Faecal proteases and immune signatures drive subtype-specific enteric neuronal activation in IBS
Abstract
Background: Luminal proteases have been implicated in epithelial barrier dysfunction and visceral hypersensitivity in irritable bowel syndrome (IBS), yet their impact on the enteric nervous system (ENS), the principal regulator of gastrointestinal function, remains unknown. Objective: To investigate whether faecal mediators differentially activate enteric neurons across IBS subtypes and whether proteolytic and proteomic profiles explain neuronal phenotypes. Design: The effects of faecal supernatants (FSN) from 21 IBS-D (diarrhoea-predominant), 9 IBS-C (constipation-predominant) and 18 healthy control (HC) patients recruited across centres in three countries on guinea pig distal colon submucous plexus neurons were assessed using a neuroimaging technique. Faecal proteolytic activities and proteomic profiles were analysed. Results: IBS-D and IBS-C supernatants evoked significantly stronger neuronal activation than HC, demonstrating that FSN directly modulate ENS. In IBS-D, but not IBS-C, effects were mediated by serine and cysteine proteases and PAR-1. Proteome analysis revealed a significant difference in 47 proteins between IBS-D and HC, including several immunoglobulin components, underlying the role of microinflammation in IBS-D. A combination of amylases, trypsin-2 and an immunoglobulin protein demonstrated high diagnostic performance to distinguish IBS-D from HC. Conclusion: These findings uncover a previously unrecognised luminal-ENS axis in IBS and reveal fundamentally different pathological mechanisms between IBS-D and IBS-C. IBS-D is characterised by proteases and PAR-1-dependent neuronal activation and a distinct immune-enriched faecal proteome, whereas mediators in IBS-C act independently of these factors. These findings establish a functional link between faecal protease activity, ENS signalling and molecular biomarkers, highlighting new therapeutic and diagnostic avenues for subtype-specific management of IBS.
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BibTeX
@article{ridzal2026faecal,
title = {{Faecal proteases and immune signatures drive subtype-specific enteric neuronal activation in IBS}},
author = {Lejla Ridžal and Thomas Frieling and Richárd Róka and Orsolya Inczefi and Péter Bacsur and Dóra Bajcsi and Michel M Neunlist and Claire Cardaillac and Vassilia Theodorou and Hongsup Yoon and Jiancheng Wang and Christina Ludwig and Susanne I Wudy and Tibor Pankotai and Zoltán G Páhi and Nooshin Mansouri and Harald Luksch and Klaus Michel and Michael Schemann and Anita Annaházi},
journal = {Gut},
year = {2026},
month = aug,
doi = {10.1136/gutjnl-2025-337949},
url = {https://hal.science/hal-05732709v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Faecal proteases and immune signatures drive subtype-specific enteric neuronal activation in IBS
AU - Lejla Ridžal
AU - Thomas Frieling
AU - Richárd Róka
AU - Orsolya Inczefi
AU - Péter Bacsur
AU - Dóra Bajcsi
AU - Michel M Neunlist
AU - Claire Cardaillac
AU - Vassilia Theodorou
AU - Hongsup Yoon
AU - Jiancheng Wang
AU - Christina Ludwig
AU - Susanne I Wudy
AU - Tibor Pankotai
AU - Zoltán G Páhi
AU - Nooshin Mansouri
AU - Harald Luksch
AU - Klaus Michel
AU - Michael Schemann
AU - Anita Annaházi
PY - 2026
DA - 2026/08/04
JO - Gut
DO - 10.1136/gutjnl-2025-337949
UR - https://hal.science/hal-05732709v1
AB - Background: Luminal proteases have been implicated in epithelial barrier dysfunction and visceral hypersensitivity in irritable bowel syndrome (IBS), yet their impact on the enteric nervous system (ENS), the principal regulator of gastrointestinal function, remains unknown. Objective: To investigate whether faecal mediators differentially activate enteric neurons across IBS subtypes and whether proteolytic and proteomic profiles explain neuronal phenotypes. Design: The effects of faecal supernatants (FSN) from 21 IBS-D (diarrhoea-predominant), 9 IBS-C (constipation-predominant) and 18 healthy control (HC) patients recruited across centres in three countries on guinea pig distal colon submucous plexus neurons were assessed using a neuroimaging technique. Faecal proteolytic activities and proteomic profiles were analysed. Results: IBS-D and IBS-C supernatants evoked significantly stronger neuronal activation than HC, demonstrating that FSN directly modulate ENS. In IBS-D, but not IBS-C, effects were mediated by serine and cysteine proteases and PAR-1. Proteome analysis revealed a significant difference in 47 proteins between IBS-D and HC, including several immunoglobulin components, underlying the role of microinflammation in IBS-D. A combination of amylases, trypsin-2 and an immunoglobulin protein demonstrated high diagnostic performance to distinguish IBS-D from HC. Conclusion: These findings uncover a previously unrecognised luminal-ENS axis in IBS and reveal fundamentally different pathological mechanisms between IBS-D and IBS-C. IBS-D is characterised by proteases and PAR-1-dependent neuronal activation and a distinct immune-enriched faecal proteome, whereas mediators in IBS-C act independently of these factors. These findings establish a functional link between faecal protease activity, ENS signalling and molecular biomarkers, highlighting new therapeutic and diagnostic avenues for subtype-specific management of IBS.
SN - 0017-5749
SN - 1468-3288
ER -