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

TLDR

Campylobacter jejuni produces the genotoxin cytolethal distending toxin (CDT), which induces DNA double‑strand breaks and has been linked to intestinal inflammation, yet its role in carcinogenesis was previously unexamined. The study aimed to assess the tumorigenic potential of CDT‑producing C. jejuni by infecting germ‑free ApcMin/+ mice fed 1 % dextran sulfate sodium. Researchers exposed cells and enteroids to bacterial lysates to measure DNA damage, performed colonic RNA‑sequencing and faecal 16S rDNA profiling, and administered rapamycin to evaluate prevention of tumorigenesis.

Abstract

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.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.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.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.