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

肠道及其寄生细菌有助于多种大脑功能和疾病。在脑-微生物群（BGM）轴内介导通讯的化学物质包括微生物群代谢物和经典神经递质，特别是GABA。这一点很重要，因为酒精是最广泛使用的GABA模拟剂之一，无论是大众娱乐还是成瘾者对个人和社会造成重大负担的强迫性行为。越来越多的证据表明，酒精诱导的微生物群改变了寻求奖励的行为，增加了发展为精神病理的风险。因此，了解各种gaba能网络如何在整个BGM中整合，并受酒精的影响，可以帮助确定更安全的替代品。该项目的商业合作伙伴GABALabs已经确定了具有这种前景的新型植物类GABA模拟剂。然而，为了开发这些化合物作为人类消费的安全饮料，有必要确定它们对gaba受体功能和哺乳动物BGM稳态的影响。这是因为BGM轴的不同部分似乎使用不同的GABA受体，因此可能导致不同的局部GABA作用和无数的生理效应。因此，该项目的目的是表征BGM轴段内和段之间的各种gaba受体通路，然后确定与酒精相比，这些化合物对gaba能信号传导和BGM稳态的影响。将采用多学科方法和监督专门知识。这将包括RNASeq转录组学来表征不同BGM细胞网络中GABA分子机制的比较，蛋白质组学来确定蛋白质表达，药物化学来从植物中获得GABA类化合物，电生理学来功能和药理学评估GABA受体调节植物，以及一套肠道、微生物组、神经和行为分析来确定它们对BGM稳态的总体影响。理想的候选人应该热衷于采用跨学科的方法来解决复杂的生物学问题，并从研究中产生影响。

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.