English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Background We have shown that Irritable Bowel Syndrome diarrhea-predominant (IBS-D) patients with a history of a dysbiotic-like onset have distinct stool metabolomic profiles versus those with a non-dysbiotic-like onset. IBS stool supernatants can sensitize mouse colonic afferent nerves via both histamine and proteases. However, it is unknown if stool supernatants from the two IBS-D subgroups modulate the excitability of nociceptive neurons via different neuroactive mediators Aims To evaluate whether there are differences in neuroactive mediators within stool supernatants from subgroups of IBS-D patients that can modulate the excitability of nociceptive neurons. Methods Stool samples from healthy control (HC) (N=5) and IBS-D patients with a dysbiotic (N=7) or non-dysbiotic-like (N=7) onset, was homogenized with Krebs solution and filtered. Proteolytic activity was assessed using casein as a substrate with and without protease inhibitors. Histamine was quantified by ELISA. DRG neurons from C57BL/6 mice were incubated overnight or acutely (30 min) with stool supernatants. Some neurons were pre-incubated with PAR2 (GB83, 10 μM) or H1R (pyrilamine, 1μM) antagonists prior to supernatant incubation. Changes in neuronal excitability were assessed with perforated patch-clamp by measuring the rheobase (current that elicits an action potential). Results Proteolytic activity in dysbiotic-like (57.9 U/μg, p&amp;lt;0.05) but not non-dysbiotic like (37.4 U/μg) stool supernatant was increased compared to HC (25.2 U/μg). Serine inhibitor decreased proteolytic activity of dysbiotic (46.6%, p&amp;lt;0.05) and non-dysbiotic (34.2%, p&amp;lt;0.01) supernatant whereas cysteine, aspartic and metalloproteases inhibitors had no effect. Histamine was increased 78% (p&amp;lt;0.05) in IBS-D compared to HC. No differences in proteolytic activity and histamine concentration between IBS-D subtypes were found. In patch-clamp recordings, overnight incubation with dysbiotic (19%, p&amp;lt;0.05) and non-dysbiotic (22%, p&amp;lt; 0.01) stool supernatant decreased rheobase of DRG neurons compared to HC. No difference in rheobase was observed between IBS-D subtypes. GB83 blocked the overnight actions of supernatants from both subgroups, but pyrilamine had no effect. In contrast, following acute incubation, pyrilamine blocked the hyperexcitability evoked by dysbiotic like supernatant (60pA vs 48pA, p&amp;lt;0.001) but had no effect on non-dysbiotic like supernatants. Conclusions Proteases in stool supernatants from IBS-D patients increase neuronal excitability but only those with a history of dysbiotic like onset acutely increase neuronal excitability through H1 receptors. These findings suggest that stool supernatants from subgroups of IBS-D may modulate nociceptor excitability via different mechanisms. Funding Agencies CIHRAmerican Neurogastroenterology and Motility Society

A242 STOOL FROM IBS-D PATIENT WITH A HISTORY OF A DYSBIOTIC AND NON-DYSBIOTIC ONSET MODULATE NEURONAL EXCITABILITY VIA DIFFERENT MECHANISMS