切换至 "中华医学电子期刊资源库"
高级检索
中华胃食管反流病电子杂志

中华胃食管反流病电子杂志 ›› 2023, Vol. 10 ›› Issue (01) : 31 -37. doi: 10.3877/cma.j.issn.2095-8765.2023.01.006

基础研究

莫沙必利通过调节5-羟色胺代谢途径改善心理应激诱发食管炎症的作用
赛甫丁·艾比布拉, 买买提·依斯热依力†(), 王永康, 迪丽达尔·阿迪里, 李义亮, 克力木·阿不都热依木   
  1. 830001　乌鲁木齐，新疆维吾尔自治区人民医院自治区普外微创研究所;830001　乌鲁木齐，新疆维吾尔自治区胃食管反流病及减重代谢外科临床研究中心
    830001　乌鲁木齐，新疆维吾尔自治区人民医院自治区普外微创研究所;830001　乌鲁木齐，新疆维吾尔自治区胃食管反流病及减重代谢外科临床研究中心;830001　乌鲁木齐，新疆维吾尔自治区人民医院基础医学教育科
    830001　乌鲁木齐，新疆维吾尔自治区人民医院自治区普外微创研究所;830001　乌鲁木齐，新疆维吾尔自治区人民医院基础医学教育科
    830001　乌鲁木齐，新疆维吾尔自治区胃食管反流病及减重代谢外科临床研究中心
  • 收稿日期:2022-12-19 出版日期:2023-02-15
  • 通信作者: 买买提·依斯热依力
  • 基金资助:
    新疆维吾尔自治区自然科学基金(2021D01C148); 新疆维吾尔自治区自然科学青年基金(2021D01C209)

Mosapride improves esophageal inflammation induced by psychological stress through regulating 5-hydroxytryptamine metabolism

Yongkang Wang, Yiliang Li   

  1. Research Institute of General and Minimally Invasive Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, China;Clinical Research Center for Gastroesophageal Reflux Disease and Weight Loss Metabolic Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, China
    Research Institute of General and Minimally Invasive Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, China;Clinical Research Center for Gastroesophageal Reflux Disease and Weight Loss Metabolic Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, China;Basic Medical Education Department, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, China
    Research Institute of General and Minimally Invasive Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, China;Basic Medical Education Department, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, China
    Clinical Research Center for Gastroesophageal Reflux Disease and Weight Loss Metabolic Surgery, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, China
  • Received:2022-12-19 Published:2023-02-15
全文 ( ) 下载PDF ( ) 导出引用
引用本文：

赛甫丁·艾比布拉, 买买提·依斯热依力, 王永康, 迪丽达尔·阿迪里, 李义亮, 克力木·阿不都热依木. 莫沙必利通过调节5-羟色胺代谢途径改善心理应激诱发食管炎症的作用[J]. 中华胃食管反流病电子杂志, 2023, 10(01): 31-37.

Yongkang Wang, Yiliang Li. Mosapride improves esophageal inflammation induced by psychological stress through regulating 5-hydroxytryptamine metabolism[J]. Chinese Journal of Gastroesophageal Reflux Disease(Electronic Edition), 2023, 10(01): 31-37.

目的

探讨莫沙必利改善心理应激小鼠5-羟色胺代谢通路、肠道菌群以及食管炎症的作用机制。

方法

选择SPF级雄性8周龄的昆明小鼠数字化随机分为正常对照组、心理应激组及莫沙必利干预组（每组6只）；心理应激组和莫沙必利组小鼠每天在自制式束缚器中限制活动2 h，其余时间3组小鼠在相同环境中自由饮水摄食，实验持续14 d；通过HE染色观察食管病理学改变；采用RT-PCR方法检测分析3组食管组织中色氨酸（TPH）、色氨酸羟化酶-1（TPH-1）、吲哚胺2，3加双氧酶-1（IDO-1）、色氨酸2，3-双加氧酶（TDO）、犬尿酸（KYN）、5-羟色胺（5-HT）、5-HT4受体（5-HT4R）、单核细胞/巨噬细胞表面标志物（F4/80、CD68）及炎症因子[白细胞介素-1β（IL-1β）IL-1β、Toll样受体4(TLR-4)、肿瘤坏死因子-α（TNF-α）]的mRNA表达水平；利用16s rRNA高通量测序技术检测3组小鼠肠道菌群，并对比分析3组小鼠的菌群组成差异。

