Cited by 478IL-33, ST2, and ILC PathwaysParasites and Host InteractionsGastrointestinal motility and disorders

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A Metabolite-Triggered Tuft Cell-ILC2 Circuit Drives Small Intestinal Remodeling

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Schneider, Christoph, O’Leary, Claire E., von Moltke, Jakob, Liang, Hong-Erh, Ang, Qi Yan, Turnbaugh, Peter J., Radhakrishnan, Sridhar, Pellizzon, Michael, Ma, Averil, Locksley, Richard M.·2018·Cell

DOI 10.1016/j.cell.2018.05.014PMC PMC6046262

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Abstract

The small intestinal tuft cell-ILC2 circuit mediates epithelial responses to intestinal helminths and protists by tuft cell chemosensory-like sensing and IL-25-mediated activation of lamina propria ILC2s. Small intestine ILC2s constitutively express the IL-25 receptor, which is negatively regulated by A20 (Tnfaip3). A20 deficiency in ILC2s spontaneously triggers the circuit and, unexpectedly, promotes adaptive small-intestinal lengthening and remodeling. Circuit activation occurs upon weaning and is enabled by dietary polysaccharides that render mice permissive for Tritrichomonas colonization, resulting in luminal accumulation of acetate and succinate, metabolites of the protist hydrogenosome. Tuft cells express GPR91, the succinate receptor, and dietary succinate, but not acetate, activates ILC2s via a tuft-, TRPM5-, and IL-25-dependent pathway. Also induced by parasitic helminths, circuit activation and small intestinal remodeling impairs infestation by new helminths, consistent with the phenomenon of concomitant immunity. We describe a metabolic sensing circuit that may have evolved to facilitate mutualistic responses to luminal pathosymbionts.

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Authors: Schneider, C., O’Leary, C. E., von Moltke, J., Liang, H.-E., Ang, Q. Y., Turnbaugh, P. J., Radhakrishnan, S., Pellizzon, M., Ma, A., & Locksley, R. M.
Affiliations: University of California, San Francisco (US)
Howard Hughes Medical Institute (US)
Corresponding author: Locksley, Richard M.
ORCID: Schneider, Christoph
O’Leary, Claire E.
Liang, Hong-Erh
Ang, Qi Yan
Turnbaugh, Peter J.
Radhakrishnan, Sridhar
Pellizzon, Michael
Ma, Averil
Locksley, Richard M.
Venue: Cell
Publisher: Elsevier BV
Published: 2018-07
Volume: 174
Issue: 2
Pages: 271-284.e14
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2018.05.014
PMC: PMC6046262
OpenAlex: W2807333794
Cited by: 478
References: 54
Citations by year: 2026: 56 · 2025: 69 · 2024: 60 · 2023: 57 · 2022: 58 · 2021: 60 · 2020: 47 · 2019: 49 · 2018: 20
FWCI: 18.90
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 376 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: NIH (AI26918, AI30663, HL128903, HL122593)
Howard Hughes Medical Institute
Sandler Asthma Basic Research Center at the UCSF
Swiss National Science Foundation (P2EZP3_162266, P300PA_171591)
Nadia’s Gift Foundation Innovator
Damon Runyon Cancer Research Foundation (DRR-42-16)
UCSF Program for Breakthrough Biomedical Research
Sandler Foundation
Searle Scholars Program (SSP-2016-1352)
Topics: Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
Life Sciences › Immunology and Microbiology › Parasitology › Parasites and Host Interactions
Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
Keywords: tuft cells, ILC2, IL-25, A20, succinic acid, acetate, GPR91, TRPM5, Tritrichomonas, intestinal helminths, concomitant immunity, dietary polysaccharides, weaning
MeSH terms: Tumor Necrosis Factor alpha-Induced Protein 3, Acetates, Animals, Dietary Fiber, Energy Metabolism, Epithelial Cells, Interleukins, Intestinal Mucosa, Intestine, Small, Mice, Inbred C57BL, Mice, Transgenic, Plasmids, Tritrichomonas, Receptors, Interleukin, Succinic Acid, Receptors, G-Protein-Coupled, TRPM Cation Channels, Mice, Receptors, Interleukin-17, Microbiota

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A Metabolite-Triggered Tuft Cell-ILC2 Circuit Drives Small Intestinal Remodeling

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