Exosomal-miR-129-2-3p derived from Fusobacterium nucleatum-infected intestinal epithelial cells promotes experimental colitis through regulating TIMELESS-mediated cellular senescence pathway

ABSTRACT

Fusobacterium nucleatum (Fn) infection is known to exacerbate ulcerative colitis (UC). However, the link between Fn-infected intestinal epithelial cell (IEC)-derived exosomes (Fn-Exo) and UC progression has not been investigated. Differentially expressed miRNAs in Fn-Exo and non-infected IECs-derived exosomes (Con-Exo) were identified by miRNA sequencing. Then, the biological role and mechanism of Fn-Exo in UC development were determined in vitro and in vivo. We found that exosomes delivered miR-129-2-3p from Fn-infected IECs into non-infected IECs, exacerbating epithelial barrier dysfunction and experimental colitis. Mechanically, Fn-Exo induces DNA damage via the miR-129-2-3p/TIMELESS axis and subsequently activates the ATM/ATR/p53 pathway, ultimately promoting cellular senescence and colonic inflammation. In conclusion, Exo-miR-129-2-3p/TIMELESS/ATM/ATR/p53 pathway aggravates cellular senescence, barrier damage, and experimental colitis. The current study revealed a previously unknown regulatory pathway in the progression of Fn-infectious UC. Furthermore, Exosomal-miR-129-2-3p in serum and TIMELESS may function as novel potential diagnostic biomarkers for UC and Fn-high-UC.

KEYWORDS:

• Fusobacterium nucleatum
• ulcerative colitis
• exosomes
• miR-129-2-3p
• TIMELESS
• cellular senescence

Acknowledgments

Not applicable.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All data generated or analyzed during this study are included in this published article and its supplementary information files. All sequencing data associated with this study have been uploaded to the NCBI (Sequence Read Archive) SRA database under the accession number PRJNA1000304 and PRJNA1000534.

Author’s contributions

Conceptualization, W.D. and S.W.; Methodology, S.W., X.W., and M.C.; Formal Analysis, X.W., M.C., Z.X., and X. L.; Investigation, S.W., X.W., M.C., Z.X., and X. L.; Resources, J. Z., and W.D.; Writing – Original Draft, S.W.; Writing – Review and Editing, W.D.; Visualization, S.W., X.W., and M.C.; Supervision, J. Z., and W.D.; Funding Acquisition, W.D. All authors reviewed and commended on the manuscript.

Consent for publication

All authors have approved the content for publication in the journal.

Ethical approval and consent to participate

The project was approved by the Institutional Review Committee of the Renmin Hospital of Wuhan University (Approval number: 2018K-C089). All animal handling protocols in this study were approved by the Institutional Animal Care and Use Committee of Renmin Hospital of Wuhan University, China (Approval number: 20181001).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2240035

Additional information

Funding

This work was supported by research grants from the National Natural Science Foundation of China (82170549 and 81870392 to W. Dong).