结果

心理应激组显著降低5-HT及5-HT4R的mRNA表达水平（P<0.001）；而莫沙必利干预显著增高5-HT及5-HT4R的mRNA水平（P<0.01）。心理应激组显著升高食管组织中5-HT代谢通路中的酶物质（IDO-1、TDO、KYN）的mRNA水平（P<0.01、P<0.001）；同时其显著降低TPH-1和TPH的mRNA表达水平（P<0.01、P<0.001）；莫沙必利干预能够改善心理应激诱导上述5-HT代谢通路酶物质的异常表达（P<0.01）。心理应激组小鼠菌群多样性较低；莫沙必利干预显著改善心理应激小鼠Helicobacteraceae（螺杆菌科）、Alloprevotella（拟普雷沃菌属）、Lactobacillaceae（乳杆菌科）等菌群的异常变化。莫沙必利显著抑制心理应激诱导食管粘膜炎症浸润反应、免疫细胞（CD68、F4/80）以及炎症因子（IL-1β、TLR-4、TNF-ɑ）的高表达（P<0.001）。

结论

莫沙必利通过调节5-羟色胺代谢途径抑制心理应激诱发肠道菌群结构异常及食管炎症的发生。

关键词: 心理应激, 5-羟色胺, 莫沙必利, 肠道菌群, 食管炎症
Objective

To explore the mechanism of Mosapride in improving 5-hyd roxytryptamine metabolic pathway, gut bacteria and esophageal inflammation in mice under stress.

Methods

8 week old SPF male mice were randomly divided into control, stress and mosapride intervention group (n=6); The mice in the stress and mosapride were restricted in the self-made restraint device for 2h every day and kept for 14 days period; The pathological changes of esophagus were observed by HE staining; tryptophan (TPH), tryptophan hydroxylase-1 (TPH-1), indoleamine 2,3 dioxygenase 1 (IDO-1), tryptophan 2,3 dioxygenase (TDO), canine uric acid (KYN), 5-HT,5-HT4R, F4/80, CD68 and inflammatory factors [interleukin-1 β (IL-1 β), toll-like receptor-4 (TLR-4), tumor necrosis factor-α (TNF-ɑ)] mRNA level were detected by RT-PCR; The 16s rRNA high-throughput sequencing technology was used to detect the intestinal flora of mice.

Results

The mRNA expression levels of 5-HT and 5-HT4R were decreased in the stress group (P<0.001); Mosapride increased the mRNA levels of 5-HT and 5-HT4R (P<0.01). The mRNA level of enzymes (IDO-1, TDO, KYN) in 5-HT metabolic pathway was increased in the stress group (P<0.01, P<0.001); stress reduced the mRNA expression levels of TPH-1 and TPH (P<0.01, P<0.001); Mosapride intervention can improve the abnormal expression of 5-HT metabolic pathway enzymes induced by stress (P<0.01). The microbial diversity of mice in stress group was low; Mosapride intervention significantly improved the abnormal changes of Helicobacterceae, Alloprevotella and Lactobacillus in stress mice. Mosapride significantly inhibited the infiltration of esophageal mucositis induced by stress, and suppressed over expressions of immune cells (CD68, F4/80) and inflammatory factors(IL-1β, TLR-4, TNF-ɑ) (P<0.001).

Conclusion

Mosapride can inhibit the occurrence of abnormal intestinal flora structure and esophageal inflammation induced by stress through regulating 5-HT metabolism.

