ABSTRACT
The anaerobic bacterium Fusobacterium nucleatum is significantly associated with human colorectal cancer (CRC) and is considered a significant contributor to the disease. The mechanisms underlying the promotion of intestinal tumor formation by F. nucleatum have only been partially uncovered. Here, we showed that F. nucleatum releases a metabolite into the microenvironment that strongly activates NF-κB in intestinal epithelial cells via the ALPK1/TIFA/TRAF6 pathway. Furthermore, we showed that the released molecule had the biological characteristics of ADP-heptose. We observed that F. nucleatum induction of this pathway increased the expression of the inflammatory cytokine IL-8 and two anti-apoptotic genes known to be implicated in CRC, BIRC3 and TNFAIP3. Finally, it promoted the survival of CRC cells and reduced 5-fluorouracil chemosensitivity in vitro. Taken together, our results emphasize the importance of the ALPK1/TIFA pathway in Fusobacterium induced-CRC pathogenesis, and identify the role of ADP-H in this process.
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Acknowledgments
We are grateful to Dr. Marion Espeli (INSERM U1160) for helpful discussions, critical comments, and corrections on the manuscript. The authors are grateful to Dr. Anne Letessier (Institut Cochin), Dr. Benoit Miotto (Institut Cochin) for their helpful discussion. The authors are grateful to Amandine Lashermes for technical input, Agnès David (INRAE, UMR 1280 PHAN, Nantes, France) and Camille Mayeur (INRAE Micalis) for SCFA analysis.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Authors contributions
Conceived and designed the experiments: CMG, CA, NL; intellectual contribution: JD, HMB; data acquisition: CMG, LS, DGW, LM, FBC, CLG, VB, AJ, CA, NL; data analysis, statistical analysis, and interpretation: CMG, DGW, CA, and NL; wrote the paper: CMG, NL; edited and revised the manuscript: JD, HMB, CA, DGW, and LM.
Data availability statement
All data are contained in the article and the supporting information.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2295384