Neonatal immune challenge followed by adult immune challenge induces epigenetic-susceptibility to aggravated visceral hypersensitivity
Neonatal immune challenge followed by adult immune challenge induces epigenetic-susceptibility to aggravated visceral hypersensitivity
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DOI：
10.1111/nmo.13081
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发表时间：
2017-09-01
影响因子：
3.5
通讯作者：
Sarna, S. K.
中科院分区：
文献类型：
--
作者：
Aguirre, J. E.;Winston, J. H.;Sarna, S. K.
背景：腹痛是炎症性肠病（IBD）的主要症状之一。已知由结肠炎症释放的炎症介质使传入神经元敏感，这是引起腹痛的原因之一。然而，并非所有IBD患者都有腹痛，一些患者在缓解期报告腹痛，提示其他病理因素对IBD患者腹痛的影响。流行病学研究发现，早期胃肠道感染是IBD症状的危险因素，成年期胃肠道感染可能引发IBD发病。我们研究了一种假设，即新生儿结肠免疫刺激后，成人结肠免疫刺激会上调脊髓BDNF，从而加重内脏敏感性，而不仅仅是成人结肠免疫刺激引起的内脏敏感性。方法：用三硝基苯磺酸对大鼠结肠进行腔内注射，诱导新生儿和成人结肠免疫攻击。关键结果：我们发现，当这些大鼠受到成年结肠免疫挑战时，新生儿免疫挑战触发了蓝斑上酪氨酸羟化酶上调的表观遗传编程。蓝斑酪氨酸羟化酶上调，上调脑脊液中去甲肾上腺素作用于肾上腺素能受体，增强pCREB与cAMP反应元件的结合，将组蛋白乙炔转移酶（HAT）募集到BDNF基因上，增强其转录，导致内脏运动对结直肠膨胀的反应加剧。HAT和肾上腺素能受体拮抗剂阻断内脏敏感性的恶化。结论与推论：HAT和肾上腺素能受体抑制剂可替代阿片类药物和非甾体抗炎药抑制IBD腹痛。
Background: Abdominal pain is one of the major symptoms of inflammatory Bowel Disease (IBD). The inflammatory mediators released by colon inflammation are known to sensitize the afferent neurons, which is one of the contributors to abdominal pain. However, not all IBD patients have abdominal pain, and some patients report abdominal pain during remission, suggesting contributions of other pathological factors to abdominal pain in IBD. Epidemiological studies found early-life gastrointestinal infections a risk factor for IBD symptoms and adult-life gastrointestinal infections may trigger the onset of IBD. We investigated the hypothesis that neonatal colon immune challenge followed by an adult colon immune challenge upregulates spinal cord BDNF that aggravates visceral sensitivity over and above that induced by adult colon immune challenge alone.Methods: We induced neonatal and adult colon immune challenges by intraluminal administration of trinitrobenzene sulfonic acid to the rat colon.Key Results: We found that neonatal immune challenge triggers epigenetic programming that upregulates tyrosine hydroxylase in the locus ceruleus when these rats are subjected to an adult colon immune challenge. The upregulation of locus ceruleus tyrosine hydroxylase, upregulates norepinephrine in the cerebrospinal fluid that acts on adrenergic receptors to enhance pCREB binding to the cAMP response element, which recruits histone acetylene transferase (HAT) to the BDNF gene to enhance its transcription resulting in aggravated visceromotor response to colorectal distension. HAT and adrenergic receptor antagonists block the aggravation of visceral sensitivity.Conclusion & Inferences: HAT and adrenergic receptor inhibitors may serve as alternates to opioids and NSAIDS in suppressing abdominal pain in IBD.