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

Gut Microbes. 2023 Jan-Dec;15(1):2240035. doi: 10.1080/19490976.2023.2240035.

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; TIMELESS; cellular senescence; exosomes; miR-129-2-3p; ulcerative colitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cellular Senescence
  • Colitis* / genetics
  • Colitis, Ulcerative* / genetics
  • Colitis, Ulcerative* / microbiology
  • Epithelial Cells / metabolism
  • Fusobacterium nucleatum / genetics
  • Fusobacterium nucleatum / metabolism
  • Gastrointestinal Microbiome*
  • Humans
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Signal Transduction / physiology
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Tumor Suppressor Protein p53
  • MicroRNAs
  • Mirn129 microRNA, human

Grants and funding

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