Adaptive changes of the gastrointestinal neuromuscolar function in a mouse model of Catechol-O-Methyl trasferase genetic reduction: implication in the pathogenesis of Irritable Bowel syndrome.

Enteric neuronal circuitries display a considerable ability to adapt to a changing microenvironment, which comprises several cellular "players", including neurons, enteric glial cells, smooth muscle cells, interstitial cells of Cajal, immune cells and commensal bacteria (Giaroni et al., 1999). In particular, gut microbiota seems to be directly involved in modulating the development and function of enteric nervous system (ENS), supporting the concept that changes in commensal microbiome composition, induced by infections or antibiotics, can perturb ENS integrity and activity. Neuronal circuitries in the ENS are known to communicate with the Central Nervous System (CNS) via vagal and sympathetic extrinsic pathways: the so called brain-gut axis. Current cutting-edge research suggests that the enteric microbiota, by modifying enteric neuronal circuitries, may communicate with the brain, thus influencing cognitive and behavioural functions. However, early life perturbations of gut microbiota can potentially influence neurodevelopment leading to functional bowel disorders later in life (Ianiro et al., 2016). There is increasing evidence showing that an altered microbiota composition may be related to functional or psychiatric disorders such as irritable bowel syndrome (Bonfrate et al., 2013; Kennedy et al., 2014) and autism (Finegold, 2011; Mayer et al., 2014). Irritable bowel syndrome (IBS) comprises a heterogeneous group of functional lower gastrointestinal tract disorders characterized by abdominal pain or discomfort associated with altered bowel habits and disordered defecation that may be exacerbated by emotional stress. This gut disorder cannot be explained by specific pathophysiologic mechanisms, since it is not associated with any structural finding or biological marker (Mach, 2004). However, the symptoms of IBS are related to combinations of several known physiological determinants such as abnormal motor reactivity, enhanced visceral hypersensitivity, altered mucosal immune and inflammatory functions (which includes changes in bacterial flora), and altered brain-ENS regulation, which is influenced by psychosocial and socio-cultural factors (Drossman, 2006; Ohman and Simren, 2010; Simren et al., 2013). Recently, the association between gut functional disorders, such as IBS, and catechol-O-methyl-transferase (COMT), an enzyme protein which regulates catecholamines levels in mammalian brain (Lundstrom et al., 1995; Mannisto and Kaakkola, 1999) has been proposed. In this perspective, IBS can be described as a disorder of the gut–brain axis (Moloney et al., 2016). The aim of the study was to determine whether a genetic-driven defective COMT activity may affect the structural and functional integrity of murine ENS. Data obtained in the COMTtransgenic mouse model have been compared to those obtained in the gastrointestinal tract of antibiotic treated-mice in order to deplete the microbiota. Data showed that the partial deletion of COMT determined anomalies in the ENS architecture, with a marked increase in protein and mRNA expression of the glial marker S100β. Excitatory cholinergic transmission and inhibitory nitrergic neurotransmission, mainly through iNOS increased expression, led to impaired gut neuromuscular contractility. In addition, an increase of GluN1 glutamatergic subunit expression, affecting visceral hypersensitivity with critical effects on gut function, was also observed. The massive antibiotic treatment determined the same alterations in ENS structure and function observed in the COMT transgenic model. Interestingly, COMT partial genetic deletion induced changes in gut microbioma composition and some commensal intestinal microbial strains underwent drastic changes. In particular, in COMT+/- mice a significant increase of Firmicutes DNA in the ileum and colon and a significant decrease of Bacterioidetes DNA in the ileum were observed with respect to control animals, suggesting that host may affect gut microbial flora arrangement. These data confirmed the importance of studying the interplay between host and microbiota, reflecting alterations in motor and sensitive parameters which resemble some features of functional gastrointestinal disorders, such as Irritable Bowel Syndrome (IBS). In conclusion, this study showed that both COMT genetic deletion as well as dysbiosis may be critical factors involved in the pathogenesis of functional gut disorders, such as IBS