An inflammasome-driven differentiation program in intestinal stem cells protects against Salmonella infection

S. Lebon; A. Habshush Menachem; N. Davidzohn; A. Katz; N. Wigoda; T. Braun; D. Yahalomi; R. Rotkopf; V. Holiar; T. Dadosh; S. Levin-Zaidman; N. Dezorella; I. Goliand; M. Kupervaser; S. Leebhoff; N. Blumberger; D. Hoffman; M. Grunewald; Y. Levin; Y. Haberman; M. Hofree; M. Biton

doi:10.1038/s41590-026-02514-6

An inflammasome-driven differentiation program in intestinal stem cells protects against Salmonella infection

S. Lebon
, A. Habshush Menachem
, N. Davidzohn
, A. Katz
, N. Wigoda
, T. Braun
, D. Yahalomi
, R. Rotkopf
, V. Holiar
, T. Dadosh
, S. Levin-Zaidman
, N. Dezorella
, I. Goliand
, M. Kupervaser
, S. Leebhoff
, N. Blumberger
, D. Hoffman
, M. Grunewald
, Y. Levin
, Y. Haberman

M. Hofree^*, M. Biton^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Intestinal stem cells (ISCs) are essential for sustaining epithelial renewal and barrier integrity, yet their role in orchestrating defense against enteric pathogens remains unclear. Here we identify a stem cell-intrinsic immune mechanism whereby Lgr5⁺ ISCs detect intracellular Salmonella enterica and activate an inflammasome-dependent differentiation program. Using fluorescent-labeled S. enterica, single-cell transcriptomics, fate mapping, organoid models, and genetic perturbations, we show that invaded ISCs undergo rapid reprogramming toward antimicrobial peptide-enriched Paneth cells via apoptosis-associated Speck-like protein containing a CARD (ASC, encoded by Pycard)-mediated inflammasome signaling. This fate switch enhances epithelial antimicrobial capacity and restricts pathogen persistence in the crypt. The response is Salmonella-specific and conserved in human intestinal organoids. Moreover, the invasion-associated transcriptional signature is enriched in ISCs from patients with Crohn’s disease. Our findings reveal that ISCs act as active sensors of bacterial invasion and initiate epithelial remodeling through inflammasome signaling, highlighting stem cell plasticity as a frontline innate immune strategy.

Original language	English
Pages (from-to)	1404-1417
Number of pages	14
Journal	Nature Immunology
Volume	27
Issue number	7
DOIs	https://doi.org/10.1038/s41590-026-02514-6
Publication status	Published - 12 May 2026

Funding

We thank R. Xavier (Broad Institute) and R. Avraham (Weizmann Institute of Science) for their critical comments and discussions. We thank S. Schwarzbaum for editing the paper, M. Kedmi for help in RNA single-cell experiments, and staff at the histology unit. We also thank J. Beumer from the Institute of Human Biology, for guidance on conducting CRISPR-Cas9-mediated gene deletion in human organoids. M.B. holds the Ernst and Kaethe Ascher Career Development Chair. This study was supported by research grants from the Center for New Scientists at the Weizmann Institute of Science, the Israel Science Foundation (grant nos. 1587/20, 3775/25 and 2451/23), the Helen and Martin Kimmel Institute for Stem Cell Research at The Weizmann Institute of Science, and the Minerva Foundation, with funding from the Federal German Ministry for Education and Research, the Moross Integrated Cancer Center, the Israel Ministry of Science (IMOS; grant no. 4631) and Cyprus-IMOS (grant no. 0007534), the Dr Gilbert S. Omenn and Martha A. Darling Weizmann Institute - Schneider Hospital Fund for Clinical Breakthroughs through Scientific Collaborations, a research grant from the Sarena Snider Foundation, the Abisch-Frenkel RNA Therapeutics Center, a research grant from the Shimon and Golde Picker and a research grant from the Herbert K. Bennett Charitable Fund and Dwek Institute for Cancer Therapy Research.

All Science Journal Classification (ASJC) codes

Immunology and Allergy
Immunology

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Lebon, S., Habshush Menachem, A., Davidzohn, N., Katz, A., Wigoda, N., Braun, T., Yahalomi, D., Rotkopf, R., Holiar, V., Dadosh, T., Levin-Zaidman, S., Dezorella, N., Goliand, I., Kupervaser, M., Leebhoff, S., Blumberger, N., Hoffman, D., Grunewald, M., Levin, Y., ... Biton, M. (2026). An inflammasome-driven differentiation program in intestinal stem cells protects against Salmonella infection. Nature Immunology, 27(7), 1404-1417. https://doi.org/10.1038/s41590-026-02514-6

