Louwies Tijs, Orock Albert, Greenwood-Van Meerveld Beverley
Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Oklahoma City VA Medical Center, Oklahoma City, OK, USA.
Neurobiol Stress. 2021 Sep 20;15:100386. doi: 10.1016/j.ynstr.2021.100386. eCollection 2021 Nov.
Stress and anxiety contribute to the pathophysiology of irritable bowel syndrome (IBS), a female-predominant disorder of the gut-brain axis, characterized by abdominal pain due to heightened visceral sensitivity. In the current study, we aimed to evaluate in female rats whether epigenetic remodeling in the limbic brain, specifically in the central nucleus of the amygdala (CeA), is a contributing factor in stress-induced visceral hypersensitivity. Our results showed that 1 h exposure to water avoidance stress (WAS) for 7 consecutive days decreased histone acetylation at the GR promoter and increased histone acetylation at the CRH promoter in the CeA. Changes in histone acetylation were mediated by the histone deacetylase (HDAC) SIRT-6 and the histone acetyltransferase CBP, respectively. Administration of the HDAC inhibitor trichostatin A (TSA) into the CeA prevented stress-induced visceral hypersensitivity through blockade of SIRT-6 mediated histone acetylation at the GR promoter. In addition, HDAC inhibition within the CeA prevented stress-induced histone acetylation of the CRH promoter. Our results suggest that, in females, epigenetic modifications in the limbic brain regulating GR and CRH expression contribute to stress-induced visceral hypersensitivity and offer a potential explanation of how stress can trigger symptoms in IBS patients.
应激和焦虑参与肠易激综合征（IBS）的病理生理过程，IBS是一种以女性为主的肠-脑轴疾病，其特征为内脏敏感性增高导致腹痛。在本研究中，我们旨在评估雌性大鼠边缘脑区，特别是杏仁核中央核（CeA）的表观遗传重塑是否是应激诱导内脏超敏反应的一个促成因素。我们的结果显示，连续7天每天1小时的避水应激（WAS）暴露，会降低CeA中糖皮质激素受体（GR）启动子处的组蛋白乙酰化，并增加促肾上腺皮质激素释放激素（CRH）启动子处的组蛋白乙酰化。组蛋白乙酰化的变化分别由组蛋白去乙酰化酶（HDAC）SIRT-6和组蛋白乙酰转移酶CBP介导。向CeA注射HDAC抑制剂曲古抑菌素A（TSA），可通过阻断SIRT-6介导的GR启动子处组蛋白乙酰化，预防应激诱导的内脏超敏反应。此外，CeA内的HDAC抑制可预防应激诱导的CRH启动子组蛋白乙酰化。我们的结果表明，在雌性大鼠中，边缘脑区调节GR和CRH表达的表观遗传修饰，促成了应激诱导的内脏超敏反应，并为应激如何触发IBS患者症状提供了一个潜在解释。
