Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China.
FASEB J. 2019 Feb;33(2):2435-2450. doi: 10.1096/fj.201800935RR. Epub 2018 Sep 27.
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-κB 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.
胆汁酸（BA）暴露增加，在腹泻为主的肠易激综合征（IBS-D）中很常见，会影响肠道功能。神经生长因子（NGF）与内脏高敏感性（VH）的发展有关。在这项研究中，我们测试了这样一个假设，即胆汁酸通过黏膜肥大细胞（MMC）-伤害感受器信号引起 VH，该信号涉及法尼醇 X 受体（FXR）/NGF/瞬时受体电位香草酸 1 型（TRPV1）轴。将 BA 经肠内给药给大鼠 15 天。检查内脏对结肠扩张的敏感性和结肠 NGF 表达。BA 引起 VH，这种作用涉及 MMC 衍生的 NGF，并伴有背根神经节中 TRPV1 表达增强。抗 NGF 治疗和 TRPV1 拮抗作用抑制了 BA 诱导的 VH。BA 诱导培养肥大细胞中 NGF mRNA 和蛋白表达和释放。具有升高结肠 BA 含量的 IBS-D 患者的结肠上清液转录诱导 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。药物拮抗和 FXR 沉默抑制了 BA 诱导的肥大细胞中 NGF 的表达和释放。丝裂原激活蛋白激酶激酶（MKK）3/6/p38 MAPK/NF-κB 信号传导是 FXR 介导的 NGF 表达和分泌的机制。研究结果表明 BA 具有 MMC 依赖性和 FXR 介导的致痛作用，并确定了 BA/FXR/NGF/TRPV1 轴作为 IBS 中疼痛处理过程中 MMC 到神经元通讯的关键参与者。-李 WT、罗 QQ、王 B、陈 X、闫 XJ、邱 HY、陈 SL 胆汁酸通过涉及法尼醇 X 受体/神经生长因子/瞬时受体电位香草酸 1 型轴的黏膜肥大细胞-伤害感受器信号引起内脏高敏感性。
