Association Between Clostridioides difficile Test Positivity and Incident Colorectal Cancer in a Multisite Hospital-Based Retrospective Cohort Analysis

IntroductionSporadic colorectal cancer (CRC) remains a significant driver of worldwide morbidity and mortality. Environmental factors associated with CRC are increasingly well-described and now include generalized colonic dysbiosis and individual enteric bacteria. Clostridioides difficile is one such species, with recent mouse model work suggesting prolonged exposure to C. difficile toxin B is conducive to colonic tumorigenesis. However, there is a dearth of real-world human evidence linking C. difficile infection and CRC. MethodsHerein, we analyzed a multicenter, longitudinal, Electronic Health Record (EHR)-based dataset to test the association between C. difficile test positivity and the risk for incident CRC utilizing unadjusted and multivariable (controlled for clinical conditions independently associated with CRC development) Cox proportional hazard modeling to compare C. difficile exposed and non-exposed cohorts ResultsWe found that individuals who tested recurrently positive for C. difficile had a significantly increased risk for incident CRC (aHR 2.05 [95% CI 1.27-3.29]) compared with those who tested positive only once (aHR 0.70 [0.45-1.10]) or never. Furthermore, we found potential trends that the effect of C. difficile test positivity on the risk for incident CRC was stronger amongst females compared with males. ImportanceThese findings help translate emerging mouse model work on C. difficile-influenced colorectal tumorigenesis and lay groundwork for more substantial human investigations into this connection. These findings also may begin to help guide the personalized deployment of novel fecal microbiota-based therapies designed to interrupt the life cycle of C. difficile within the gut of human hosts and, potentially, prevent long-term health sequelae of chronic C. difficile infection.