Objective Campylobacter jejuni produces a genotoxin, cytolethal distending toxin (CDT), which has DNAse activity and causes DNA double-strand breaks. Although C. jejuni infection has been shown to promote intestinal inflammation, the impact of this bacterium on carcinogenesis has never been examined.
Design Germ-free (GF) ApcMin/+ mice, fed with 1% dextran sulfate sodium, were used to test tumorigenesis potential of CDT-producing C. jejuni. Cells and enteroids were exposed to bacterial lysates to determine DNA damage capacity via γH2AX immunofluorescence, comet assay and cell cycle assay. To examine the interplay of CDT-producing C. jejuni, gut microbiome and host in tumorigenesis, colonic RNA-sequencing and faecal 16S rDNA sequencing were performed. Rapamycin was administrated to investigate the prevention of CDT-producing C. jejuni-induced tumorigenesis.
Results GF ApcMin/+ mice colonised with human clinical isolate C. jejuni81–176 developed significantly more and larger tumours when compared with uninfected mice. C. jejuni with a mutated cdtB subunit, mutcdtB, attenuated C. jejuni-induced tumorigenesis in vivo and decreased DNA damage response in cells and enteroids. C. jejuni infection induced expression of hundreds of colonic genes, with 22 genes dependent on the presence of cdtB. The C. jejuni-infected group had a significantly different microbial gene expression profile compared with the mutcdtB group as shown by metatranscriptomic data, and different microbial communities as measured by 16S rDNA sequencing. Finally, rapamycin could diminish the tumorigenic capability of C. jejuni.
Conclusion Human clinical isolate C. jejuni 81–176 promotes colorectal cancer and induces changes in microbial composition and transcriptomic responses, a process dependent on CDT production.
- campylobacter jejuni
- colon carcinogenesis
- infective colitis
- bacterial enterotoxins
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ZH and RZG are co-first authors
Contributors Study concept and design (ZH, RZG, JC); Acquisition, analysis and interpretation of data (ZH, RZG, RCN, JLP, MWD, ST, BP, GM, JV, DRH); Drafting of the manuscript (ZH, RZD, JC); Statistical analysis (ZH, RZG, RCN, JLP, MWD, ST, BP, GM); Essential reagents (JV, DRH), Obtained funding (JC, DRH); Study supervision (JC). All authors reviewed and approved the manuscript.
Funding This study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK073338), University of Florida Health Cancer Center (UFHCC) Funds and University of Florida Department of Medicine Gatorade Fund to CJ, UFHCC Funds to RZG, China Scholarship Council (CSC) funds to ZH and National Institute of Health R01AI065539 to DRH. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Competing interests None declared.
Patient consent Not required.
Ethics approval All animal experiments were approved by the Institutional Animal Care and Use Committee of the University of Florida (Protocol #s: 20169606 and 201608025).
Provenance and peer review Not commissioned; externally peer reviewed.
Correction notice This article has been corrected since it published Online First. The co-first author statement has been added.