新生期应激损伤对炎症性肠病表观遗传易感性的潜在诱导及调控靶点

Inflammatory bowel disease (IBD) is a complex and common gastrointestinal disease often associated with early trauma and mental illness. Early-life infection may contribute to long lasting changes in the function of immune and neuroendocrine system,and increase adult disease susceptibility. Recent experiments in animals we also found that chronic stress can increase the visceral hypersensitivity and ulcerative colitis; and IBD also comorbidity with anxiety and depression. We hypothesized that the environmental changes of the neonatal inflammation and maternal deprivation that can damage the endothelial barrier, activates the immune system, as the environment challenges in adult, it can easily lead to the development of IBD. In accordance with the finding of methylated DNA segments in mucosal sample of IBD patients，we hypothesize the multiple stimulations and inflammatory environment interactions may lead to the epigenetic susceptibility which is the potential cause of IBD. However，there are no any experimental studies about the inflammatory environment interaction inducing epigenetic susceptibility about IBD risk so far. We suggested that the neonate-environment interaction or stress target multiple systems/organs, such as the SAM-axis, innate immunity and epithelial barrier, whose dysfunction together aggravates the immune response to adult-environment interaction. Dysfunction of the NF-κB signaling and sensitization of the SAM-axis are critical to aggravated immune response and increase of epithelial permeability. It will aggravate enteric immune，and lead to the development of epigenetic susceptibility. Epigenetic modulations of genes encoding proinflammatory cytokines and epithelial junction proteins in response to environmental challenges mediate aberrant transcription, and HDAC inhibitors show potential as therapeutic agents to IBD. Our proposal is significant in identifying epigenetic susceptibility to aggravated immune response. Epigenetic modulations for early-life stress may interpret the molecular mechanism which inducing the development of IBD，and provide scientific basis for the prevention and treatment of IBD.

炎症性肠病IBD是复杂的胃肠道疾病，常与早期创伤和精神症状相关联。生命早期感染可导致免疫及神经内分泌长期改变，增加疾病易感性。我们前期研究证实慢性应激增加肠道敏感性和IBD的焦虑抑郁并发症，加之患者肠粘膜中DNA甲基化片段的发现，我们推测新生期炎性或母婴分离环境因素会损伤内皮屏障，炎性环境多重刺激，激活神经免疫系统，当成年环境再次改变时，表观遗传易感性改变，增加引发IBD形成风险。但尚无多重应激交互作用诱导遗传易感性导致IBD的具体研究。我们尝试用阶段刺激免疫强化的方式，探讨新生炎性应激后，NF-κB信号转导异常、交感神经系统致敏、内皮通透性增加，导致成年期表观遗传易感性IBD的发展。细胞因子基因编码的表观遗传调控和内皮连接蛋白对炎性环境再应激的反应可介导转录异常，其中组蛋白乙酰化酶抑制可作为IBD的潜在治疗靶标。早期应激的神经免疫调控可阐释诱导IBD发生的分子机制，为其防治提供科学依据。

生命早期感染、创伤可导致免疫及神经内分泌长期改变，增加疾病易感性，并与成年期的精神异常症状相关联。我们的本项研究证实联合早期的感染及成年期的慢性应激可以增加成年肠道敏感性和焦虑抑郁并发症，并成功建立慢性内脏痛—焦虑共病模型。在构建和验证共病模型的同时通过包括电生理、行为学等实验，也证明中药单体草乌甲素通过参与调控、影响模型大鼠的dynorphin A/κ 阿片受体及小胶质细胞的研究进而缓解成年期的内脏痛敏及焦虑情绪，充分证明本模型的表面效度、结构效度及预测效度，确认慢性内脏痛-焦虑共病的发生机制。.我们同时还证明成年期损伤内皮屏障，炎性环境多重刺激的环境因素会同样激活神经免疫系统，继而我们尝试用阶段刺激免疫强化的方式，探讨当成年环境再次改变时，小鼠的痛觉过敏及抑郁样行为评估及相关NF-κB信号转导异常，证明了抑郁焦虑和慢性疼痛共病中谷氨酸转运体-1介导哺乳动物雷帕霉素靶蛋白自噬调节机制。.生命早期应激会显著增加青春期及成年个体遭受精神疾病的易感性。我们进一步利用大鼠哺乳期母婴分离模拟新生期应激来构建动物模型，首先探讨了不同分离周期对幼年大鼠精神及认知行为的影响，发现长期重复的母爱剥夺会导致幼年大鼠明显的社会认知障碍，而不影响其学习记忆功能。新生期母婴分离会诱导幼年大鼠前额叶皮层催产素受体表达的显著下调，而受其调控的胞内下游Erk/MEK信号通路也被抑制，研究结果证明了催产素及其受体系统是脑内调节社交行为的重要机制，其表达受组蛋白甲基化调控，该机制介导了新生期应激导致幼年大鼠社交受损的表观遗传机制。