Belelli Delia, Lambert Jeremy J, Wan Murphy Lam Yim, Monteiro Ana Rita, Nutt David J, Swinny Jerome D
GABA Labs (Research) Ltd., Hemel Hempstead HP2 5HD, UK.
Division of Neuroscience, School of Medicine, Medical Sciences Institute, Dundee University, Dundee DD1 5HL, UK.
Brain. 2025 May 13;148(5):1479-1506. doi: 10.1093/brain/awae413.
Convergent data across species paint a compelling picture of the critical role of the gut and its resident microbiota in several brain functions and disorders. The chemicals mediating communication along these sophisticated highways of the brain-gut-microbiome (BGM) axis include both microbiota metabolites and classical neurotransmitters. Amongst the latter, GABA is fundamental to brain function, mediating most neuronal inhibition. Until recently, GABA's role and specific molecular targets in the periphery within the BGM axis had received limited attention. Yet, GABA is produced by neuronal and non-neuronal elements of the BGM, and recently, GABA-modulating bacteria have been identified as key players in GABAergic gut systems, indicating that GABA-mediated signalling is likely to transcend physiological boundaries and species. We review the available evidence to better understand how GABA facilitates the integration of molecularly and functionally disparate systems to bring about overall homeostasis and how GABA perturbations within the BGM axis can give rise to multi-system medical disorders, thereby magnifying the disease burden and the challenges for patient care. Analysis of transcriptomic databases revealed significant overlaps between GABAAR subunits expressed in the human brain and gut. However, in the gut, there are notable expression profiles for a select number of subunits that have received limited attention to date but could be functionally relevant for BGM axis homeostasis. GABAergic signalling, via different receptor subtypes, directly regulates BGM homeostasis by modulating the excitability of neurons within brain centres responsible for gastrointestinal (GI) function in a sex-dependent manner, potentially revealing mechanisms underlying the greater prevalence of GI disturbances in females. Apart from such top-down regulation of the BGM axis, a diverse group of cell types, including enteric neurons, glia, enteroendocrine cells, immune cells and bacteria, integrate peripheral GABA signals to influence brain functions and potentially contribute to brain disorders. We propose several priorities for this field, including the exploitation of available technologies to functionally dissect components of these GABA pathways within the BGM, with a focus on GI and brain-behaviour-disease. Furthermore, in silico ligand-receptor docking analyses using relevant bacterial metabolomic datasets, coupled with advances in knowledge of GABAAR 3D structures, could uncover new ligands with novel therapeutic potential. Finally, targeted design of dietary interventions is imperative to advancing their therapeutic potential to support GABA homeostasis across the BGM axis.
跨物种的趋同数据描绘了一幅令人信服的画面，展示了肠道及其常驻微生物群在多种脑功能和疾病中的关键作用。沿脑-肠-微生物群（BGM）轴这些复杂通路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。在后者中，γ-氨基丁酸（GABA）对脑功能至关重要，介导大多数神经元抑制作用。直到最近，GABA在BGM轴外周的作用和特定分子靶点受到的关注有限。然而，GABA由BGM的神经元和非神经元成分产生，最近，调节GABA的细菌已被确定为GABA能肠道系统的关键参与者，这表明GABA介导的信号可能跨越生理界限和物种。我们回顾现有证据，以更好地理解GABA如何促进分子和功能不同的系统整合以实现整体稳态，以及BGM轴内的GABA紊乱如何导致多系统医学疾病，从而加重疾病负担和患者护理挑战。转录组数据库分析显示，人类大脑和肠道中表达的GABA受体亚基之间存在显著重叠。然而，在肠道中，有一些特定亚基具有显著的表达谱，这些亚基迄今受到的关注有限，但可能与BGM轴稳态功能相关。GABA能信号通过不同的受体亚型，以性别依赖的方式调节负责胃肠（GI）功能的脑中枢内神经元的兴奋性，直接调节BGM稳态，这可能揭示了女性胃肠功能紊乱患病率更高的潜在机制。除了对BGM轴的这种自上而下的调节外，包括肠神经元、神经胶质细胞、肠内分泌细胞、免疫细胞和细菌在内的多种细胞类型整合外周GABA信号以影响脑功能，并可能导致脑部疾病。我们提出了该领域的几个优先事项，包括利用现有技术在功能上剖析BGM内这些GABA通路的组成部分，重点是胃肠和脑-行为-疾病。此外，使用相关细菌代谢组数据集进行计算机模拟配体-受体对接分析，结合GABA受体3D结构知识的进展，可能会发现具有新治疗潜力的新配体。最后，有针对性地设计饮食干预措施对于提高其支持BGM轴GABA稳态的治疗潜力至关重要。
