Targeting mast cells in the treatment of functional gastrointestinal disorders

Enhanced knowledge of the pathophysiological basis of functional gastrointestinal disorders indicates that low-grade mucosal inflammation and mast cell hyperplasia are common findings. Mast cells are multipotent and mucosa-dwelling residents are uniquely located to communicate with host immune and nervous supersystems and with the gut microflora to provide tight microenvironmental conditions. Maintenance of homeostasis within this integrated defense system is crucial for symbiotic health, whereas breakdown of that balance might lead to uncontrolled mucosal and systemic inflammation. Numerous advances have recently emerged in the understanding of regulatory mechanisms of mast cell activation, development and homing to mucosal surfaces, as well as of the role of mast cells in key steps of mucosal inflammation. Such observations have stimulated the development of candidate drugs, such as tryptase or Syk inhibitors, that might be useful for the treatment of gastrointestinal functional disorders.

Introduction

Despite being the most frequent cause for digestive consultation, functional gastrointestinal disorders have been paid little scientific attention for decades. The recently released Rome III classification for functional gastrointestinal disorders includes 28 adult and 17 pediatric entities [1]. Because of common symptomatic overlap among these disorders and the lack of information on the underlying mechanisms in many of them, here we focus on the two most well-studied and representative entities: functional dyspepsia and, mainly, irritable bowel syndrome (IBS).

Functional dyspepsia and IBS share physiopathological abnormalities, including visceral hypersensitivity and altered motor reactivity in the context of distorted central and peripheral neuro-immune regulation, which might well explain some of the clinical manifestations. Although a variety of factors might influence the initiation, development and perpetuation of such abnormalities, psychosocial factors, such as life stress, anxiety or depression, genetic predisposition and gastrointestinal infections, appear to be robustly associated, both epidemiologically and mechanistically.

Convincing evidence indicates that mast cells (MCs) participate in the modulation of a wide variety of gastrointestinal physiological and pathological processes, including the regulation of epithelial barrier, mucosal immune function and host bacterial defense, motility and visceral sensitivity [2^•]. In IBS, synaptic-like contacts between MCs and enteric nerve fibers have been detected in the colonic mucosa, as well as increased MC numbers and MC products in both the small bowel and colon [3^•]. This anatomical relationship provides a physical substrate for bidirectional communication between the central nervous system and the gut by which stress, luminal bacteria and other regulatory factors might influence gastrointestinal physiology and inflammation. The mediators and pathways responsible for MC hyperplasia and activation in the gastrointestinal mucosa of some patients with functional gastrointestinal disorders have not been defined.

Although MCs might release their contents abruptly and massively, following antigen-induced activation via high-affinity receptors for IgE (FcɛRIs), most observations point towards a slower and probably more selective emptying of granule contents, piecemeal degranulation, as the predominant mechanism involved in the regulation of autoimmune and chronic inflammatory disorders [4]. The biological consequences of the activation and degranulation of MCs are extremely complex and diverse, providing multiple levels of pharmacological intervention (Figure 1). Yet, it is not clear whether prevention or stimulation of MC function and growth is, in the end, good or bad for the control of gastrointestinal inflammation and related clinical symptoms, although molecular [5] and phenotypic [6] characterization of human MCs in the gastrointestinal tract might help to demonstrate this role. Acknowledging these limitations, in this review, we focus only on the most promising and rational therapies directed to modulate MC effects on gastrointestinal physiology that might be applicable for common functional gastrointestinal disorders.