Bile acids induce visceral hypersensitivity via mucosal mast cell-to-nociceptor signaling that involves the farnesoid X receptor/nerve growth factor/transient receptor potential vanilloid 1 axis
Bile acids induce visceral hypersensitivity via mucosal mast cell-to-nociceptor signaling that involves the farnesoid X receptor/nerve growth factor/transient receptor potential vanilloid 1 axis
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胆汁酸通过粘膜肥大细胞至伤害感受器信号传导诱导内脏过敏，该信号传导涉及法尼醇 X 受体 - 神经生长因子 - 瞬时受体电位香草酸 1 轴
DOI：
10.1096/fj.201800935rr
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发表时间：
2019-02-01
期刊：
影响因子：
4.8
通讯作者：
Chen, Sheng-Liang
中科院分区：
文献类型：
--
作者：
Li, Wen-Ting;Luo, Qing-Qing;Chen, Sheng-Liang
结肠胆汁酸（BA）暴露增加，常见于肠易激综合征（IBS-D），可影响肠道功能。神经生长因子（NGF）与内脏高敏感性（VH）的发生有关。在这项研究中，我们测试的假设，BA通过粘膜肥大细胞（MMC）的伤害感受器信号，其中涉及法尼醇X受体（FXR）/神经生长因子/瞬时受体电位香草酸（TRPV）1轴引起VH。将BA结肠内给予大鼠15 d。内脏对结直肠扩张的敏感性和结肠NGF表达进行了检查。BA引起VH，这种效应涉及MMC衍生的NGF，并伴有背根神经节中TRPV 1表达增强。抗NGF处理和TRPV 1拮抗剂抑制BA诱导的VH。BA诱导培养的肥大细胞表达和释放NGFmRNA和蛋白。IBS-D患者的结肠上清液具有升高的结肠BA含量，其转录诱导NGF表达。在FXR-/-小鼠中，BA处理后内脏敏感性和结肠NGF表达没有改变。药理学拮抗作用和FXR沉默抑制BA诱导的肥大细胞中NGF的表达和释放。丝裂原活化蛋白激酶激酶（MKK）3/6/p38 MAPK/NF-B信号转导机制负责FXR介导的NGF表达和分泌。这些发现显示了BAs的MMC依赖性和FXR介导的原伤害感受效应，并将BA/FXR/NGF/TRPV 1轴确定为IBS疼痛处理期间MMC与神经元通信的关键参与者。T.，Luo，Q.-问：Wang，B.，陈旭，严，X- J.，邱，H.-是的，陈思L.胆汁酸通过粘膜肥大细胞-伤害感受器信号传导诱导内脏高敏感性，该信号传导涉及法尼醇X受体/神经生长因子/瞬时受体电位香草酸1轴。
Increased colonic bile acid (BA) exposure, frequent in diarrhea-predominant irritable bowel syndrome (IBS-D), can affect gut function. Nerve growth factor (NGF) is implicated in the development of visceral hypersensitivity (VH). In this study, we tested the hypothesis that BAs cause VH via mucosal mast cell (MMC)-to-nociceptor signaling, which involves the farnesoid X receptor (FXR)/NGF/transient receptor potential vanilloid (TRPV)1 axis. BAs were intracolonically administered to rats for 15 d. Visceral sensitivity to colorectal distention and colonic NGF expression were examined. BAs caused VH, an effect that involved MMC-derived NGF and was accompanied by enhanced TRPV1 expression in the dorsal root ganglia. Anti-NGF treatment and TRPV1 antagonism inhibited BA-induced VH. BAs induced NGF mRNA and protein expression and release in cultured mast cells. Colonic supernatants from patients with IBS-D with elevated colonic BA content transcriptionally induced NGF expression. In FXR-/- mice, visceral sensitivity and colonic NGF expression were unaltered after BA treatment. Pharmacological antagonism and FXR silencing suppressed BA-induced NGF expression and release in mast cells. Mitogen-activated protein kinase kinase (MKK) 3/6/p38 MAPK/NF-B signaling was mechanistically responsible for FXR-mediated NGF expression and secretion. The findings show an MMC-dependent and FXR-mediated pronociceptive effect of BAs and identify the BA/FXR/NGF/TRPV1 axis as a key player in MMC-to-neuron communication during pain processing in IBS.Li, W.-T., Luo, Q.-Q., Wang, B., Chen, X., Yan, X.-J., Qiu, H.-Y., Chen, S.-L. Bile acids induce visceral hypersensitivity via mucosal mast cell-to-nociceptor signaling that involves the farnesoid X receptor/nerve growth factor/transient receptor potential vanilloid 1 axis.