The role of Mrgpr (Mas-related G protein-coupled receptor) signaling in the activation of mast cells in irritable bowel syndrome.

Irritable bowel syndrome (IBS) is a highly prevalent chronic gastrointestinal disorder characterized by abdominal pain and an altered bowel habit in the absence of organic disease. While the exact pathophysiology underlying the abdominal pain in IBS patients is not fully established yet, mast cells have been put forward to play an important role, mainly in IBS-D (diarrhea-predominant IBS). Upon activation, mast cells release different mediators that subsequently sensitize afferent nerves, thereby leading to visceral hypersensitivity resulting in abdominal pain complaints. Mast cell activation can occur via an IgE-dependent or IgE-independent system. Recently, researchers demonstrated an important role for the Mas-related G-protein coupled receptor MRGPRX2/Mrgprb2 in the IgE-independent mast cell activation pathway in itch. Besides, Mrgprb2 was found to be expressed by connective tissue mast cells in mouse colon in close proximity to colonic nerves. Furthermore, the human ortholog MRGPRX2 is expressed in human colon mast cells and an increased MRGPRX2 mRNA expression has been reported in distinct subsets of IBS patients. Taken together, these preliminary data point towards a potential interesting role for MRGPRX2/Mrgprb2 in IBS-D. Therefore, the overall objective of this project is to strengthen our knowledge of MRGPRX2 expression and function in the colon of IBS-D patients and the therapeutic potential of MRGPRX2 by evaluating their role in mast cell activation and visceral pain in a fundamental mouse model. In Work Package 1, we intend to characterize the expression pattern and location of MRGPRX2 in human colon biopsies from controls and IBS-D patients, using qPCR, immunohistochemical techniques and in situ hybridization. In Work Package 2, we will investigate the functional role of MRGPRX2 in mast cell priming and activation using human mast cell cultures and a novel colon organoid model. In Work Package 3, we aim to explore the functional role of Mrgprb2 in visceral hypersensitivity in a fundamental set-up in mice. Sensitivity will be assessed both in vitro using afferent nerve measurements from colon segments, and separately in vivo by studying the visceromotor response to colorectal distension.

Keywords:IBS, IRRITABLE BOWEL, MAST CELLS

Disciplines:Gastro-enterology