Gastrointestinal tumors remain a global health challenge, with high incidence and mortality. Among them, colorectal cancer (CRC) carries the heaviest burden and serves as a key model for how the gut microbiota contributes to tumor development. Traditionally, Clostridioides difficile (C. difficile) has been viewed as the culprit behind antibiotic-associated diarrhea and pseudomembranous colitis, but mounting evidence suggests its influence may extend beyond infection to promoting gastrointestinal malignancies.
To synthesize this field, Professors Anhua Wu and Chunhui Li from the Center for Infection Control at Xiangya Hospital, Central South University, China, led a team that published a comprehensive review, "Clostridioides difficile: A Suspected Pro-Carcinogenic Bacterium for Gastrointestinal Tumors," in the Chinese Medical Journal on November 20, 2025. The review proposes that C. difficile infection (CDI) may be a previously underappreciated pro-carcinogenic factor in CRC and possibly other gastrointestinal cancers, offering a fresh angle for research and prevention strategies.
The review first outlines the clinical and biological features of C. difficile, a gram-positive, spore-forming anaerobe whose spores germinate in the colon when the normal microbiota is disrupted, especially after antibiotic use. Its key toxins—TcdA, TcdB, and binary toxin CDT—damage the epithelial cytoskeleton, induce apoptosis, and trigger intense inflammation, leading to diarrhea, colitis, and a high recurrence rate that repeatedly injures the colonic mucosa.
Epidemiological data further link CDI to CRC: the incidence of both has risen in parallel. Patients with CRC—particularly those with impaired immunity—show higher C. difficile colonization, and the bacterium is more frequently detected in tumor tissue than in adjacent normal mucosa. Large cohort studies suggest that CRC is diagnosed more often in the years following CDI, and obese individuals with CDI are more likely to develop CRC than those without infection. Although these associations do not prove causality, they raise important questions about how CDI may reshape the colonic tumor microenvironment and promote malignant transformation.
To frame these observations, the authors introduce several microbiological models of CRC etiology, including the alpha-bug hypothesis, driver–passenger model, keystone pathogen hypothesis, hit-and-run model, and common ground hypothesis. These conceptual frameworks describe how specific bacteria can initiate carcinogenesis, reshape the microbiome, or exploit tumor niches created by other factors. Within this context, C. difficile may function as a "passenger" that takes advantage of a susceptible mucosa and, through sustained inflammation and barrier disruption, accelerates malignant evolution.
Mechanistically, the review outlines seven interrelated pathways through which CDI may promote CRC development: toxic effects, pro-inflammatory responses, immune evasion, metabolic reprogramming, oxidative stress, cellular senescence, and biofilm formation plus microbial metabolites. Although C. difficile toxins are not classical genotoxins, they generate reactive oxygen species that damage DNA, weaken the epithelial barrier, and increase exposure to carcinogens. Toxin-driven inflammation recruits neutrophils and myeloid cells, fosters IL-17-dominated immune responses, and supports a pro-tumorigenic milieu, while immune-suppressive remodeling—such as impaired anti-tumor immunity and altered eosinophil responses—allows transformed cells to escape surveillance.
The authors also emphasize that CDI can intersect with cancer-associated metabolic changes: early infection inhibits glycolysis and tricarboxylic acid cycle activity in host cells, pointing to metabolic reprogramming, whereas persistent oxidative stress and toxin-induced senescence of enteric glial cells drive chronic inflammation and DNA damage. In addition, C. difficile participates in complex biofilm communities on the colonic mucosa; these biofilms, together with altered bacterial metabolites like secondary bile acids and short-chain fatty acids, modulate immune surveillance, epithelial proliferation, and mutational burden.
Despite these converging lines of evidence, Prof. Li cautions that C. difficile should still be regarded as a "suspected accomplice" rather than a proven initiator of CRC. "Pinpointing where C. difficile fits along the continuum from dysbiosis and chronic colitis to neoplasia will require rigorous longitudinal and mechanistic studies," he notes. "Priorities include defining CDI risk factors in susceptible populations, charting interactions between C. difficile and the tumor microenvironment, and determining whether CDI history should inform CRC screening strategies."
The authors further suggest that C. difficile may also contribute to other gastrointestinal malignancies, including gastric, pancreatic, and biliary tract cancers. Expanding research in these areas could reveal novel microbial biomarkers and therapeutic targets. By reframing C. difficile from an infectious pathogen to a potential player in cancer biology, the review opens a new chapter in understanding—and ultimately mitigating—the carcinogenic potential of the gut microbiome.
Reference
DOI: https://doi.org/10.1097/CM9.0000000000003834
About Professor Anhua Wu from Central South University
Prof. Anhua Wu is a Professor of Internal Medicine and Chief Physician of Infectious Diseases at Xiangya Hospital, Central South University, and the honorary director of its Infection Control Center, as well as Editor-in-Chief of the Chinese Journal of Infection Control and a recipient of the State Council Special Government Allowance and "Changjiang Scholar." He has long specialized in hospital infection control and multidrug-resistant organism prevention, publishing over 300 papers with more than 6,000 citations, and leading or participating in multiple national guidelines and standards on antimicrobial stewardship and healthcare-associated infection surveillance and management.
About Professor Chunhui Li from Central South University
Professor Chunhui Li, Deputy Director of the Infection Control Center at Xiangya Hospital, Central South University, is a Chief Physician, Professor/Researcher, PhD Supervisor, and Executive Editor-in-Chief of the Chinese Journal of Infection Control. He has long been engaged in hospital infection control and antimicrobial resistance research, with significant achievements in elucidating the pathogenesis of Clostridioides difficile and developing new therapeutics and vaccines. He has led multiple national R&D and NSFC projects, was selected for three national and provincial talent programs, published over 40 SCI papers, contributed to several national health standards, and made important contributions to COVID-19 control and China's medical aid missions in Africa.
About Zou Ju, PhD candidate of Central South University
Zou Ju is a PhD student at Xiangya Hospital, Central South University, and has published more than 10 SCI-indexed papers as a first or co-first author.
Biyue Tian, Master's student of Central South University
Biyue Tian, Master of Genetics from Central South University, Technician at the Center for Prevention and Control of Superbug Infections of Xiangya Hospital, focuses on the molecular mechanisms of bacterial antimicrobial resistance.
Funding information
This work was supported by the National Key Research and Development Program of China (Nos. 2022YFC2009801 and 2022YFC2009805), Scientific and Technological Personnel Lifting Project in Hunan Province (No. 2023TJ-Z11), the National Natural Science Foundation of China–China State Railway Group Co., Ltd. Railway Fundamental Research Joint Fund (No. U2368213), Changsha Science and Technology Plan Project (No. kq2202059), and Innovation and Technology Commercialization Fund of Xiangya Hospital, Central South University (No. 2024ZHJJ06).
