS) are urgently needed. The gut microbiome, reflected in fecal samples, is likely mechanistically linked to CRC progression and may serve as a non\u2010invasive biomarker. Accordingly, we leveraged baseline fecal samples from <jats:italic>N<\/jats:italic>\u2009=\u2009166 stage I\u2013III CRC patients in the ColoCare Study, a prospective cohort of newly diagnosed CRC patients. We sequenced the V3 and V4 regions of the 16S rRNA gene to characterize fecal bacteria. We calculated estimates of alpha diversity, beta diversity, and <jats:italic>a priori<\/jats:italic>\u2010 and exploratory\u2010selected bacterial presence\/absence and relative abundance. Associations of microbial metrics with DFS were estimated using multivariable Cox proportional hazards models. We found that alpha diversity was strongly associated with improved DFS, most strongly among rectal cancer patients (Shannon HR<jats:sub>rectum<\/jats:sub>\u2009=\u20090.40 95% CI\u2009=\u20090.19, 0.87; <jats:italic>p<\/jats:italic>\u2009=\u2009.02). Overall microbiome composition differences (beta diversity), as characterized by principal coordinate axes, were statistically significantly associated with DFS. <jats:italic>Peptostreptococcus<\/jats:italic> was statistically significantly associated with worse DFS (HR\u2009=\u20091.62, 95% CI\u2009=\u20091.13, 2.31; <jats:italic>p<\/jats:italic>\u2009=\u2009.01 per 1\u2010SD) and Order Clostridiales was associated with improved DFS (HR\u2009=\u20090.62, 95% CI\u2009=\u20090.43\u20130.88; <jats:italic>p<\/jats:italic>\u2009=\u2009.01 per 1\u2010SD). In exploratory analyses, <jats:italic>Coprococcus<\/jats:italic> and <jats:italic>Roseburia<\/jats:italic> were strongly associated with improved DFS. Overall, higher bacterial diversity and multiple bacteria were strongly associated with DFS. Metagenomic sequencing to elucidate species, gene, and functional level details among larger, diverse patient populations are critically needed to support the microbiome as a biomarker of CRC outcomes.<\/jats:p>","DOI":"10.1002\/ijc.35342","type":"journal-article","created":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T08:53:56Z","timestamp":1738313636000},"page":"64-73","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["The gut microbiome is associated with disease\u2010free survival in stage I\u2013III colorectal cancer patients"],"prefix":"10.1002","volume":"157","author":[{"given":"Doratha A.","family":"Byrd","sequence":"first","affiliation":[{"name":"H. Lee Moffitt Cancer Center and Research Institute  Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Damerell","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery Heidelberg University Hospital  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3041-8259","authenticated-orcid":false,"given":"Maria F.","family":"Gomez Morales","sequence":"additional","affiliation":[{"name":"H. Lee Moffitt Cancer Center and Research Institute  Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5677-3518","authenticated-orcid":false,"given":"Stephanie R.","family":"Hogue","sequence":"additional","affiliation":[{"name":"H. Lee Moffitt Cancer Center and Research Institute  Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tengda","family":"Lin","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute  Salt Lake City Utah USA"},{"name":"Department of Population Health Sciences University of Utah  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2030-9676","authenticated-orcid":false,"given":"Jennifer","family":"Ose","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute  Salt Lake City Utah USA"},{"name":"Department of Population Health Sciences University of Utah  Salt Lake City Utah USA"},{"name":"Department of Information and Communication Faculty for Media Information and Design University of Applied Sciences and Arts  Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Himbert","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute  Salt Lake City Utah USA"},{"name":"Department of Population Health Sciences University of Utah  Salt Lake City Utah USA"},{"name":"Clinical and Translational Epidemiology Unit Massachusetts General Hospital  Boston Massachusetts USA"},{"name":"Department of Epidemiology Harvard T.H. Chan School of Public Health  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mmadili N.","family":"Ilozumba","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute  Salt Lake City Utah USA"},{"name":"Department of Population Health Sciences University of Utah  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Kahlert","sequence":"additional","affiliation":[{"name":"Department of General, Visceral and Transplantation Surgery Heidelberg University Hospital  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Shibata","sequence":"additional","affiliation":[{"name":"Department of Surgery University of Tennessee Health Science Center  Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1079-2606","authenticated-orcid":false,"given":"Adetunji T.","family":"Toriola","sequence":"additional","affiliation":[{"name":"Washington University in St. Louis  St. Louis Missouri USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher I.","family":"Li","sequence":"additional","affiliation":[{"name":"Public Health Sciences Division Fred Hutchinson Cancer Research Center  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8040-3341","authenticated-orcid":false,"given":"Jane","family":"Figueiredo","sequence":"additional","affiliation":[{"name":"Samuel Oschin Comprehensive Cancer Institute Cedars\u2010Sinai Medical Center  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. 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