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 language | English (US) |
|---|---|
| Journal | Gut |
| DOIs | |
| State | Accepted/In press - Jan 1 2018 |
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Keywords
- bacterial enterotoxins
- campylobacter jejuni
- colon carcinogenesis
- infective colitis
ASJC Scopus subject areas
- Gastroenterology
Cite this
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 journal › Article
}
TY - JOUR
T1 - Campylobact er jejuni promotes colorectal tumorigenesis through the action of cytolethal distending toxin
AU - He, Zhen
AU - Gharaibeh, Raad Z.
AU - Newsome, Rachel C.
AU - Pope, Jllian L.
AU - Dougherty, Michael W.
AU - Tomkovich, Sarah
AU - Pons, Benoit
AU - Mirey, Gladys
AU - Vignard, Julien
AU - Hendrixson, David R
AU - Jobin, Christian
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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.
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.
KW - bacterial enterotoxins
KW - campylobacter jejuni
KW - colon carcinogenesis
KW - infective colitis
UR - http://www.scopus.com/inward/record.url?scp=85056091623&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85056091623&partnerID=8YFLogxK
U2 - 10.1136/gutjnl-2018-317200
DO - 10.1136/gutjnl-2018-317200
M3 - Article
C2 - 30377189
AN - SCOPUS:85056091623
JO - Gut
JF - Gut
SN - 0017-5749
ER -