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    • In the last years a plethora of

    2021-09-17

    In the last years, a plethora of studies overstepped the classic concept of the ENS as purely modulator of GI secretion and motility, focusing on its potential as source of substances acting on immune cells and consequently involved in the control of local inflammatory events, as in the Inflammatory Bowel Diseases (IBD). IBD are common GI multifactorial pathologies, including Crohn's Disease and Ulcerative Colitis, characterized by a chronic intestinal inflammatory reaction causing both acute GI symptoms (i.e. cramping, diarrhoea) and a progressive and severe impairment of gut functions [31]. Although IBD aetiology is currently unknown, aberrant T-cell-based mucosal immune system activation against normal components of commensal microbiota is recognized as a milestone in the physiopathology of IBD [87], [88]. Accordingly, current available therapies have been based on different anti-inflammatory drugs attempting to reduce inflammatory mediator levels in the gut, i.e. corticosteroids and cytokines-specific NNC 55-0396 [89], [90]. Although such agents have shown some success for treatment of moderate IBD, unfortunately they are also related with major side effects, and are not associated with the eradication of the chronic immune reaction [91]. Hence, in the attempt to develop novel and more effective therapeutic strategies for IBD, different research groups draw their attention on the importance of the “neuroimmune dialogue” between the ENS and the intestinal mucosal immune system [92], [93]. To date, different studies have already shown the presence of receptors for neural mediators on the surface of a range of immune cells, and the effect of their activation on essential processes like phagocytosis, cytokine production and proliferation [94], [95]. Accordingly, some authors reported pro- or anti-inflammatory effects of neuropeptides, namely substance P and VIP, whilst other studies addressed the different effect of serotonin and ACh in the modulation of the enteric inflammatory event [96], [97], [98]. Even the enteric purinergic system seems to play an important role, since ATP and adenosine strongly control inflammation through an opposite and coordinated regulation of immune cell activity [99]. However, further investigations are required in order to establish the therapeutic potential of these and other enteric mediators in the IBD-related inflammation. Recently, GABA has been suggested to be one of the substances involved in the regulation of immune cell activity and inflammatory events, since GABA receptors were found on dendritic cells, macrophages and T-cells, all of them possessing the necessary metabolic machinery for GABA production and release [26]. GABAA agonists have been shown to reduce macrophage cytokine production and to inhibit T-cell proliferation, whilst GABAB agonists decreased TNF-α production from peripheral blood mononucleated cells and inhibited IL-6 and IL-12 release from microglial cells [27], [28], [29]. Taken as a whole, these actions indicate a potential anti-inflammatory action of GABA via inhibition of major inflammatory events mediated by different immune cells. Accordingly, subsequent studies supported this likely anti-inflammatory role of GABA, demonstrating a positive action of pharmacological GABA treatment on animal models of inflammation. As an example, oral GABA treatment ameliorates the inflammatory process both in non-obese diabetic mice and in a mouse model of rheumatoid arthritis [100], [101]. Furthermore, GABAA agonists improved experimental encefalomielitis and allergic asthma, whilst GABAB agonists displayed a positive effect in dermatitis models [25], [27], [28]. Although scarce investigations have addressed the possible action of GABA on GI inflammation, a pioneer study by Dudley et al. [102] demonstrated that the anti-epileptic drug topiramate, possessing GABAA agonism properties, ameliorates macroscopic and microscopic GI inflammation score in the 2,4,6-trinitrobenzenesulfonic acid-induced rat model of IBD. Unfortunately, the authors did not investigate the mechanism underlying topiramate-induced effect on IBD inflammation, and so further investigations are required to disclose the involvement of GABA signalling in the neuroimmune interaction controlling IBD physiopathology. Although preliminary, overall these observations suggest GABA as a putative neuroimmune modulator influencing both systemic and enteric inflammation via a currently quite unknown immune GABAergic system, whose pharmacological targeting could lead to novel therapeutic strategies addressing the enteric “neuroimmune dialogue” (Fig. 4). It is worth noting that recent studies provide evidence for the intestinal microbiota as a novel source of enteric GABA [103]. Since intestinal microbiota alteration is one of the most common shared hallmarks of inflammation-related GI disorders [104], [105], a better comprehension of GABA effect in the intestinal inflammatory event could reveal a possible functional interplay among the microbiota, the immune system and the enteric nervous system in the physiopathology of GI inflammation.