Key words: stress, 5-hydroxytryptamine, mosapride, bacteria, inflammation
表1 实时定量RT-PCR引物序列
指标 上游引物(5'-3') 下游引物(5'-3')
CD68 AAAGGCCGTTACTCTCCTGC ACTCGGGCTCTGATGTAGGT
F4/80 TGGGAAAGACTGGATTCTGGG TTGCATGTTCAGGGCAAACG
TPH AATGCCCGTCTTTGATGGGT TTTCCTACCCTCTGCACCAC
TPH-1 AACTCCAGTGGCTTTGAGGT CATGGTGAATCTGAATGAAGATGA
IDO-1 GGCACCAAGCCTGATATCCT AGAAGCTGCGATTTCCACCA
TDO GAAAGGTCTGGAAGAGGAGTTC CACGGTATGACAGTCGTCGT
KYN ACTGGAGGAGCTGCCTGATA GGGGGAGCTGACTCTAAGGA
5-HT ACCACTCTGAAGCGCAAACA TGTCTGGTATAGGCACTGACC
5-HT4R GTGGGAGAGTCAGTGTCACC ATTGTCCCAGGGGCCTAAGT
IL-1β GTACCTGTCCTGCGTGTTGA TCAGGCGGGCTTTAAGTGAG
TLR-4 GAGGAAGCACAAGGCTGGAT AGCCACGTGAACGAACATCT
TNF-ɑ ATGGCCTCCCTCTCATCAGT GAGGCAACCTGACCACTCTC
GAPDH GTCACCAACTGGGACGACAT AGAGCGTAGCCCTCGTAGAT
图1 各组5-HT及其受体的mRNA表达水平(n=6) 注：5-HT 为5-羟色胺。与control 组比较，***P<0.001；与stress组比较，##P<0.01
图2 各组5-HT代谢通路酶类的mRNA表达水平(n=6) 注：IDO-1为吲哚胺2，3加双氧酶-1；TDO 为色氨酸2,3-双加氧酶；TPH-1为色氨酸羟化酶-1；5-HT 为5-羟色胺。与control 组比较，**P<0.01，***P<0.001；与stress组比较，#P<0.05，##P<0.01
图3 各组TPH和KYN的mRNA表达水平(n=6) 注：TPH为色氨酸；KYN为犬尿酸；与control 组比较，**P<0.01***P<0.001；与stress组比较，##P <0.01
图4 各组小鼠肠道微生物群落结构分析(n=6)
图5 各组食管组织HE染色及免疫细胞的mRNA表达水平(n=6) 注：与control 组比较，**P<0.01；与stress组比较，##P<0.01
图6 各组食管组织炎症因子的mRNA表达水平(n=6) 注：IL-1β为白细胞介素-1β；TLR-4为Toll样受体4；TNF-α为肿瘤坏死因子-α。与control组比较，***P<0.001；与stress组比较，###P<0.001
1
Mahoney LB, Rosen R. The spectrum of reflux phenotypes[J]. Gastroenterol Hepatol (NY), 2019, 15(12): 646-654.
2
Liang S, Wu X, Jin F. Gut-brain psychology: rethinking psychology from the microbiota–gut–brain axis[J]. Front Integr Neurosci, 2018, 12: 33.
3
杨艳, 张艇, 张芳旭, 等．莫沙必利片联合奥美拉唑镁肠溶片治疗质子泵抑制药-难治性胃食管反流病患者的临床研究[J]. 中国临床药理学杂志, 2021, 37(21): 2875-2877.
4
Broers C, Geeraerts A, Boecxstaens V, et al. The role of serotonin in the control of esophageal sensitivity assessed by multimodal stimulation in health[J]. Neurogastroenterol Motil, 2021, 33(3): e14057.
5
买买提·依斯热依力, 吾布力卡斯木·吾拉木, 艾克拜尔·艾力,等. 慢性束缚应激对小鼠胃食管的影响[J/OL]. 中华胃食管反流病电子杂志, 2018, 5(2): 14-18.
6
买买提·依斯热依力, 艾克拜尔·艾力, 买买提艾力·艾则孜, 等．心理应激对小鼠脂肪组织黄嘌呤氧化酶表达、活性及相关指标的影响[J]. 中国应用生理学杂志, 2019, 35(6): 494-499.
7
Liang S, Wu X, Hu X, et al. recognizing depression from the microbiota–gut–brain axis[J]. Int J Mol Sci, 2018, 19(6): 1592.
8
Liu MY, Zhang LJ, Zhou YX, et al. 5-hydroxytryptamine changes under different pretreatments on rat models of myocardial infarction and/or depression[J]. Chin Med J (Engl), 2017, 130(18): 2219-2225.
9
Carhart-Harris RL, Nutt DJ. Serotonin and brain function: a tale of two receptors[J]. J Psychopharmacol, 2017, 31(9): 1091-1120.
10
Fuertig R, Azzinnari D, Bergamini G, et al. Mouse chronicsocial stress increases blood and brain kynurenine pathway activity and fearbehaviour:Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase[J]. Brain Behav Immun, 2016, 54: 59-72.
