2. Academic Validation
  3. Bacterial ADP-heptose triggers stem cell regeneration in the intestinal epithelium following injury

Bacterial ADP-heptose triggers stem cell regeneration in the intestinal epithelium following injury

  • Cell Stem Cell. 2025 Aug 7;32(8):1235-1250.e6. doi: 10.1016/j.stem.2025.06.009.
Shawn Goyal 1,  Cynthia X Guo 2,  Ojas Singh 1,  Adrienne Ranger 1,  Caitlin F Harrigan 3,  Justin Meade 1,  Alexander Luchak 4,  Derek K Tsang 4,  Herbert Y Gaisano 5,  Nan Gao 6,  Scott A Yuzwa 1,  Jeffrey L Wrana 7,  Dana J Philpott 8,  Scott D Gray-Owen 9,  Stephen E Girardin 10
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
  • 2 Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • 3 Department of Computer Science, University of Toronto, Toronto, ON, Canada; Vector Institute for Artificial Intelligence, Toronto, ON, Canada.
  • 4 Department of Immunology, University of Toronto, Toronto, ON, Canada.
  • 5 Department of Medicine and Physiology, University of Toronto, Toronto, ON, Canada.
  • 6 Department of Pharmacology, Physiology & Neuroscience, New Jersey Medical School Rutgers University, Newark, NJ, USA.
  • 7 Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
  • 8 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada.
  • 9 Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. Electronic address: scott.gray.owen@utoronto.ca.
  • 10 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Immunology, University of Toronto, Toronto, ON, Canada. Electronic address: stephen.girardin@utoronto.ca.
PMID: 40651470 DOI: 10.1016/j.stem.2025.06.009
Abstract

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.

Keywords

Alpk1; CLU; Tifa; innate immunity; intestine; regeneration; revival stem cell.

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