Gut · 2026
Faecal proteases and immune signatures drive subtype-specific enteric neuronal activation in IBS.
СтатьяНазвание и аннотация: Перевод в очереди
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Ridžal Lejla, Frieling Thomas, Róka Richárd, Inczefi Orsolya, Bacsur Péter, Bajcsi Dóra, Neunlist Michel M, Cardaillac Claire, Theodorou Vassilia, Yoon Hongsup, Wang Jiancheng, Ludwig Christina, Wudy Susanne I, Pankotai Tibor, Páhi Zoltán G, Mansouri Nooshin, Luksch Harald, Michel Klaus, Schemann Michael, Annaházi Anita
Аннотация
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.
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.