Otaru Nize, Ye Kun, Mujezinovic Denisa, Berchtold Laura, Constancias Florentin, Cornejo Fabián A, Krzystek Adam, de Wouters Tomas, Braegger Christian, Lacroix Christophe, Pugin Benoit
Laboratory of Food Biotechnology, Department of Health Sciences and Technology, ETH Zürich, Zürich, Switzerland.
Nutrition Research Unit, University Children's Hospital Zürich, Zürich, Switzerland.
Front Microbiol. 2021 Apr 15;12:656895. doi: 10.3389/fmicb.2021.656895. eCollection 2021.
The high neuroactive potential of metabolites produced by gut microbes has gained traction over the last few years, with metagenomic-based studies suggesting an important role of microbiota-derived γ-aminobutyric acid (GABA) in modulating mental health. Emerging evidence has revealed the presence of the glutamate decarboxylase (GAD)-encoding gene, a key enzyme to produce GABA, in the prominent human intestinal genus . Here, we investigated GABA production by in culture and metabolic assays combined with comparative genomics and phylogenetics. A total of 961 genomes were analyzed and 17 metabolically and genetically diverse human intestinal isolates representing 11 species were screened . Using the model organism DSM 2079, we determined GABA production kinetics, its impact on milieu pH, and we assessed its role in mitigating acid-induced cellular damage. We showed that the GAD-system consists of at least four highly conserved genes encoding a GAD, a glutaminase, a glutamate/GABA antiporter, and a potassium channel. We demonstrated a high prevalence of the GAD-system among with 90% of all genomes (96% in human gut isolates only) harboring all genes of the GAD-system and 16 intestinal strains producing GABA (ranging from 0.09 to 60.84 mM). We identified glutamate and glutamine as precursors of GABA production, showed that the production is regulated by pH, and that the GAD-system acts as a protective mechanism against acid stress in , mitigating cell death and preserving metabolic activity. Our data also indicate that the GAD-system might represent the only amino acid-dependent acid tolerance system in . Altogether, our results suggest an important contribution of in the regulation of the GABAergic system in the human gut.
在过去几年中，肠道微生物产生的代谢物具有高神经活性的潜力已受到关注，基于宏基因组学的研究表明，微生物群衍生的γ-氨基丁酸（GABA）在调节心理健康方面发挥着重要作用。新出现的证据显示，在人类肠道的优势菌属中存在编码谷氨酸脱羧酶（GAD）的基因，GAD是产生GABA的关键酶。在此，我们通过培养和代谢测定，结合比较基因组学和系统发育学，研究了[具体菌属]产生GABA的情况。共分析了961个[具体菌属]基因组，并筛选了代表11个物种的17种代谢和遗传多样的人类肠道分离株。使用模式生物[具体菌属]DSM 2079，我们确定了GABA的产生动力学、其对环境pH的影响，并评估了其在减轻酸诱导的细胞损伤中的作用。我们发现GAD系统至少由四个高度保守的基因组成，分别编码一种GAD、一种谷氨酰胺酶、一种谷氨酸/GABA反向转运蛋白和一种钾通道。我们证明GAD系统在[具体菌属]中普遍存在，90%的所有[具体菌属]基因组（仅人类肠道分离株中为96%）含有GAD系统的所有基因，16株肠道[具体菌属]菌株产生GABA（范围从0.09到60.84 mM）。我们确定谷氨酸和谷氨酰胺是GABA产生的前体，表明其产生受pH调节，并且GAD系统在[具体菌属]中作为一种抗酸应激的保护机制，减轻细胞死亡并保持代谢活性。我们的数据还表明，GAD系统可能是[具体菌属]中唯一依赖氨基酸的耐酸系统。总之，我们的结果表明[具体菌属]在人类肠道中对GABA能系统的调节具有重要作用。
