Abstract
Background & aimsThe causes of gastrointestinal complaints in irritable bowel syndrome (IBS) remain poorly understood. Altered nerve function has emerged as an important pathogenic factor as IBS mucosal biopsy supernatants consistently activate enteric and sensory neurons. We investigated the neurally active molecular components of such supernatants from patients with IBS and quiescent ulcerative colitis (UC).MethodEffects of supernatants from 7 healthy controls (HC), 20 IBS and 12 UC patients on human and guinea pig submucous neurons were studied with neuroimaging techniques. We identify differentially expressed proteins with proteome analysis.ResultsNerve activation by IBS supernatants was prevented by the protease activated receptor 1 (PAR1) antagonist SCHE79797. UC supernatants also activated enteric neurons through protease dependent mechanisms but without PAR1 involvement. Proteome analysis of the supernatants identified 204 proteins, among them 17 proteases as differentially expressed between IBS, UC and HC. Of those the four proteases elastase 3a, chymotrypsin C, proteasome subunit type beta-2 and an unspecified isoform of complement C3 were significantly more abundant in IBS compared to HC and UC supernatants. Of eight proteases, which were upregulated in IBS, the combination of elastase 3a, cathepsin L and proteasome alpha subunit-4 showed the highest prediction accuracy of 98% to discriminate between IBS and HC groups. Elastase synergistically potentiated the effects of histamine and serotonin–the two other main neuroactive substances in the IBS supernatants. A serine protease inhibitor isolated from the probiotic Bifidobacterium longum NCC2705 (SERPINBL), known to inhibit elastase-like proteases, prevented nerve activation by IBS supernatants.ConclusionProteases in IBS and UC supernatants were responsible for nerve activation. Our data demonstrate that proteases, particularly those signalling through neuronal PAR1, are biomarker candidates for IBS, and protease profiling may be used to characterise IBS.
Highlights
The enteric nervous system (ENS) in the gut wall coordinates and maintains normal gut functions
Nerve activation by irritable bowel syndrome (IBS) supernatants was prevented by the protease activated receptor 1 (PAR1) antagonist SCHE79797
Proteases in IBS and ulcerative colitis (UC) supernatants were responsible for nerve activation
Summary
The enteric nervous system (ENS) in the gut wall coordinates and maintains normal gut functions. The use of mucosal biopsies and biopsy supernatants became a powerful tool to investigate gut pathologies and to link altered cellular behavior with gut dysfunctions [2] Evidence for this is that mucosal biopsy supernatants from IBS patients, but not from healthy controls, activate enteric neurons [3], vagal afferents [4] as well as spinal afferents [5]. Proteases are responsible for acute nerve activation and account for desensitization of nerve responses This explains why a mediator cocktail containing the neuroactive components of the IBS biopsy supernatants evokes less activation of enteric neurons in biopsies from IBS patients compared to healthy controls [10]. We investigated the neurally active molecular components of such supernatants from patients with IBS and quiescent ulcerative colitis (UC)
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