Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 238 Jiefang Rd, Wuhan, 430060, Hubei, People's Republic of China.
Key Laboratory of Hubei Province for Digestive System Diseases, Wuhan, People's Republic of China.
Dig Dis Sci. 2018 Dec;63(12):3329-3338. doi: 10.1007/s10620-018-5261-7. Epub 2018 Aug 29.
Irritable bowel syndrome (IBS) is a common disease with intestinal dysmotility, whose mechanism remains elusive. TMEM16A is a calcium-activated chloride channel (CaCC) involved in intestinal slow-wave generation.
To investigate whether TMEM16A is involved in colonic dysmotility in IBS.
A rat model of IBS was established by chronic water avoidance stress (WAS). Colonic pathological alterations were evaluated histologically, and intestinal motility was assessed by intestinal transit time (ITT) and fecal water content (FWC). Visceral sensitivity was determined by visceromotor response (VMR) to colorectal distension (CRD). TMEM16A expression was evaluated by RT-PCR, Western blot, and immunofluorescence. Colonic muscle strip contractility was measured by isometric transducers, and the effect of niflumic acid (NFA), a CaCC antagonist, on colonic motility was examined.
After 10 days of WAS exposure, ITT was decreased and FWC was elevated. Furthermore, VMR magnitude of WAS rats in response to CRD was significantly enhanced. Protein and mRNA levels of TMEM16A in colon were considerably increased after WAS. The percentage of TMEM16A-positive neurons in myenteric plexus (MP) of WAS rats was significantly higher than controls. Pharmacological blockade of TMEM16A activity by NFA considerably enhanced ITT, with concentration-dependent declines in FWC and VMR magnitude in NFA-treated rats. Further, spontaneous contraction of colonic strips of NFA-treated rats was significantly ameliorated in a concentration-dependent manner in vitro.
Upregulation of TMEM16A in MP neurons may play an important role in chronic stress-induced colonic hypermotility, making CaCC-blocking drugs a putatively effective treatment method for colonic hypermotility in IBS.
肠易激综合征（IBS）是一种常见的肠道动力障碍性疾病，其发病机制尚不清楚。TMEM16A 是一种参与肠道慢波产生的钙激活氯离子通道（CaCC）。
探讨 TMEM16A 是否参与 IBS 结肠动力障碍。
采用慢性避水应激（WAS）建立大鼠 IBS 模型。组织学评估结肠病理改变，通过肠道传输时间（ITT）和粪便含水量（FWC）评估肠道运动，通过结直肠扩张（CRD）内脏运动反应（VMR）评估内脏敏感性。通过 RT-PCR、Western blot 和免疫荧光评估 TMEM16A 表达。通过等速换能器测量结肠肌条收缩性，并检测 CaCC 拮抗剂尼氟灭酸（NFA）对结肠运动的影响。
WAS 暴露 10 天后，ITT 降低，FWC 升高。此外，WAS 大鼠对 CRD 的 VMR 幅度显著增强。WAS 后结肠 TMEM16A 蛋白和 mRNA 水平显著增加。WAS 大鼠肌间神经丛（MP）中 TMEM16A 阳性神经元的百分比明显高于对照组。NFA 对 TMEM16A 活性的药理学阻断可显著增强 ITT，且 NFA 处理大鼠的 FWC 和 VMR 幅度呈浓度依赖性下降。此外，体外 NFA 处理大鼠的结肠条自发性收缩呈浓度依赖性显著改善。
MP 神经元中 TMEM16A 的上调可能在慢性应激诱导的结肠高动力性中起重要作用，使 CaCC 阻断药物成为 IBS 结肠高动力性的潜在有效治疗方法。
