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Colonic Hypermotility in a Rat Model of Irritable Bowel Syndrome Is Associated with Upregulation of TMEM16A in Myenteric Plexus.
Dig Dis Sci 2018; 63(12):3329-3338DD

Abstract

BACKGROUND

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.

AIMS

To investigate whether TMEM16A is involved in colonic dysmotility in IBS.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.

Authors+Show Affiliations

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.Department of Gastroenterology, Renmin Hospital of Wuhan University, No. 238 Jiefang Rd, Wuhan, 430060, Hubei, People's Republic of China. yubp62@163.com. Key Laboratory of Hubei Province for Digestive System Diseases, Wuhan, People's Republic of China. yubp62@163.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30155840

Citation

Lin, Meng-Juan, and Bao-Ping Yu. "Colonic Hypermotility in a Rat Model of Irritable Bowel Syndrome Is Associated With Upregulation of TMEM16A in Myenteric Plexus." Digestive Diseases and Sciences, vol. 63, no. 12, 2018, pp. 3329-3338.
Lin MJ, Yu BP. Colonic Hypermotility in a Rat Model of Irritable Bowel Syndrome Is Associated with Upregulation of TMEM16A in Myenteric Plexus. Dig Dis Sci. 2018;63(12):3329-3338.
Lin, M. J., & Yu, B. P. (2018). Colonic Hypermotility in a Rat Model of Irritable Bowel Syndrome Is Associated with Upregulation of TMEM16A in Myenteric Plexus. Digestive Diseases and Sciences, 63(12), pp. 3329-3338. doi:10.1007/s10620-018-5261-7.
Lin MJ, Yu BP. Colonic Hypermotility in a Rat Model of Irritable Bowel Syndrome Is Associated With Upregulation of TMEM16A in Myenteric Plexus. Dig Dis Sci. 2018;63(12):3329-3338. PubMed PMID: 30155840.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Colonic Hypermotility in a Rat Model of Irritable Bowel Syndrome Is Associated with Upregulation of TMEM16A in Myenteric Plexus. AU - Lin,Meng-Juan, AU - Yu,Bao-Ping, Y1 - 2018/08/29/ PY - 2018/01/10/received PY - 2018/08/20/accepted PY - 2018/8/30/pubmed PY - 2019/4/12/medline PY - 2018/8/30/entrez KW - Gastrointestinal motility KW - Interstitial cells of Cajal KW - Irritable bowel syndrome KW - Myenteric plexus SP - 3329 EP - 3338 JF - Digestive diseases and sciences JO - Dig. Dis. Sci. VL - 63 IS - 12 N2 - BACKGROUND: 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. AIMS: To investigate whether TMEM16A is involved in colonic dysmotility in IBS. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. SN - 1573-2568 UR - https://www.unboundmedicine.com/medline/citation/30155840/Colonic_Hypermotility_in_a_Rat_Model_of_Irritable_Bowel_Syndrome_Is_Associated_with_Upregulation_of_TMEM16A_in_Myenteric_Plexus_ L2 - https://doi.org/10.1007/s10620-018-5261-7 DB - PRIME DP - Unbound Medicine ER -