Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic; Department of Physiology, Faculty of Science, Charles University, Prague, Czech Republic.
Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Brain Behav Immun. 2018 Oct;73:615-624. doi: 10.1016/j.bbi.2018.07.007. Epub 2018 Jul 7.
The commensal microbiota affects brain functioning, emotional behavior and ACTH and corticosterone responses to acute stress. However, little is known about the role of the microbiota in shaping the chronic stress response in the peripheral components of the hypothalamus-pituitary-adrenocortical (HPA) axis and in the colon. Here, we studied the effects of the chronic stress-microbiota interaction on HPA axis activity and on the expression of colonic corticotropin-releasing hormone (CRH) system, cytokines and 11β-hydroxysteroid dehydrogenase type 1 (11HSD1), an enzyme that determines locally produced glucocorticoids. Using specific pathogen-free (SPF) and germ-free (GF) BALB/c mice, we showed that the microbiota modulates emotional behavior in social conflicts and the response of the HPA axis, colon and mesenteric lymph nodes (MLN) to chronic psychosocial stress. In the pituitary gland, microbiota attenuated the expression of Fkbp5, a gene regulating glucocorticoid receptor sensitivity, while in the adrenal gland, it attenuated the expression of genes encoding steroidogenesis (MC2R, StaR, Cyp11a1) and catecholamine synthesis (TH, PNMT). The pituitary expression of CRH receptor type 1 (CRHR1) and of proopiomelanocortin was not influenced by microbiota. In the colon, the microbiota attenuated the expression of 11HSD1, CRH, urocortin UCN2 and its receptor, CRHR2, but potentiated the expression of cytokines TNFα, IFNγ, IL-4, IL-5, IL-6, IL-10, IL-13 and IL-17, with the exception of IL-1β. Compared to GF mice, chronic stress upregulated in SPF animals the expression of pituitary Fkbp5 and colonic CRH and UCN2 and downregulated the expression of colonic cytokines. Differences in the stress responses of both GF and SPF animals were also observed when immunophenotype of MLN cells and their secretion of cytokines were analyzed. The data suggest that the presence of microbiota/intestinal commensals plays an important role in shaping the response of peripheral tissues to stress and indicates possible pathways by which the environment can interact with glucocorticoid signaling.
共生微生物群会影响大脑功能、情绪行为以及急性应激时的促肾上腺皮质激素（ACTH）和皮质酮反应。然而，对于微生物群在塑造下丘脑-垂体-肾上腺（HPA）轴外周成分和结肠中慢性应激反应的作用，我们知之甚少。在这里，我们研究了慢性应激-微生物群相互作用对 HPA 轴活性以及结肠中促肾上腺皮质激素释放激素（CRH）系统、细胞因子和 11β-羟类固醇脱氢酶 1（11HSD1）表达的影响，11HSD1 是一种决定局部产生糖皮质激素的酶。使用特定病原体无菌（SPF）和无菌（GF）BALB/c 小鼠，我们表明微生物群调节了社会冲突中的情绪行为以及 HPA 轴、结肠和肠系膜淋巴结（MLN）对慢性心理社会应激的反应。在垂体中，微生物群减弱了 Fkbp5 的表达，Fkbp5 是一种调节糖皮质激素受体敏感性的基因，而在肾上腺中，它减弱了编码类固醇生成（MC2R、StaR、Cyp11a1）和儿茶酚胺合成（TH、PNMT）的基因的表达。CRH 受体 1（CRHR1）和前阿黑皮素原的垂体表达不受微生物群影响。在结肠中，微生物群减弱了 11HSD1、CRH、UCN2 及其受体 CRHR2 的表达，但增强了细胞因子 TNFα、IFNγ、IL-4、IL-5、IL-6、IL-10、IL-13 和 IL-17 的表达，除了 IL-1β。与 GF 小鼠相比，慢性应激在 SPF 动物中上调了垂体 Fkbp5 和结肠 CRH 和 UCN2 的表达，下调了结肠细胞因子的表达。当分析 MLN 细胞的免疫表型及其细胞因子的分泌时，GF 和 SPF 动物的应激反应也存在差异。数据表明，微生物群/肠道共生体的存在在塑造外周组织对压力的反应方面起着重要作用，并表明环境可以通过哪些途径与糖皮质激素信号相互作用。
