Enteric neuronal Piezo1 maintains mechanical and immunological homeostasis by sensing force

Zili Xie¹, Lillian Rose², Jing Feng³, Yonghui Zhao⁴, Yisi Lu², Harry Kane², Timothy J Hibberd⁵, Xueming Hu¹, Zhen Wang⁶, Kaikai Zang⁴, Xingliang Yang¹, Quentin Richardson², Rahmeh Othman², Olivia Venezia², Ademi Zhakyp², Fang Gao¹, Nobuya Abe⁶, Keren Vigeland², Hongshen Wang², Camren Branch², Coco Duizer², Liwen Deng², Xia Meng⁶, Lydia Zamidar⁶, Max Hauptschein², Ronan Bergin⁷, Xinzhong Dong⁸, Issac M Chiu², Brian S Kim⁹, Nick J Spencer⁵, Hongzhen Hu¹⁰, Ruaidhrí Jackson¹¹

Affiliations

¹ Department of Dermatology, The Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount Sinai, New York, NY 10019, USA; Department of Anesthesiology, The Center for the Study of Itch & Sensory Disorders, Washington University School of Medicine, St. Louis, MO 63130, USA.
² Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.
³ Department of Anesthesiology, The Center for the Study of Itch & Sensory Disorders, Washington University School of Medicine, St. Louis, MO 63130, USA; Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Science, University of Chinese Academy of Sciences, Beijing, China.
⁴ Department of Anesthesiology, The Center for the Study of Itch & Sensory Disorders, Washington University School of Medicine, St. Louis, MO 63130, USA.
⁵ Visceral Neurophysiology Laboratory, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.
⁶ Department of Dermatology, The Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount Sinai, New York, NY 10019, USA.
⁷ Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Ireland.
⁸ The Solomon H. Snyder Department of Neuroscience, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁹ Department of Dermatology, The Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount Sinai, New York, NY 10019, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Allen Discovery Center for Neuroimmune Interactions, New York, NY 10029, USA.
¹⁰ Department of Dermatology, The Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount Sinai, New York, NY 10019, USA; Department of Anesthesiology, The Center for the Study of Itch & Sensory Disorders, Washington University School of Medicine, St. Louis, MO 63130, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Allen Discovery Center for Neuroimmune Interactions, New York, NY 10029, USA; The Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: hongzhen.hu@mssm.edu.
¹¹ Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: ruaidhri_jackson@hms.harvard.edu.

PMID: 40132579
PMCID: PMC12048284 (available on 2026-05-01)
DOI: 10.1016/j.cell.2025.02.031

Enteric neuronal Piezo1 maintains mechanical and immunological homeostasis by sensing force

Zili Xie et al. Cell. 2025.

. 2025 May 1;188(9):2417-2432.e19.

doi: 10.1016/j.cell.2025.02.031. Epub 2025 Mar 24.

Authors

Affiliations

¹ Department of Dermatology, The Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount Sinai, New York, NY 10019, USA; Department of Anesthesiology, The Center for the Study of Itch & Sensory Disorders, Washington University School of Medicine, St. Louis, MO 63130, USA.
² Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.
³ Department of Anesthesiology, The Center for the Study of Itch & Sensory Disorders, Washington University School of Medicine, St. Louis, MO 63130, USA; Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Science, University of Chinese Academy of Sciences, Beijing, China.
⁴ Department of Anesthesiology, The Center for the Study of Itch & Sensory Disorders, Washington University School of Medicine, St. Louis, MO 63130, USA.
⁵ Visceral Neurophysiology Laboratory, College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia.
⁶ Department of Dermatology, The Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount Sinai, New York, NY 10019, USA.
⁷ Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Ireland.
⁸ The Solomon H. Snyder Department of Neuroscience, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁹ Department of Dermatology, The Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount Sinai, New York, NY 10019, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Allen Discovery Center for Neuroimmune Interactions, New York, NY 10029, USA.
¹⁰ Department of Dermatology, The Mark Lebwohl Center for Neuroinflammation and Sensation, Icahn School of Medicine at Mount Sinai, New York, NY 10019, USA; Department of Anesthesiology, The Center for the Study of Itch & Sensory Disorders, Washington University School of Medicine, St. Louis, MO 63130, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Allen Discovery Center for Neuroimmune Interactions, New York, NY 10029, USA; The Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: hongzhen.hu@mssm.edu.
¹¹ Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: ruaidhri_jackson@hms.harvard.edu.

PMID: 40132579
PMCID: PMC12048284 (available on 2026-05-01)
DOI: 10.1016/j.cell.2025.02.031

Abstract

The gastrointestinal (GI) tract experiences a myriad of mechanical forces while orchestrating digestion and barrier immunity. A central conductor of these processes, the enteric nervous system (ENS), detects luminal pressure to regulate peristalsis independently of extrinsic input from the central and peripheral nervous systems. However, how the ∼500 million enteric neurons that reside in the GI tract sense and respond to force remains unknown. Herein, we establish that the mechanosensor Piezo1 is functionally expressed in cholinergic enteric neurons. Optogenetic stimulation of Piezo1⁺ cholinergic enteric neurons drives colonic motility, while Piezo1 deficiency reduces cholinergic neuronal activity and slows peristalsis. Additionally, Piezo1 deficiency in cholinergic enteric neurons abolishes exercise-induced acceleration of GI motility. Finally, we uncover that enteric neuronal Piezo1 function is required for motility alterations in colitis and acts to prevent aberrant inflammation and tissue damage. This work uncovers how the ENS senses and responds to mechanical force.

Keywords: Piezo1; cholinergic neurons; enteric nervous system; inflammation; inflammatory bowel disease; mechanosensation; motility; neuro-immune; peristalsis.

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Conflict of interest statement

Declaration of interests H.H. has served as a consultant for Formation Bio and Almirall on topics unrelated to this manuscript, and his lab has received sponsored research from Triveni Bio. B.S.K. is founder of KliRNA Biotech; he has served as a consultant for 23andMe, ABRAX Japan, AbbVie, Almirall, Amgen, Arcutis Biotherapeutics, Arena Pharmaceuticals, argenx, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Cara Therapeutics, Clexio Biosciences, Eli Lilly and Company, Escient Pharmaceuticals, Evommune, Galderma, Genentech, GlaxoSmithKline, Granular Therapeutics, Incyte Corporation, Innovaderm Research, Janssen, Kiniksa, LEO Pharma, Maruho, Novartis, Pfizer, Recens Medical, Regeneron Pharmaceuticals, Sanofi, Septerna, Triveni Bio, Vial, and WebMD; he has stock in ABRAX Japan, KliRNA Biotech, Locus Biosciences, and Recens Medical; he holds a patent for the use of janus kinase 1 (JAK1) inhibitors for chronic pruritus; and he has a patent pending for the use of JAK inhibitors for interstitial cystitis.

References

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Enteric neuronal Piezo1 maintains mechanical and immunological homeostasis by sensing force

Affiliations

Enteric neuronal Piezo1 maintains mechanical and immunological homeostasis by sensing force

Authors

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Conflict of interest statement

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