The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner
The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner
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DOI：
10.1038/mp.2012.77
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发表时间：
2013-06-01
影响因子：
11
通讯作者：
Cryan, J. F.
中科院分区：
文献类型：
--
作者：
Clarke, G.;Grenham, S.;Cryan, J. F.
肠道细菌定植对免疫和内分泌系统的出生后发育和成熟具有重要作用。这些过程是中枢神经系统(CNS)信号传递的关键因素。微生物群-肠道-脑轴的调节对于维持包括中枢神经系统在内的动态平衡至关重要。然而，关于微生物群对5-羟色胺能系统的影响的数据很少。无菌动物是研究这类现象的一种有效的临床前工具。在这里，我们显示，与常规定居的对照动物相比，雄性GF动物海马区5-羟色胺及其主要代谢物5-羟基吲哚乙酸的浓度显著升高。此外，这种改变是性别特异性的，与免疫和神经内分泌的影响形成鲜明对比，这在两性中都很明显。5-羟色胺的前体色氨酸在雄性GF动物血浆中的浓度增加，这表明微生物群可以通过体液途径影响中枢5-羟色胺能神经传递。有趣的是，尽管色氨酸的外周可获得性恢复到基线值，但断奶后对GF动物的定植不足以扭转成年后早期生命中缺乏微生物区系的CNS神经化学后果。此外，随着肠道微生物区系的恢复，GF动物的焦虑程度也会正常化。这些结果表明，缺乏正常的肠道微生物区系可以严重干扰中枢神经系统的神经传递，这种异常的神经化学特征(但不是行为特征)在以后的生命中抵抗恢复正常的肠道菌群。
Bacterial colonisation of the intestine has a major role in the post-natal development and maturation of the immune and endocrine systems. These processes are key factors underpinning central nervous system (CNS) signalling. Regulation of the microbiome-gut-brain axis is essential for maintaining homeostasis, including that of the CNS. However, there is a paucity of data pertaining to the influence of microbiome on the serotonergic system. Germ-free (GF) animals represent an effective preclinical tool to investigate such phenomena. Here we show that male GF animals have a significant elevation in the hippocampal concentration of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid, its main metabolite, compared with conventionally colonised control animals. Moreover, this alteration is sex specific in contrast with the immunological and neuroendocrine effects which are evident in both sexes. Concentrations of tryptophan, the precursor of serotonin, are increased in the plasma of male GF animals, suggesting a humoral route through which the microbiota can influence CNS serotonergic neurotransmission. Interestingly, colonisation of the GF animals post weaning is insufficient to reverse the CNS neurochemical consequences in adulthood of an absent microbiota in early life despite the peripheral availability of tryptophan being restored to baseline values. In addition, reduced anxiety in GF animals is also normalised following restoration of the intestinal microbiota. These results demonstrate that CNS neurotransmission can be profoundly disturbed by the absence of a normal gut microbiota and that this aberrant neurochemical, but not behavioural, profile is resistant to restoration of a normal gut flora in later life.