Author(s): Irene Martinucci aff1 , Corrado Blandizzi [*] aff2 , Nicola de Bortoli aff1 , Massimo Bellini aff1 , Luca Antonioli aff2 , Marco Tuccori aff2 , Matteo Fornai aff2 , Santino Marchi aff1 , Rocchina Colucci aff2
dopamine; functional constipation; functional dyspepsia; functional gastrointestinal disorders; irritable bowel syndrome; noradrenaline; polymorphism; serotonin
Functional gastrointestinal (GI) disorders (FGIDs) comprises a number of heterogeneous syndromes, for which clinical investigations do not reveal any evident organic cause [1 ]. FGIDs affect a large part of the general population with irritable bowel syndrome (IBS), functional constipation (FC) and functional dyspepsia (FD) representing the most prevalent conditions [2,3 ]. According to Rome III criteria, IBS is characterized by abdominal pain or discomfort and changes in bowel habit (constipation and/or diarrhea) [ 4 ]. FC presents as chronic difficult, infrequent or seemingly incomplete defecation, which does not meet IBS criteria [4 ]. FD is defined by the presence of gastroduodenal symptoms, such as bothersome postprandial fullness, early satiation and epigastric pain, and its current diagnostic categories comprise: postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS) [5 ].
From a pathogenic standpoint, FGIDs are considered as multifactorial in nature with alterations of GI motility, visceral hypersensitivity and psychopathological comorbidities playing a pivotal role [5,6 ]. However, the pathophysiological mechanisms underlying FGIDs remain poorly understood and, in parallel, there is a substantial lack of effective medical therapies, with available drugs often resulting in unsatisfactory outcomes or adverse effects. Consequently, owing to their chronic or recurrent course, FGIDs result in a significant social burden, with a relevant negative impact on both quality of life and healthcare costs [7,8 ].
Based on current evidence, the predisposing factors to FGID symptoms include a combination of environmental (e.g., diet, infections, stressful events) and genetic factors [9 ]. Studies on families and twins have given support to the influence of hereditary factors in both IBS and FD [10,11 ], and, consequently, efforts are being made to evaluate whether polymorphisms of a number of candidate genes are linked to FGIDs or their phenotypes (i.e., intermediate phenotypes or clinical presentation/severity) [9,12,13 ]. Nevertheless, even though currently a large body of data substantiate the contribution of genetics to FGIDs, at present it is not possible to define precisely which specific variants are actually associated with FGIDs (or their clinical phenotypes), that likely represent heterogeneous, multifactorial, polygenic complex disorders. Indeed, as better discussed below, several limitations of association studies still oppose relevant barriers against the assessment of the exact roles played by genetic polymorphisms in FGIDs and prevent reliable quantitative estimations of the genetic polymorphisms that are encountered in the population of patients with FGIDs. Of note, the role of genetics has been scarcely investigated in patients with FC.
The homeostasis of digestive tract is ensured by networks of intrinsic and extrinsic regulatory pathways, and their dysfunctions may contribute to the GI symptoms that characterize FGIDs [14,15 ]. In this context, great attention has been paid to aminergic mediators (i.e., noradrenaline or NA; serotonin, 5-hydroxytryptamine or 5-HT; dopamine or DA), owing to their pivotal roles...