Bacterially produced metabolites protect C. elegans neurons from degeneration
Bacterially produced metabolites protect C. elegans neurons from degeneration
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DOI：
10.1371/journal.pbio.3000638
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发表时间：
2020-03-01
期刊：
影响因子：
9.8
通讯作者：
Calixto, Andrea
中科院分区：
文献类型：
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作者：
Urrutia, Arles;Garcia-Angulo, Victor A.;Calixto, Andrea
秀丽隐杆线虫及其同源细菌饮食为研究饮食和微生物群对宿主生理的影响提供了可靠、广泛的模型。尽管如此，饮食是如何影响神经元死亡速度的，在很大程度上仍然未知。许多模型已经在秀丽隐杆线虫中被用作神经变性的替代物。其中之一是秀丽隐杆线虫菌株表达机械感觉异常蛋白4 （MEC-4d）变性素/上皮Na+ (DEG/ENaC)通道的神经毒性等位基因，该等位基因可导致触觉受体神经元（trn）的进行性变性。利用该模型，我们的研究评估了各种膳食细菌对神经变性动力学的影响。尽管在常规用于秀丽隐杆线虫维持的菌株（大肠杆菌OP50）中，trn的退化是稳定的，并在成年期完成，但在环境和其他实验室菌株中，trn的退化显著减少。引人注目的是，在大肠杆菌HT115菌株中，神经保护作用达到了40%以上。HT115的保护作用一直持续到动物的老年，而且并不局限于trn。少量HT115在OP50细菌上以及被紫外线杀死的HT115仍然足以产生神经保护作用。HT115中蠕虫的早期生长保护了OP50中后期生长过程中神经元的变性。HT115饮食促进DAF-16（转录因子FOXO家族的同源物）的核易位，这一现象先前被报道为该系统中胰岛素受体下调引起的神经保护的基础。此外，daf-16功能丧失突变可消除ht115驱动的神经保护。比较基因组学、转录组学和代谢组学方法确定了神经递质γ -氨基丁酸（GABA）和乳酸盐是大肠杆菌HT115和OP50之间产生的代谢物差异。HT115突变体缺乏谷氨酸脱羧酶基因（gad），该基因催化谷氨酸转化GABA，失去了产生GABA的能力，也停止了神经退行性变。此外，在大肠杆菌OP50中原位添加GABA或异源表达谷氨酸脱羧酶可赋予该菌株神经保护活性。特异性的秀丽隐杆线虫GABA转运体和受体需要ht115介导的完全神经保护。此外，乳酸补充也增加了OP50的前腹侧微管（AVM）神经元的存活。总之，这些结果表明细菌产生的GABA和其他代谢物在宿主中发挥神经保护作用，突出了饮食中神经活性化合物在神经系统稳态中的作用。
Caenorhabditis elegans and its cognate bacterial diet comprise a reliable, widespread model to study diet and microbiota effects on host physiology. Nonetheless, how diet influences the rate at which neurons die remains largely unknown. A number of models have been used in C. elegans as surrogates for neurodegeneration. One of these is a C. elegans strain expressing a neurotoxic allele of the mechanosensory abnormality protein 4 (MEC-4d) degenerin/epithelial Na+ (DEG/ENaC) channel, which causes the progressive degeneration of the touch receptor neurons (TRNs). Using this model, our study evaluated the effect of various dietary bacteria on neurodegeneration dynamics. Although degeneration of TRNs was steady and completed at adulthood in the strain routinely used for C. elegans maintenance (Escherichia coli OP50), it was significantly reduced in environmental and other laboratory bacterial strains. Strikingly, neuroprotection reached more than 40% in the E. coli HT115 strain. HT115 protection was long lasting well into old age of animals and was not restricted to the TRNs. Small amounts of HT115 on OP50 bacteria as well as UV-killed HT115 were still sufficient to produce neuroprotection. Early growth of worms in HT115 protected neurons from degeneration during later growth in OP50. HT115 diet promoted the nuclear translocation of DAF-16 (ortholog of the FOXO family of transcription factors), a phenomenon previously reported to underlie neuroprotection caused by down-regulation of the insulin receptor in this system. Moreover, a daf-16 loss-of-function mutation abolishes HT115-driven neuroprotection. Comparative genomics, transcriptomics, and metabolomics approaches pinpointed the neurotransmitter gamma-aminobutyric acid (GABA) and lactate as metabolites differentially produced between E. coli HT115 and OP50. HT115 mutant lacking glutamate decarboxylase enzyme genes (gad), which catalyze the conversion of GABA from glutamate, lost the ability to produce GABA and also to stop neurodegeneration. Moreover, in situ GABA supplementation or heterologous expression of glutamate decarboxylase in E. coli OP50 conferred neuroprotective activity to this strain. Specific C. elegans GABA transporters and receptors were required for full HT115-mediated neuroprotection. Additionally, lactate supplementation also increased anterior ventral microtubule (AVM) neuron survival in OP50. Together, these results demonstrate that bacterially produced GABA and other metabolites exert an effect of neuroprotection in the host, highlighting the role of neuroactive compounds of the diet in nervous system homeostasis.