2025-09-22 トロント大学
<関連情報>
- https://www.utoronto.ca/news/study-reveals-how-bacteria-made-sugar-triggers-intestinal-stem-cell-regeneration
- https://www.cell.com/cell-stem-cell/abstract/S1934-5909(25)00231-0
細菌由来ADP-ヘプトースが損傷後の腸管上皮における幹細胞再生を促進 Bacterial ADP-heptose triggers stem cell regeneration in the intestinal epithelium following injury
Shawn Goyal ∙ Cynthia X. Guo ∙ Ojas Singh ∙ … ∙ Dana J. Philpott ∙ Scott D. Gray-Owen ∙ Stephen E. Girardin
Cell Stem Cell Published:July 11, 2025
DOI:https://doi.org/10.1016/j.stem.2025.06.009
Graphical abstract
Highlights
- The ALPK1-TIFA pathway in intestinal stem cells detects bacterial ADP-heptose
- Activation of ALPK1-TIFA triggers TNF-mediated apoptosis in intestinal stem cells
- Paneth cells dedifferentiate to restore stem cells via TGF-β/YAP-dependent pathways
Summary
ADP-heptose (ADP-Hep), a metabolite produced by gram-negative bacteria, is detected in the host cytosol by the kinase ALPK1, which engages TIFA-dependent innate immune responses. However, the function of ALPK1-TIFA signaling in primary cells and in physiological settings remains poorly understood. Here, we showed that, in the intestinal epithelium, ALPK1 and TIFA were mainly expressed by the intestinal stem cell (ISC) pool, where they controlled the replacement of homeostatic ISCs by new revival stem cells (revSCs) following injury. Mechanistically, ADP-Hep triggered pro-inflammatory nuclear factor κB (NF-κB) signaling and tumor necrosis factor (TNF)-dependent ISC apoptosis, which initiated a transforming growth factor β (TGF-β)- and YAP-dependent revSC program. Single-cell transcriptomics and lineage-tracing experiments identified Paneth cells as a cell of origin for revSC induction in response to ADP-Hep. In vivo, revSC emergence following irradiation or dextran-sodium-sulfate-induced injury was blunted in Tifa-/- mice. Together, our work reveals that ALPK1-TIFA signaling contributes to ISC turnover in response to bacterial detection in the intestine.
