Mast cell modulation: A novel therapeutic strategy for abdominal pain in irritable bowel syndrome

Abstract

Irritable bowel syndrome (IBS) is one of the most prevalent gastrointestinal disorders characterized by recurrent abdominal pain and an altered defecation pattern. Chronic abdominal pain represents the hallmark IBS symptom and is reported to have the most bothersome impact on the patient's quality of life. Unfortunately, effective therapeutic strategies reducing abdominal pain are lacking, mainly attributed to a limited understanding of the contributing mechanisms. In the past few years, exciting new insights have pointed out that altered communication between gut immune cells and pain-sensing nerves acts as a hallmark driver of IBS-related abdominal pain. In this review, we aim to summarize our current knowledge on altered neuro-immune crosstalk as the main driver of altered pain signaling, with a specific focus on altered mast cell functioning herein, and highlight the relevance of targeting mast cell-mediated mechanisms as a novel therapeutic strategy for chronic abdominal pain in IBS patients.

Graphical abstract

Figure 1

Clinical characteristics of IBS (A) Rome IV criteria for the clinical diagnosis of IBS. (B) Visceral hypersensitivity is the main driver of abdominal pain experienced by IBS patients, and it presents as an abnormally increased pain sensitivity from the bowel, mainly characterized by allodynia (red) and hyperalgesia (orange). Allodynia refers to the process where stimuli that normally are perceived as non-painful are perceived as painful. Hyperalgesia refers to the process where stimuli that normally are perceived as painful are perceived as even more painful.

Figure 2

Neuroanatomy of the colonic nociceptive innervation Colonic pain sensation is mediated by specialized afferent nerves, the splanchnic and pelvic nerves, of which the pseudo unipolar neuronal cell bodies are in the dorsal root ganglia (DRGs) located near the spinal cord. The peripheral nerve endings of these afferent nerves reside in the different layers of the gut wall (mucosa, submucosa, and muscularis externa), where they act as sentinels that detect potential dangers. As opposed to the enteric nervous system (ENS), comprising a local and intrinsic neuronal signaling circuitry, gut nociceptors are part of an extrinsic gut-to-brain signaling axis that transmits its pain signals via the splanchnic and pelvic nerves to the DRG and spinal cord. In the dorsal horn of the spinal cord, this nociceptive input is integrated by spinal cord neurons and further transmitted toward the brain, resulting in pain perception. ENS, enteric nervous system.

Figure 3

Molecular mechanisms involved in abnormal pain signaling in IBS patients The IBS microenvironment is characterized by increased levels of pro-nociceptive mediators such as serotonin, histamine, proteases, growth factors, etc. Through the activation of their cognate receptors on gut nociceptive nerve endings, these mediators can directly activate and modulate the functioning of gut nociceptors (1). Increased signaling by pro-nociceptive mediators induces an increased expression and upregulation of pro-nociceptive ion channels, mostly TRP channels (2). Moreover, pro-nociceptive mediators trigger intracellular signaling cascades that activate downstream protein kinases, resulting in TRP channel phosphorylation and sensitization (3). Collectively, these pro-nociceptive mediators and their effects on TRP channel functioning are the hallmark mechanism underlying aberrant nociceptor excitability in IBS patients. GFR, growth factor receptor; 5-HT, serotonin; 5-HT3R, serotonin 3 receptor; H1R, histamine 1 receptor; PAR2, protease-activated receptor 2; MRGPRs, Mas-related G Protein-coupled receptors; TRP, transient receptor potential; PKA, protein kinase A; PKC, protein kinase C.

Figure 4

Mast cell-targeted therapies as novel treatment strategy for IBS (A) An effective therapeutic strategy is to target the increased degranulation of gut mast cells. This can be achieved using mast cell stabilizing drugs (cromolyn sodium, ketotifen), which block exocytosis and thereby prevent the release of mediators by activated mast cells. An alternative approach is to prevent IgE-dependent or IgE-independent activation of mast cells. For IgE-dependent signaling, this can be achieved by monoclonal anti-IgE antibodies (omalizumab) that target IgE antibodies and thereby prevent the binding of IgE antibodies to FcεRI receptors on gut mast cells. For IgE-independent signaling, this could be achieved by MRGPRX2 receptor antagonists. Alternatively, Siglec-8 is an inhibitory receptor expressed on mast cells which, upon activation by monoclonal anti-Siglec-8 antibodies, initiates intracellular signaling cascades that prevent that IgE-mediated and non-IgE-mediated activation resulting in mast cell degranulation. (B) Targeting mast cell mediator signaling represents a very promising therapeutic strategy in IBS. This therapeutic approach relies on blocking the receptors for pro-nociceptive mast cell mediators such as serotonin (alosetron, ramosetron) or histamine (ebastine), thereby effectively preventing pro-nociceptive signaling on the gut pain innervation. IgE, immunoglobulin E; FceR1, Immunoglobulin E receptor; 5-HT, serotonin; 5-HT3R, serotonin 3 receptor; H1R, histamine 1 receptor.