Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice
Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice
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DOI：
10.1113/jphysiol.2004.063388
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发表时间：
2004-07-01
影响因子：
5.5
通讯作者：
Koga, Y
中科院分区：
文献类型：
--
作者：
Sudo, N;Chida, Y;Koga, Y
本地微生物群对宿主生理功能有多种有益作用；然而，关于出生后微生物定植是否会影响大脑可塑性的发展和随后的生理系统反应，人们知之甚少。为了验证这些微生物可能会影响神经系统的发育，从而控制对应激的内分泌反应，我们通过比较无菌小鼠（GF）、无特定病原体小鼠（SPF）和非生物小鼠来研究下丘脑-垂体-肾上腺（HPA）对应激的反应。抑制应激作用下，GF小鼠血浆ACTH和皮质酮水平明显高于SPF小鼠，但乙醚刺激作用下则没有。此外，GF小鼠在皮层和海马中的脑源性神经营养因子表达水平也比SPF小鼠低。用婴儿双歧杆菌重组可逆转GF小鼠过度的HPA应激反应。相比之下，与肠致病性大肠杆菌的单关联，而不是与缺乏易位内膜受体基因的突变株的单关联，增强了对应激的反应。重要的是，GF小鼠的HPA反应增强在早期阶段通过SPF粪便重建得到了部分纠正，但在后期进行的任何重建都没有得到纠正，因此表明在早期发育阶段暴露于微生物是HPA系统完全容易受到抑制性神经调节的必要条件。这些结果表明，共生菌群可以影响小鼠出生后HPA应激反应的发展。
Indigenous microbiota have several beneficial effects on host physiological functions; however, little is known about whether or not postnatal microbial colonization can affect the development of brain plasticity and a subsequent physiological system response. To test the idea that such microbes may affect the development of neural systems that govern the endocrine response to stress, we investigated hypothalamic-pituitary adrenal (HPA) reaction to stress by comparing germfree (GF), specific pathogen free (SPF) and gnotobiotic mice. Plasma ACTH and corticosterone elevation in response to restraint stress was substantially higher in GF mice than in SPF mice, but not in response to stimulation with ether. Moreover, GF mice also exhibited reduced brain-derived neurotrophic factor expression levels in the cortex and hippocampus relative to SPF mice. The exaggerated HPA stress response by GF mice was reversed by reconstitution with Bifidobacterium infantis. In contrast, monoassociation with enteropathogenic Escherichia coli, but not with its mutant strain devoid of the translocated intimin receptor gene, enhanced the response to stress. Importantly, the enhanced HPA response of GF mice was partly corrected by reconstitution with SPF faeces at an early stage, but not by any reconstitution exerted at a later stage, which therefore indicates that exposure to microbes at an early developmental stage is required for the HPA system to become fully susceptible to inhibitory neural regulation. These results suggest that commensal microbiota can affect the postnatal development of the HPA stress response in mice.