{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T16:02:59Z","timestamp":1779724979112,"version":"3.53.1"},"posted":{"date-parts":[[2026,5,22]]},"group-title":"Gastroenterology","reference-count":30,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"crossref","award":["P30 AG024824"],"award-info":[{"award-number":["P30 AG024824"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01CA196845"],"award-info":[{"award-number":["R01CA196845"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Cancer Research UK Cancer\/ NCI","award":["C10674\/A27140"],"award-info":[{"award-number":["C10674\/A27140"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["T32 A1007291"],"award-info":[{"award-number":["T32 A1007291"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Cancer Institute","award":["U54CA274367"],"award-info":[{"award-number":["U54CA274367"]}]},{"name":"Page Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Recent mouse model data demonstrate that chronic colonization with toxigenic\n                    <jats:italic>Clostridioides difficile<\/jats:italic>\n                    promotes colonic tumorigenesis via intraluminal toxin B (TcdB), its main virulence factor. In a prior multisite hospital cohort, we found that history of positive\n                    <jats:italic>tcdB<\/jats:italic>\n                    stool testing was associated with increased CRC risk in a dose-dependent manner, though limited by small sample size. We aimed to validate this association in a larger cohort with extended follow-up and greater geographic distribution using the Veterans Health Administration (VHA) Corporate Data Warehouse (CDW).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We conducted a retrospective cohort study among adults receiving care through the VA from 2000-2025 who underwent\n                    <jats:italic>C. difficile<\/jats:italic>\n                    testing. Data collected from the VHA CDW and National Death Index (NDI) included demographics, comorbidities, medications, CRC risk factors, and cancer incidence and death. The first\n                    <jats:italic>C. difficile<\/jats:italic>\n                    test date defined cohort entry; individuals with prior CRC were excluded. Ever\n                    <jats:italic>C. difficile<\/jats:italic>\n                    positivity was defined by a positive PCR or EIA results. The number of positive tests (episodes) was also determined to define recurrent positivity. Follow-up time ended at the first occurrence of CRC incidence or mortality, death from other causes, or censor date. Follow-up time was split for individuals who converted from negative to positive, with follow-up time updated accordingly. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) for\n                    <jats:italic>C. difficile<\/jats:italic>\n                    exposure and CRC incidence and mortality after adjustment for confounders. Tests for linear trend and tests for interaction were conducted to assess effect modification by sex and IBD status, while time-lag intervals were evaluated for 1, 3, 5, and 10 years before the outcome.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Among 806,844 veterans with\n                    <jats:italic>C. difficile testing<\/jats:italic>\n                    , those with positive tests were more likely to be older, male, to have diabetes, to use aspirin, and to have a lower BMI than those with negative tests. Race and IBD prevalence were similar between the groups. There was no overall association between ever\n                    <jats:italic>C. difficile<\/jats:italic>\n                    positivity and CRC incidence (HR = 0.99, 95% CI 0.93-1.05). However, recurrent\n                    <jats:italic>C. difficile<\/jats:italic>\n                    positivity was associated with increased risk in a dose-response manner [2-3 episodes HR = 1.30 (95% CI 1.16-1.47), and &gt;3 episodes HR = 1.58 (95% CI 1.17-2.14) compared to negative tests; ptrend&lt; 0.001]. Further, ever\n                    <jats:italic>C. difficile<\/jats:italic>\n                    positivity was associated with increased CRC mortality risk (HR = 1.21, 95% CI 1.13-1.30;\n                    <jats:italic>p<\/jats:italic>\n                    &lt; 0.001). Recurrent\n                    <jats:italic>C. difficile<\/jats:italic>\n                    positivity was associated with increased mortality risk but was particularly strong for those with &gt;3 episodes among individuals with IBD (HR=3.84, 95% CI 1.98-7.45). In sensitivity analyses, the increased risk of CRC incidence and mortality attenuated beyond 10 years.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>\n                    Prior positive\n                    <jats:italic>C. difficile<\/jats:italic>\n                    testing was associated with increased CRC incidence and mortality in a dose-dependent manner, particularly among patients with IBD. These findings extend animal model evidence, epidemiologically establishing\n                    <jats:italic>C. difficile<\/jats:italic>\n                    presence as an independent risk factor for subsequent colorectal tumorigenesis and supporting investigation into recurrent CDI, especially among patients with IBD, as a potential modifiable CRC risk factor.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.20.26353667","type":"posted-content","created":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T00:40:28Z","timestamp":1779496828000},"source":"Crossref","is-referenced-by-count":0,"title":["Association between\n                  <i>Clostridioides difficile<\/i>\n                  infection and colorectal cancer incidence and mortality in a National Veterans Affairs Cohort"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6015-7232","authenticated-orcid":false,"given":"SB","family":"Rifkin","sequence":"first","affiliation":[{"name":"University of Michigan Medicine, Division of Gastroenterology and Hepatology, Ann Arbor, MI, USA"},{"name":"John D. 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