Decreased miR-199 augments visceral pain in patients with IBS through translational upregulation of TRPV1.
Decreased miR-199 augments visceral pain in patients with IBS through translational upregulation of TRPV1.
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DOI：
10.1136/gutjnl-2013-306464
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发表时间：
2016-05
期刊：
影响因子：
24.5
通讯作者：
Verne GN
中科院分区：
文献类型：
--
作者：
Zhou Q;Yang L;Larson S;Basra S;Merwat S;Tan A;Croce C;Verne GN
许多肠易激综合征IBS患者不仅有腹痛，而且可能患有内脏高敏感性和内脏伤害性感受增强。此外，IBS几乎没有有效的治疗药物，疾病的机制尚不清楚。我们的目标是：（i）确定人类结肠中microRNA（miRNA）的表达，信号传导和靶点（ii）在体外验证与IBS相关的miRNA变化，特别是miR-199，其与瞬时受体电位香草素1型（TRPV 1）基因互补;和（iii）确定调节体内miRNA（尤其是miR-199）的表达是否通过TRPV 1信号传导逆转内脏高敏感性的相关变化和病理标志。我们评估了45例肠易激综合征（IBS-D）患者和40例对照组（1）内脏疼痛严重程度评分和（2）结肠镜活检。在miRNA阵列分析后评估人结肠中的miRNA表达。进行荧光素酶测定以确认miR-199和TRPV 1表达之间的关系。采用内脏高敏感大鼠模型，研究miR-199及其靶基因（TRPV 1）在背根神经节（DRG）和结肠中的表达。肠miR-199 a/B表达在IBS-D中显著降低，这与内脏疼痛评分和TRPV 1表达增加直接相关。通过腹膜内注射lenti-miR-199 a前体体内上调miR-199 a通过减少TRPV 1信号传导降低内脏高敏感性。结肠miR-199 a/B减少与IBS-D患者内脏痛相关类似地，大鼠DRG和结肠组织中miR-199 a表达减少与内脏高敏感性升高相关。miR-199 a的体内上调通过抑制TRPV 1信号传导减少内脏疼痛。因此，miR-199前体可能是治疗内脏疼痛患者的有希望的治疗候选者。
Many patients with irritable bowel syndrome IBS not only have abdominal pain but also may suffer from visceral hypersensitivity and heighted visceral nociception. Moreover, IBS has few effective therapeutic agents and mechanisms of disease are unclear. Our goals were to (i) identify microRNA (miRNA) expression, signalling and targets in human colon (controls; patients with IBS); (ii) verify in vitro, IBS-associated changes in miRNAs, especially miR-199, which is complementary to the transient receptor potential vanilloid type 1 (TRPV1) gene; and (iii) determine whether modulating the expression of miRNAs in vivo, especially miR-199, reverses associated changes and pathological hallmarks of visceral hypersensitivity via TRPV1 signalling. We evaluated 45 patients with diarrhoea-predominant IBS (IBS-D) and 40 controls with (1) visceral pain severity score and (2) colonoscopy with biopsies. miRNA expression was evaluated in human colon following miRNA array analysis. Luciferase assays were done to confirm relationships between miR-199 and TRPV1 expression. A rat model of visceral hypersensitivity was used to study miR-199 and its target gene (TRPV1) expression in dorsal root ganglion (DRG) and colon in vivo. Gut miR-199a/b expression in IBS-D was significantly decreased, which correlated directly with both increased visceral pain scores and TRPV1 expression. In vivo upregulation of miR-199a by intraperitoneal injection of lenti-miR-199a precursors decreased visceral hypersensitivity via diminished TRPV1 signalling. Decreased colonic miR-199a/b correlates with visceral pain in patients with IBS-D. Similarly, reduced miR-199a expression in rat DRG and colon tissue is associated with heightened visceral hypersensitivity. In vivo upregulation of miR-199a decreases visceral pain via inhibition of TRPV1 signalling. Thus, miR-199 precursors may be promising therapeutic candidates for the treatment in patients with visceral pain.