Campylobact er jejuni promotes colorectal tumorigenesis through the action of cytolethal distending toxin

Zhen He, Raad Z. Gharaibeh, Rachel C. Newsome, Jllian L. Pope, Michael W. Dougherty, Sarah Tomkovich, Benoit Pons, Gladys Mirey, Julien Vignard, David R Hendrixson, Christian Jobin

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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 3H2AX 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.

Original languageEnglish (US)
JournalGut
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Campylobacter jejuni
Carcinogenesis
Campylobacter Infections
Sirolimus
Ribosomal DNA
DNA Damage
Microbial Genes
RNA Sequence Analysis
Dextran Sulfate
Comet Assay
Double-Stranded DNA Breaks
cytolethal distending toxin
Mutagens
Transcriptome
Genes
Fluorescent Antibody Technique
Colorectal Neoplasms
Cell Cycle
Inflammation
Bacteria

Keywords

  • bacterial enterotoxins
  • campylobacter jejuni
  • colon carcinogenesis
  • infective colitis

ASJC Scopus subject areas

  • Gastroenterology

Cite this

He, Z., Gharaibeh, R. Z., Newsome, R. C., Pope, J. L., Dougherty, M. W., Tomkovich, S., ... Jobin, C. (Accepted/In press). Campylobact er jejuni promotes colorectal tumorigenesis through the action of cytolethal distending toxin. Gut. https://doi.org/10.1136/gutjnl-2018-317200

Campylobact er jejuni promotes colorectal tumorigenesis through the action of cytolethal distending toxin. / He, Zhen; Gharaibeh, Raad Z.; Newsome, Rachel C.; Pope, Jllian L.; Dougherty, Michael W.; Tomkovich, Sarah; Pons, Benoit; Mirey, Gladys; Vignard, Julien; Hendrixson, David R; Jobin, Christian.

In: Gut, 01.01.2018.

Research output: Contribution to journalArticle

He, Z, Gharaibeh, RZ, Newsome, RC, Pope, JL, Dougherty, MW, Tomkovich, S, Pons, B, Mirey, G, Vignard, J, Hendrixson, DR & Jobin, C 2018, 'Campylobact er jejuni promotes colorectal tumorigenesis through the action of cytolethal distending toxin', Gut. https://doi.org/10.1136/gutjnl-2018-317200
He, Zhen ; Gharaibeh, Raad Z. ; Newsome, Rachel C. ; Pope, Jllian L. ; Dougherty, Michael W. ; Tomkovich, Sarah ; Pons, Benoit ; Mirey, Gladys ; Vignard, Julien ; Hendrixson, David R ; Jobin, Christian. / Campylobact er jejuni promotes colorectal tumorigenesis through the action of cytolethal distending toxin. In: Gut. 2018.
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abstract = "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 3H2AX 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.",
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AU - Gharaibeh, Raad Z.

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AU - Pope, Jllian L.

AU - Dougherty, Michael W.

AU - Tomkovich, Sarah

AU - Pons, Benoit

AU - Mirey, Gladys

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AB - 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 3H2AX 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.

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