BDNF contributes to IBS-like colonic hypersensitivity via activating the enteroglia-nerve unit.
BDNF contributes to IBS-like colonic hypersensitivity via activating the enteroglia-nerve unit.
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BDNF 通过激活肠神经细胞导致类似 IBS 的结肠过敏。
DOI：
10.1038/srep20320
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发表时间：
2016-02-03
影响因子：
4.6
通讯作者：
Li YQ
中科院分区：
文献类型：
--
作者：
Wang P;Du C;Chen FX;Li CQ;Yu YB;Han T;Akhtar S;Zuo XL;Tan XD;Li YQ
过度表达的结肠脑源性神经营养因子（BDNF）已被报道与肠易激综合征（IBS）患者的腹痛有关。然而，其神经病理机制尚不清楚。我们在这里调查肠神经胶质细胞（EGCs）和肠神经在IBS样内脏高敏感性的参与。结果显示，IBS患者结肠粘膜中胶质细胞酸性蛋白（GFAP）、酪氨酸受体激酶B（Trk B）和P物质（SP）均显著升高。在内脏高敏感小鼠的结肠中也观察到这些蛋白质的上调，但在BDNF +/−小鼠的结肠中没有观察到。在功能上，TrkB或EGC抑制剂或BDNF敲低显著抑制小鼠内脏高敏感性。使用EGC细胞系，我们发现重组人脑源性神经营养因子（r-HuBDNF）可以通过TrkB-磷脂酶C γ 1途径直接激活EGC，从而诱导SP的显着上调。此外，r-HuBDNF激活的EGC培养基的上清液，而不是单独的r-HuBDNF，触发了分离的肠肠系膜传入神经的放电显着增强。单独的r-HuBDNF可以独立地引起肠系膜传入机械超敏反应，并且这种作用被激活的EGCs协同增强。我们认为EGC-肠神经单位可能参与了IBS样内脏高敏感性的形成，并且这一过程可能是由BDNF-TrkB通路激活启动的。
The over-expressed colonic brain-derived neurotrophic factor (BDNF) has been reported to be associated with abdominal pain in patients with irritable bowel syndrome (IBS). However, the neuropathological mechanism is unclear. We here investigated the involvement of enteroglial cells (EGCs) and enteric nerves in IBS-like visceral hypersensitivity. We showed that glial fibrillary acidic protein (GFAP), tyrosine receptor kinase B (TrkB) and substance P (SP) were significantly increased in the colonic mucosa of IBS patients. The upregulation of those proteins was also observed in the colon of mice with visceral hypersensitivity, but not in the colon of BDNF+/− mice. Functionally, TrkB or EGC inhibitors, or BDNF knockdown significantly suppressed visceral hypersensitivity in mice. Using the EGC cell line, we found that recombinant human BDNF (r-HuBDNF) could directly activate EGCs via the TrkB-phospholipase Cγ1 pathway, thereby inducing a significant upregulation of SP. Moreover, supernatants from r-HuBDNF-activated EGC culture medium, rather than r-HuBDNF alone, triggered markedly augmented discharges in isolated intestinal mesenteric afferent nerves. r-HuBDNF alone could cause mesenteric afferent mechanical hypersensitivity independently, and this effect was synergistically enhanced by activated EGCs. We conclude that EGC-enteric nerve unit may be involved in IBS-like visceral hypersensitivity, and this process is likely initiated by BDNF-TrkB pathway activation.