Comparative effects of alcohol and GABA mimetics on the brain-gut-microbiota (BGM) function

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The gut and its resident bacteria contribute to a variety of brain functions and disorders.The chemicals mediating communication within the braingut-microbiota (BGM) axis include both microbiota metabolites and classical neurotransmitters, notably GABA. This is important because alcohol is one of the most widely consumed GABA mimetic agents, both recreationally throughout the populace or compulsively by addicts with a significant burden to individuals and society. Accumulating evidence implicate alcoholinduced microbiota's alterations in reward-seeking behaviour and increased risk of developing psychopathology. Therefore, understanding how various GABAergic networks are integrated throughout the BGM, and influenced by alcohol, could help identifying safer alternatives.The commercial partner for this project, GABALabs, has identified novel, botanical, GABA mimetic agents that hold such promise. However, to develop these compounds as safe beverages for human consumption, it is essential to determine their effects on GABA-receptor function and mammalian BGM homeostasis. This is because different segments of the BGM axis appear to employ divergent GABA receptors, thus likely resulting in varied local GABA actions and a myriad of physiological effects. Therefore, the aims of this project are to characterise the various GABA-receptor pathways within and between segments of the BGM axis, and then determine the impact of these compounds upon GABAergic signalling and BGM homeostasis in comparison to alcohol.A multidisciplinary approach and supervisory expertise will be adopted. This will include RNASeq transcriptomics to characterise the comparative GABA molecular machinery within the different BGM cellular networks, proteomic to determine protein expression, medicinal chemistry to derive GABAmimetic compounds from botanicals, electrophysiology to functionally and pharmacologically assess GABA receptor modulating botanicals, and a suite of intestinal, microbiome, neural and behavioural assays to determine their overall effects on BGM homeostasis. The ideal candidate should be keen to adopt a cross-disciplinary approach to addressing complex biological questions and delivering impact from research.