Department of Molecular Biology and Microbiology, Tufts University, 150 Harrison Ave, Boston, MA, 02111, United States.
Department of Neuroscience, Tufts University, 150 Harrison Ave, Boston, MA, 02111, United States.
Psychoneuroendocrinology. 2020 Nov;121:104808. doi: 10.1016/j.psyneuen.2020.104808. Epub 2020 Jul 24.
Anxiety disorders are the most prevalent mental health disorder worldwide, with a lifetime prevalence of 5-7 % of the human population. Although the etiology of anxiety disorders is incompletely understood, one aspect of host health that affects anxiety disorders is the gut-brain axis. Adolescence is a key developmental window in which stress and anxiety disorders are a major health concern. We used adolescent female mice in a gastrointestinal (GI) colonization model to demonstrate that the commensal fungus Candida albicans affects host health via the gut-brain axis. In mice, bacterial members of the gut microbiota can influence the host gut-brain axis, affecting anxiety-like behavior and the hypothalamus-pituitary-adrenal (HPA) axis which produces the stress hormone corticosterone (CORT). Here we showed that mice colonized with C. albicans demonstrated increased anxiety-like behavior and increased basal production of CORT as well as dysregulation of CORT production following acute stress. The HPA axis and anxiety-like behavior are negatively regulated by the endocannabinoid N-arachidonoylethanolamide (AEA). We demonstrated that C. albicans-colonized mice exhibited changes in the endocannabinoidome. Further, increasing AEA levels using the well-characterized fatty acid amide hydrolase (FAAH) inhibitor URB597 was sufficient to reverse both neuroendocrine phenotypes in C. albicans-colonized mice. Thus, a commensal fungus that is a common colonizer of humans had widespread effects on the physiology of its host. To our knowledge, this is the first report of microbial manipulation of the endocannabinoid (eCB) system that resulted in neuroendocrine changes contributing to anxiety-like behavior.
焦虑障碍是全球最普遍的精神健康障碍，其终生患病率为 5-7%。尽管焦虑障碍的病因尚未完全阐明，但宿主健康的一个方面影响焦虑障碍，那就是肠道-大脑轴。青春期是一个关键的发育窗口，在此期间，压力和焦虑障碍是一个主要的健康问题。我们使用胃肠道（GI）定植模型中的青春期雌性小鼠证明，共生真菌白色念珠菌通过肠道-大脑轴影响宿主健康。在小鼠中，肠道微生物群的细菌成员可以影响宿主的肠道-大脑轴，影响焦虑样行为和下丘脑-垂体-肾上腺（HPA）轴，后者产生应激激素皮质酮（CORT）。在这里，我们表明，定植了白色念珠菌的小鼠表现出焦虑样行为增加，皮质酮（CORT）的基础产量增加，以及急性应激后 CORT 产生失调。HPA 轴和焦虑样行为受内源性大麻素 N-花生四烯酸乙醇酰胺（AEA）的负调节。我们证明，定植了白色念珠菌的小鼠表现出内源性大麻素组的变化。此外，使用经过充分研究的脂肪酸酰胺水解酶（FAAH）抑制剂 URB597 增加 AEA 水平足以逆转定植了白色念珠菌的小鼠的神经内分泌表型。因此，一种常见的人类共生真菌对其宿主的生理产生了广泛的影响。据我们所知，这是第一个报告微生物操纵内源性大麻素（eCB）系统导致神经内分泌变化从而导致焦虑样行为的报告。
