Introduction

Stress is a known trigger for the symptoms of irritable bowel syndrome (IBS), a gastrointestinal (GI) disorder that presents with abnormal bowel habits and abdominal pain due to visceral hypersensitivity. While behavioral therapies have been used to attenuate IBS symptoms, the underlying mechanisms by which these therapies interact with stress-induced pathology remains to be delineated. Here we use a rat model to test the hypothesis that exposure to environmental enrichment (EE) inhibits stress-induced changes within the brain-gut axis to prevent visceral and somatic hypersensitivity and colonic hyperpermeability.

Methods

Female rats (n = 8/group) were housed in EE one week before and one week during exposure to water avoidance stress (WAS) while controls were housed in standard cages (SH). One day after the final WAS exposure, colonic and somatic sensitivity were assessed by the visceromotor response (VMR) to colorectal distension (CRD) and withdrawal threshold elicited by an electronic von Frey on the hind paw of the rats respectively. All rats were returned to SH for 3 weeks before colonic and somatic sensitivity were reassessed on day 28. The rats were then immediately euthanized and the spinal cord was collected to assess changes in neuronal activation (assessed via ERK phosphorylation) in response to noxious CRD. A separate cohort of animals (n = 8/group) that did not undergo behavioral assessments was euthanized the day after the final WAS exposure and the central nucleus of the amygdala (CeA) was collected to investigate WAS and EE induced epigenetic changes at the glucocorticoid receptor (GR) and corticotrophin releasing hormone (CRH) promoter. The colon from these rats was also collected to assess colonic permeability via changes in transepithelial electrical resistance (TEER) in vitro.

Results

Exposure to stress persistently increased VMR to CRD (P < 0.01) and decreased the hind paw withdrawal threshold (P < 0.001) in female rats. WAS also decreased TEER in the colon tissue of female rats (p = 0.05). In the CeA, WAS induced a decrease in histone acetylation at the GR promoter but increased histone acetylation at the CRH promoter and reduced GR-CRH interactions in the CeA. Analysis of the spinal cord showed that WAS increased CRD-evoked ERK phosphorylation in the dorsal horn. Exposure to EE prevented WAS-induced changes in the CeA, dorsal horn and colon respectively to prevent visceral and somatic hypersensitivity.

Conclusion

Our data reveals that behavioral therapies can produce long lasting molecular and epigenetic changes that can prevent stress-induced pathologies even after completion of the therapy. These results highlight the potential mechanisms by which behavioral therapies may ameliorate visceral pain associated stress-related pathologies such as the irritable bowel syndrome.

中文翻译：

---

环境富集可防止压力诱导的杏仁核中央核糖皮质激素受体和促肾上腺皮质激素释放激素表达的表观遗传变化，从而抑制内脏超敏反应

介绍

压力是肠易激综合征 (IBS) 症状的已知触发因素，肠易激综合征 (IBS) 是一种胃肠道 (GI) 疾病，表现为内脏过敏引起的异常排便习惯和腹痛。虽然行为疗法已被用于减轻 IBS 症状，但这些疗法与压力引起的病理相互作用的潜在机制仍有待描述。在这里，我们使用大鼠模型来检验以下假设，即暴露于环境富集 (EE) 会抑制脑-肠轴内压力引起的变化，以防止内脏和躯体超敏反应和结肠通透性过高。

方法

雌性大鼠 ( n  = 8/组) 在暴露于水避免压力 (WAS) 前一周和一周期间被安置在 EE 中，而对照组被安置在标准笼子 (SH) 中。在最后一次 WAS 暴露后一天，结肠和躯体敏感性分别通过对结肠直肠扩张 (CRD) 的内脏运动反应 (VMR) 和由大鼠后爪上的电子 von Frey 引发的退缩阈值进行评估。在第 28 天重新评估结肠和躯体敏感性之前，所有大鼠都返回 SH 3 周。然后立即对大鼠实施安乐死并收集脊髓以评估神经元激活的变化（通过 ERK 磷酸化评估）以响应有害的 CRD。一组单独的动物（n = 8/组）未接受行为评估的人在最终 WAS 暴露后的第二天被安乐死，并收集杏仁核中央核 (CeA) 以研究 WAS 和 EE 诱导的糖皮质激素受体 (GR) 和促皮质激素释放的表观遗传变化激素（CRH）启动子。还收集了来自这些大鼠的结肠，以通过体外跨上皮电阻 (TEER) 的变化来评估结肠通透性。

结果

暴露于压力持续增加雌性大鼠 CRD 的 VMR ( P  < 0.01) 并降低后爪缩回阈值 ( P  < 0.001)。WAS 还降低了雌性大鼠结肠组织中的 TEER（p  = 0.05）。在 CeA 中，WAS 在 GR 启动子处诱导组蛋白乙酰化降低，但在 CRH 启动子处增加组蛋白乙酰化并减少 CeA 中的 GR-CRH 相互作用。脊髓分析表明，WAS 增加了背角中 CRD 诱发的 ERK 磷酸化。暴露于 EE 分别阻止了 WAS 引起的 CeA、背角和结肠的变化，以防止内脏和躯体超敏反应。

结论

我们的数据显示，行为疗法可以产生持久的分子和表观遗传变化，即使在治疗完成后也可以预防压力引起的病理。这些结果突出了行为疗法可能改善与压力相关的内脏疼痛相关的病理（如肠易激综合征）的潜在机制。