<i>Campylobacter jejuni</i> promotes colorectal tumorigenesis through the action of cytolethal distending toxin.

Abstract

<i>Campylobacter jejuni</i> produces a genotoxin, cytolethal distending toxin (CDT), which has DNAse activity and causes DNA double-strand breaks. Although <i>C. jejuni</i> infection has been shown to promote intestinal inflammation, the impact of this bacterium on carcinogenesis has never been examined. Germ-free (GF) <i>Apc^Min/+</i> mice, fed with 1% dextran sulfate sodium, were used to test tumorigenesis potential of CDT-producing <i>C. jejuni</i>. 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 <i>C. jejuni</i>, 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 <i>C. jejuni</i>-induced tumorigenesis. GF <i>Apc^Min/+</i> mice colonised with human clinical isolate <i>C. jejuni</i>81-176 developed significantly more and larger tumours when compared with uninfected mice. <i>C. jejuni</i> with a mutated <i>cdtB</i> subunit, mut<i>cdtB</i>, attenuated <i>C. jejuni</i>-induced tumorigenesis in vivo and decreased DNA damage response in cells and enteroids. <i>C. jejuni</i> infection induced expression of hundreds of colonic genes, with 22 genes dependent on the presence of c<i>dtB.</i> The <i>C. jejuni</i>-infected group had a significantly different microbial gene expression profile compared with the mut<i>cdtB</i> group as shown by metatranscriptomic data, and different microbial communities as measured by 16S rDNA sequencing. Finally, rapamycin could diminish the tumorigenic capability of <i>C. jejuni</i>. Human clinical isolate <i>C. jejuni</i> 81-176 promotes colorectal cancer and induces changes in microbial composition and transcriptomic responses, a process dependent on CDT production.