In the last thirty years accumulating data

In the last thirty years, accumulating data have addressed a role for GABA in the modulation of gastrointestinal (GI) functions via its possible involvement in the circuitry of the enteric nervous system (ENS). The ENS is a complex neuronal network located within the gut wall, capable of regulating, independently of the central nervous system (CNS), GI functions, namely motility, secretions, blood flow, and the enteric immune system. However, the effective role and functional significance of GABA in the ENS are far from being clear. Enteric GABA sources include neurons containing the GABA-synthesizing enzyme (L-glutamate decarboxylase, GAD), the highest activity being reported in the myenteric plexus, and mucosal endocrine-like cells, suggesting a role of GABA as both a neural and endocrine mediator in the GI tract [1]. GABAergic neuronal cells, mainly interneurons, occur both in submucosal and myenteric plexus throughout the GI tract, with a particular representation in the large intestine where they account for 5–8% of the total myenteric neurons [2]. GABA is potentially involved both in secretory and motor GI function, exerting either a stimulatory or inhibitory action on the neuronal activity, via activation of GABA receptors. At least three types of GABA receptors have been characterized, named GABAA, GABAB and GABAC receptors [3], [4]. GABAA receptors are ionotropic receptors, in particular pentameric chloride channels constituted by a combination of different subunits, including α (1–6), β (1–3), γ (1–3), δ, ɛ, θ, π, ρ. Because enteric neurons sustain elevated intracellular Cl− concentration, via a specific sodium-potassium-chloride symporter, activation of GABAA receptors in the ENS results in an excitatory effect, in contrast to the well-known inhibitory effect in the CNS [5]. GABAB receptors are heterodimeric metabotropic G protein-coupled receptors negatively acting on presynaptic voltage-activated Ca2+ channels and positively acting on postsynaptic inwardly rectifying K+ channels [6], [7]. Ionotropic GABAC receptors are pentameric chloride channels entirely composed of ρ subunits, which were firstly characterized in retinal neurons [8]. The International Union of Pharmacology Committee has previously recommended classifying GABAC receptors as a subclass of GABAA receptors. However, accumulating data strongly support the distinct pharmacology, structure, function, genetic and localization of these receptors [9], [10]. Although functional GABA receptors have been found both on airway and aortic smooth muscle [11], [12], nerve-free GI smooth muscle ctab medical abbreviation are reported to be unresponsive to addition of GABA [13]. Pharmacological studies addressing GABAergic effect in the GI tract have shown tetrodoxin (TTX)-sensitive effect of GABA, suggesting a neurogenic action of GABA and consequently a neural localization of GABA receptors in the GI tract [14], [15], [16]. Accordingly, immunohistochemical studies have revealed a heterogeneous distribution of GABAA and GABAB receptors in the ENS, localized on both submucosal and myenteric neurons [17], [18]. Moreover, functional studies have shown that GABAA and GABAB agonists differently influenced the activity of cholinergic and Nonadrenergic Noncholinergic (NANC) enteric neurons, depending on the species and the GI tract examined [19], [20], [21], [22]. Although RT-PCR studies have reported GABAC receptor subunit mRNAs in the rat duodenum, ileum and colon [23], consistent with observations of selective GABAC agonist effect on GI functions in rodents [24], to date very little is known about the exact localization and role of GABAC receptors in the GI tract. Therefore, our current knowledge could represent just “the tip of the iceberg” of the functional significance of the GABAergic signalling in the gut. Recently, GABA has been considered a potential key factor within the so-called nerve-driven immunity [25], [26], [27], [28], [29]. Different immune cells are equipped with components of the GABAergic system, including GAD, GABA transporters and GABA receptors, and GABA seems to be involved in modulating the immune response, mainly via a negative regulation of both pro-inflammatory cytokine production and immune cell proliferation. Accumulating evidence have demonstrated that a complex and fine tuning of immune response within the Gut-Associated Lymphoid Tissue (GALT) is crucial for the maintenance of tolerance to harmless antigens in the enteric microenvironment, i.e. food antigens and commensal microbiota components [30]. Indeed, defects in this regulation are strictly related with the development of GI chronic inflammatory pathological conditions, including food allergy and Inflammatory Bowel Diseases (IBD), which are associated with an improper T-cell over-reaction and an increase in pro-inflammatory mediators, as TNF-α, IFN-γ and IL-4 [31]. In this context, an additional potential role of the GABAergic system in the gut, both in physiological and pathological states, can be suggested. In physiological conditions, GABA could contribute to maintain the “tolerogenic state” within the GALT by controlling both T-cell proliferation and cytokine levels, acting synergically with classic gut “immune homeostasis’ guardians”, such as Regulatory T cells [32]. In GI inflammatory states, a drug-induced increase in GABA signalling could contribute to dampen the immune reaction by decreasing T-cell activity and inflammatory mediator levels, in the attempt to restore the immune steady-state in the gut. Hence, we can speculate that the GABAergic system could meet the criteria to be considered both a neuromodulatory system in the ENS, balancing excitatory and inhibitory neural signals, and a “connecting bridge”, ensuring a functional cooperation between the nervous system and the immune system. Given the necessity of novel therapeutic targets for different motor and inflammatory GI disorders, i.e. chronic intestinal pseudo-obstruction (CIP), postoperative ileus (POI) and IBD, a comprehensive understanding of the role of the GABAergic system in the gut should be encouraged for its possible contribution both in the improvement of currently available therapies and in the development of innovative and more effective treatments. Therefore, the aim of this review is to summarize the current evidence about the role of GABA in the modulation of both GI motility and immune cell activity and inflammation, in the attempt to propel the development of new therapeutic strategies specifically targeting the so-called “neuroimmune dialogue” in the gut.