Intestinal chemosensitivity in irritable bowel syndrome associates with small intestinal TRPV channel expression

Abstract

Background: Irritable bowel syndrome (IBS) patients often experience mealassociated symptoms. However, the underlying mechanisms are unclear. Aim:To determine small intestinal mechanisms of lipid-induced symptoms and rectal hypersensitivity in IBS Methods: We recruited 26 IBS patients (12 IBS-C, 14 IBS-D) and 15 healthy volunteers (HV). In vivo permeability was assessed using saccharide excretion assay.Rectal sensitivity was assessed using a barostat before and after small bowel lipid infusion; symptoms were assessed throughout. Next, an extended upper endoscopy with probe-based confocal laser endomicroscopy (pCLE) was performed with changes induced by lipids. Duodenal and jejunal mucosal biopsies were obtained for transcriptomics.Results: Following lipid infusion, a higher proportion of HV than IBS patients reported no pain, no nausea, no fullness and no urgency (P < 0.05 for all). In a model adjusted for sex and anxiety, IBS-C and IBS-D patients had lower thresholds for first rectal sensation (P = 0.0007) and pain (P = 0.004) than HV. In vivo small intestinal permeability and mean pCLE scores were similar between IBS patients and HV. Postlipid, pCLE scores were higher than pre-lipid but were not different between groups. Baseline duodenal transient receptor potential vanilloid (TRPV) 1 and 3 expression was increased in IBS-D, and TRPV3 in IBS-C. Duodenal TRPV1 expression correlated with abdominal pain (r = 0.51, FDR = 0.01), and inversely with first rectal sensation (r = −0.48, FDR = 0.01) and pain (r = −0.41, FDR = 0.02) thresholds. Conclusion:Lipid infusion elicits a greater symptom response in IBS patients than HV, which is associated with small intestinal expression of TRPV channels. TRPVmediated small intestinal chemosensitivity may mediate post-meal symptoms in IBS.

Immune Activation in Functional Dyspepsia: Bystander Becoming the Suspect

“…More recently, a 12-week treatment with the H 1 R antagonist ebastine decreased abdominal pain and reduced hypersensitivity to distention compared to placebo, with inhibition of H 1 R-mediated neuronal sensitization rather than immunomodulatory properties suggested to underly this effect ( Wouters et al, 2016 ). Also, TRPV1 and -3 were implicated in chemosensitivity to lipids in IBS patients, potentially resulting in postprandial symptoms, while increased duodenal TRPV1 expression was linked to abdominal and rectal pain scores ( Grover et al, 2021 ). Of note, hypersensitivity to oral intake of capsaicin – a major TRPV1 agonist – has been demonstrated in FD patients ( Hammer, 2018 ), which could be explained by increased TRPV1 expression.…”

Ca2+-Permeable Channels/Ca2+ Signaling in the Regulation of Ileal Na+/Gln Co-Transport in Mice

“…Recently, the expression and function of transient receptor potential (TRP) channels in the GI tract have attracted extensive attention; TRPV1-6 channels have been shown to be stably expressed in IEC as non-selective cation channels with Na + and Ca 2+ permeability (Voets et al, 2004;Rao et al, 2006;Ueda et al, 2009;Fothergill et al, 2016;Maurino et al, 2020;Manneck et al, 2021). Although TRPV channels in GI sensory neurons have been studied extensively (De Petrocellis et al, 2012;Maurino et al, 2020;Grover et al, 2021), our study is the first to demonstrate the involvement of Ca 2+ entry via TRPV channels in the regulation of ileal Gln transport in IEC. Na + /Ca 2+ influx mediated by TRPV channels could activate bidirectional ion exchange (NCX), whose transport direction depends on Na + and Ca 2+ gradients and membrane potentials Zhao et al, 2021).…”

Current Treatment Options and Therapeutic Insights for Gastrointestinal Dysmotility and Functional Gastrointestinal Disorders

“…Visceral sensitivity is affected by the gut immune response in a manner relative to the proximity of neurons to immune cells as well as the propagation level of inflammatory reactions ( Barbara et al, 2004 ; Aguilera-Lizarraga et al, 2021 ). More importantly, visceral hypersensitivity is a key pathophysiological mechanism leading to the development of FGIDs ( Singh et al, 2016 ; Black et al, 2020b ; Grover et al, 2021 ). Visceral hypersensitivity can be explained by an increased perception of gut mechano-chemical stimulation, which typically manifests in an aggravated feeling of pain and burning ( Farzaei et al, 2016 ; Bellono et al, 2017 ).…”

“…( Farzaei et al, 2016 ). Furthermore, upregulation of TRPV1 has been associated with abdominal pain in IBS patients in a plethora of studies ( Akbar et al, 2008 ; Grover et al, 2021 ).…”