Sensory neuron-mast cell crosstalk in IBS pathophysiology

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Irritable bowel syndrome (IBS) affects ~9% of the worldwide population and is the most common outpatient gastrointestinal diagnosis. Abdominal pain is the most important cause of morbidity in this patient population and available treatments for abdominal pain in IBS are limited, untargeted, symptom-based, and often ineffective. This is partly due to a lack of a better understanding of underlying pathogenic mechanisms and poses a significant knowledge gap. Increased intestinal permeability and visceral hypersensitivity are key pathogenic features in patients with IBS. However, what causes VH and barrier dysfunction in IBS is poorly understood. Mast cells have been proposed as a key player in barrier dysfunction and visceral hypersensitivity in IBS. However, several fundamental questions about mast cell activation remain unanswered which hinders our understanding of barrier dysfunction and visceral hypersensitivity in IBS. Our preliminary data suggests that the level of Substance P (released by sensory neurons) is increased in patients with diarrhea-predominant IBS (IBS-D). This is accompanied by increased MRGPRX2 expression at mRNA and protein levels in patients with IBS-D. Furthermore, our in vitro studies confirm that Substance P can activate colonic mast cells to release disease-promoting mediators and in vivo studies suggest that Substance P-mediated activation of MRGPRX2 plays a key role in visceral hypersensitivity and barrier dysfunction in IBS rodent models. Thus, there is a critical need to delineate the role of Substance P and its receptor MRGPRX2 in IBS pathophysiology, which would bring us closer to the goal of precision medicine targeting underlying pathophysiology rather than the current symptom-based management of IBS. The long-term goal of this project is to advance our understanding of VH and barrier dysfunction in IBS to build the foundational knowledge to develop effective and targeted therapies for IBS. The objective is to delineate the underlying mechanisms of bidirectional crosstalk between sensory neurons and mast cells in IBS and establish its role in IBS pathophysiology. The central hypothesis is that Substance P-mediated activation of MRGPRX2 in colonic mast cells drives VH and barrier dysfunction in IBS in a feed-forward cycle. In Aim 1, we will determine the role and mechanisms of Substance P-mediated colonic mast cell activation in IBS using rodent colonic mast cell culture and human colonic biopsies (from healthy control and IBS-D biopsies). In Aim 2, we will elucidate the contributions of MRGPRX2-mediated mast cell activation to IBS pathophysiology in vivo using two validated rodent models. Completion of these aims will provide fundamental insights into sensory neuron-mast cell interactions in IBS and provide proof of principle for a future R01 proposal to definitively establish the role of Substance P and MRGPRX2 in IBS pathophysiology, delineate the molecular mechanisms of SubstanceP-Mrgprb2 pathway barrier dysfunction and visceral hypersensitivity and define the final part of crosstalk i.e. role of mast cells in Substance P release in IBS.