11
Kiyozumi Y, Baba Y, Okadome K, et al. Indoleamine 2, 3‐dioxygenase 1 promoter hypomethylation is associated with poor prognosis in patients with esophageal cancer[J]. Cancer Sci, 2019, 110(6): 1863-1871.
12
Distrutti E, Monaldi L, Ricci P, et al. Gut microbiota role in irritable bowel syndrome: New therapeutic strategies[J]. World J Gastro enterol, 2016, 22(7): 2219-2241.
13
Mbongue JC, Nicholas DA, Torrez TW, et al. The role of indoleamine 2, 3-dioxygenase in immune suppression and autoimmunity[J]. Vaccines (Basel), 2015, 3(3): 703-729.
14
Hillman L, Yadlapati R, Thuluvath AJ, et al. A review of medical therapy for proton pump inhibitor nonresponsive gastroesophageal reflux disease[J]. Dis Esophagus, 2017, 30(9): 1-15.
15
韩士举, 林强, 韩伟, 等．选择性5-羟色胺再摄取抑制剂在胃食管反流病治疗中的应用现状[J]. 实用医学杂志, 2021, 37(22): 2946-2949.
16
姜志茹, 赵雷, 郭海, 等．5-羟色胺在非糜烂性反流病中表达的研究[J]. 胃肠病学和肝病学杂志, 2017, 26(11): 1282-1284.
17
艾合麦提·喀斯木, 买买提·依斯热依力, 克力木·阿布都热依木．肠道菌群在胃食管反流病发病中的作用及相关性研究进展[J]. 中国医师杂志, 24(8): 1273-1276.
18
Chow CFW, Che S, Qin HY, et al. From psychology to physicality: how nerve growth factor transduces early life stress into gastrointestinal motility disorders later in life[J]. Cell Cycle, 2019, 18(16): 1824-1829.
[1] 李丹阳, 李满祥. 肠道菌群失调在肺动脉高压发病中的研究进展[J]. 中华肺部疾病杂志(电子版), 2023, 16(03): 432-434.
[2] 何吉鑫, 杨燕妮, 王继伟, 李建国, 谢铭. 肠道菌群及肠道代谢产物参与慢性便秘发生机制的研究进展[J]. 中华结直肠疾病电子杂志, 2023, 12(06): 495-499.
[3] 乔小梅, 孔凯丽, 方敬爱, 张晓东. "肠-皮肤轴"与尿毒症皮肤病变的关系研究进展[J]. 中华肾病研究电子杂志, 2023, 12(05): 291-294.
[4] 李娜, 朱国贞. 肠道菌群及其代谢产物在急性肾损伤中的作用研究进展[J]. 中华肾病研究电子杂志, 2023, 12(04): 215-219.
[5] 王宁, 刘彦哲, 吴紫莺, 曾超, 雷光华, 沙婷婷, 王伊伦. 基于孟德尔随机化研究探讨肠道菌群与肌少症表型的因果关联[J]. 中华老年骨科与康复电子杂志, 2023, 09(06): 333-342.
[6] 李子彤, 李林斌, 马涛, 高共鸣, 农鲁明. 经椎间孔椎体间融合术（TLIF）后对侧早期神经根性疼痛的危险因素分析[J]. 中华老年骨科与康复电子杂志, 2023, 09(05): 269-274.
[7] 屈霄, 王靓, 陆萍, 何斌, 孙敏. 外周血炎症因子及肠道菌群特征与活动性溃疡性结肠炎患者病情的相关性分析[J]. 中华消化病与影像杂志(电子版), 2023, 13(06): 466-470.
[8] 孙晗, 武侠. 成人肠易激综合征患者肠道菌群特征与不同分型患者生活质量和精神症状的相关性[J]. 中华消化病与影像杂志(电子版), 2023, 13(06): 461-465.
[9] 廖想, 李爽, 曾瑶. 2012-2021年粪菌移植研究的趋势及热点分析[J]. 中华消化病与影像杂志(电子版), 2023, 13(02): 93-99.
[10] 张大涯, 陈世锔, 陈润祥, 张晓冬, 李达, 白飞虎. 肠道微生物群对代谢相关脂肪性肝病发展的影响[J]. 中华临床医师杂志(电子版), 2023, 17(07): 828-833.
[11] 韩家超, 王飞飞, 柳子宁, 胡冀陶, 孟泽松, 雒月云, 王贵英. 二甲双胍的作用机制研究进展[J]. 中华临床医师杂志(电子版), 2023, 17(03): 349-355.
[12] 杜青瑶, 曹颖雯, 林健雄, 郝润, 王静敏, 徐锐权, 寇晓霞. 肠道菌群促进诺如病毒感染的机制[J]. 中华临床实验室管理电子杂志, 2023, 11(04): 241-244,255.
[13] 刘艳, 唐神结. 肠道菌群与抗结核药及其所致肝损伤的相关性研究进展[J]. 中华诊断学电子杂志, 2023, 11(02): 82-86.
[14] 阿孜古丽·阿力木江, 买买提·依斯热依力, 王婧, 王永康, 陆萍, 克力木·阿不都热依木. 心理应激对雌性小鼠胃黏膜炎症和卵巢功能早衰的影响[J]. 中华胃食管反流病电子杂志, 2023, 10(02): 69-76.
[15] 金泽平, 董晶, 柳云鹏, 汪阳. 菌群-肠道-脑轴与缺血性卒中危险因素关系的研究进展[J]. 中华脑血管病杂志(电子版), 2023, 17(05): 510-517.
阅读次数
全文


摘要

版权所有 中华医学会 中华医学电子音像出版社有限责任公司  京ICP备14006079号-1  网络出版服务许可证：(署)网出证(京)字第075号