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title = "An inflammasome-driven differentiation program in intestinal stem cells protects against Salmonella infection",

abstract = "Intestinal stem cells (ISCs) are essential for sustaining epithelial renewal and barrier integrity, yet their role in orchestrating defense against enteric pathogens remains unclear. Here we identify a stem cell-intrinsic immune mechanism whereby Lgr5+ ISCs detect intracellular Salmonella enterica and activate an inflammasome-dependent differentiation program. Using fluorescent-labeled S. enterica, single-cell transcriptomics, fate mapping, organoid models, and genetic perturbations, we show that invaded ISCs undergo rapid reprogramming toward antimicrobial peptide-enriched Paneth cells via apoptosis-associated Speck-like protein containing a CARD (ASC, encoded by Pycard)-mediated inflammasome signaling. This fate switch enhances epithelial antimicrobial capacity and restricts pathogen persistence in the crypt. The response is Salmonella-specific and conserved in human intestinal organoids. Moreover, the invasion-associated transcriptional signature is enriched in ISCs from patients with Crohn{\textquoteright}s disease. Our findings reveal that ISCs act as active sensors of bacterial invasion and initiate epithelial remodeling through inflammasome signaling, highlighting stem cell plasticity as a frontline innate immune strategy.",

author = "S. Lebon and \{Habshush Menachem\}, A. and N. Davidzohn and A. Katz and N. Wigoda and T. Braun and D. Yahalomi and R. Rotkopf and V. Holiar and T. Dadosh and S. Levin-Zaidman and N. Dezorella and I. Goliand and M. Kupervaser and S. Leebhoff and N. Blumberger and D. Hoffman and M. Grunewald and Y. Levin and Y. Haberman and M. Hofree and M. Biton",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2026.",

year = "2026",

month = may,

day = "12",

doi = "10.1038/s41590-026-02514-6",

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Lebon, S, Habshush Menachem, A, Davidzohn, N, Katz, A, Wigoda, N, Braun, T, Yahalomi, D, Rotkopf, R , Holiar, V , Dadosh, T , Levin-Zaidman, S , Dezorella, N , Goliand, I , Kupervaser, M, Leebhoff, S, Blumberger, N, Hoffman, D, Grunewald, M, Levin, Y, Haberman, Y, Hofree, M & Biton, M 2026, 'An inflammasome-driven differentiation program in intestinal stem cells protects against Salmonella infection', Nature Immunology, vol. 27, no. 7, pp. 1404-1417. https://doi.org/10.1038/s41590-026-02514-6

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T1 - An inflammasome-driven differentiation program in intestinal stem cells protects against Salmonella infection

AU - Lebon, S.

AU - Habshush Menachem, A.

AU - Davidzohn, N.

AU - Katz, A.

AU - Wigoda, N.

AU - Braun, T.

AU - Yahalomi, D.

AU - Rotkopf, R.

AU - Holiar, V.

AU - Dadosh, T.

AU - Levin-Zaidman, S.

AU - Dezorella, N.

AU - Goliand, I.

AU - Kupervaser, M.

AU - Leebhoff, S.

AU - Blumberger, N.

AU - Hoffman, D.

AU - Grunewald, M.

AU - Levin, Y.

AU - Haberman, Y.

AU - Hofree, M.

AU - Biton, M.

PY - 2026/5/12

Y1 - 2026/5/12

N2 - Intestinal stem cells (ISCs) are essential for sustaining epithelial renewal and barrier integrity, yet their role in orchestrating defense against enteric pathogens remains unclear. Here we identify a stem cell-intrinsic immune mechanism whereby Lgr5+ ISCs detect intracellular Salmonella enterica and activate an inflammasome-dependent differentiation program. Using fluorescent-labeled S. enterica, single-cell transcriptomics, fate mapping, organoid models, and genetic perturbations, we show that invaded ISCs undergo rapid reprogramming toward antimicrobial peptide-enriched Paneth cells via apoptosis-associated Speck-like protein containing a CARD (ASC, encoded by Pycard)-mediated inflammasome signaling. This fate switch enhances epithelial antimicrobial capacity and restricts pathogen persistence in the crypt. The response is Salmonella-specific and conserved in human intestinal organoids. Moreover, the invasion-associated transcriptional signature is enriched in ISCs from patients with Crohn’s disease. Our findings reveal that ISCs act as active sensors of bacterial invasion and initiate epithelial remodeling through inflammasome signaling, highlighting stem cell plasticity as a frontline innate immune strategy.

AB - Intestinal stem cells (ISCs) are essential for sustaining epithelial renewal and barrier integrity, yet their role in orchestrating defense against enteric pathogens remains unclear. Here we identify a stem cell-intrinsic immune mechanism whereby Lgr5+ ISCs detect intracellular Salmonella enterica and activate an inflammasome-dependent differentiation program. Using fluorescent-labeled S. enterica, single-cell transcriptomics, fate mapping, organoid models, and genetic perturbations, we show that invaded ISCs undergo rapid reprogramming toward antimicrobial peptide-enriched Paneth cells via apoptosis-associated Speck-like protein containing a CARD (ASC, encoded by Pycard)-mediated inflammasome signaling. This fate switch enhances epithelial antimicrobial capacity and restricts pathogen persistence in the crypt. The response is Salmonella-specific and conserved in human intestinal organoids. Moreover, the invasion-associated transcriptional signature is enriched in ISCs from patients with Crohn’s disease. Our findings reveal that ISCs act as active sensors of bacterial invasion and initiate epithelial remodeling through inflammasome signaling, highlighting stem cell plasticity as a frontline innate immune strategy.

UR - https://www.scopus.com/pages/publications/105038815301

U2 - 10.1038/s41590-026-02514-6

DO - 10.1038/s41590-026-02514-6

M3 - Article

C2 - 42120792

AN - SCOPUS:105038815301

SN - 1529-2908

VL - 27

SP - 1404

EP - 1417

JO - Nature Immunology

JF - Nature Immunology

IS - 7

ER -

An inflammasome-driven differentiation program in intestinal stem cells protects against Salmonella infection

Abstract

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