Electroacupuncture Alleviates Functional Constipation in Mice by Activating Enteric Glial Cell Autophagy via PI3K/AKT/mTOR Signaling

WANG Lu; CHEN Ying; XU Ming-min; CAO Wei; ZHENG Qian-hua; ZHOU Si-yuan; YAO Jun-peng; XI Meng-han; QIN Hai-yan; LI Ying; ZHANG Wei

doi:10.1007/s11655-023-3594-3

Your Location：

Home >

Browse articles >

Electroacupuncture Alleviates Functional Constipation in Mice by Activating Enteric Glial Cell Autophagy via PI3K/AKT/mTOR Signaling

Acupuncture Research | Updated：2023-04-27

- Electroacupuncture Alleviates Functional Constipation in Mice by Activating Enteric Glial Cell Autophagy via PI3K/AKT/mTOR Signaling
- Chinese Journal of Integrative Medicine Vol. 29, Issue 5, Pages: 459-469(2023)
- Affiliations：
  
  1.Acupuncture and Tuina School, Chengdu University of Traditional Chinese Medicine, Chengdu (610075), China
  2.School of Traditional Chinese Medicine, Jinan University, Guangzhou (510632), China
- Author bio：
  
  Dr. ZHANG Wei, E-mail: zhangwei@cdutcm.edu.cn
- Funds：
- DOI：10.1007/s11655-023-3594-3
  CLC：
- Published：2023-05，
  
  Published Online：28 March 2023，
  
  Accepted：11 November 2022
Scan for full text
WANG Lu, CHEN Ying, XU Ming-min, et al. Electroacupuncture Alleviates Functional Constipation in Mice by Activating Enteric Glial Cell Autophagy via PI3K/AKT/mTOR Signaling. [J]. Chinese Journal of Integrative Medicine 29(5):459-469(2023)
DOI：

WANG Lu, CHEN Ying, XU Ming-min, et al. Electroacupuncture Alleviates Functional Constipation in Mice by Activating Enteric Glial Cell Autophagy via PI3K/AKT/mTOR Signaling. [J]. Chinese Journal of Integrative Medicine 29(5):459-469(2023) DOI： 10.1007/s11655-023-3594-3.

摘要

Abstract

Objective:

To investigate autophagy-related mechanisms of electroacupuncture (EA) action in improving gastrointestinal motility in mice with functional constipation (FC).

Methods:

According to a random number table

the Kunming mice were divided into the normal control

FC and EA groups in Experiment Ⅰ. The autophagy inhibitor 3-methyladenine (3-MA) was used to observe whether it antagonized the effects of EA in Experiment Ⅱ. An FC model was established by diphenoxylate gavage. Then the mice were treated with EA stimulation at Tianshu (ST 25) and Shangjuxu (ST 37) acupoints. The first black stool defecation time

the number

weight

and water content of 8-h feces

and intestinal transit rate were used to assess intestinal transit. Colonic tissues underwent histopathological assessment

and the expressions of autophagy markers microtubule-associated protein 1 light chain 3 (LC3) and Beclin-1 were detected by immunohistochemical staining. The expressions of phosphoinositide 3-kinases (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) signaling pathway members were investigated by Western blot and quantitative reverse transcription-polymerase chain reaction

respectively. The relationship between enteric glial cells (EGCs) and autophagy was observed by confocal immunofluorescence microscopy

localization analysis

and electron microscopy.

Results:

EA treatment shortened the first black stool defecation time

increased the number

weight

and water content of 8-h feces

and improved the intestinal transit rate in FC mice (

0.01). In terms of a putative autophagy mechanism

EA treatment promoted the expressions of LC3 and Beclin-1 proteins in the colonic tissue of FC mice (

0.05)

with glialfibrillary acidic protein (GFAP) and LC3 significantly colocalized. Furthermore

EA promoted colonic autophagy in FC mice by inhibiting PI3K/AKT/mTOR signaling (

0.05 or

0.01). The positive effect of EA on intestinal motility in FC mice was blocked by 3-MA.

Conclusion:

EA treatment can inhibit PI3K/AKT/mTOR signaling in the colonic tissues of FC mice

thereby promoting EGCs autophagy to improve intestinal motility.

关键词

Keywords

electroacupuncturegastrointestinal motilityautophagyenteric glial cellsChinese medicine

references

Sperber AD, Bangdiwala SI, Drossman DA, et al. Worldwide prevalence and burden of functional gastrointestinal disorders, results of Rome foundation global study. Gastroenterol 2021;160:99-114.e3.

Koppen IJN, Vriesman MH, Saps M, et al. Prevalence of functional defecation disorders in children: a systematic review and meta-analysis. J Pediatr 2018;198:121-130.e6.

Drossman DA, Hasler WL. Rome Ⅳ-functional GI disorders:disorders of gut-brain interaction. Gastroenterology 2016;150:1257-1261.

Camilleri M, Ford AC, Mawe GM, et al. Chronic constipation. Nat Rev Dis Primers 2017;3:17095.

Rao SS, Rattanakovit K, Patcharatrakul T. Diagnosis and management of chronic constipation in adults. Nat Rev Gastroenterol Hepatol 2016;13:295-305.

The Lancet Gastroenterology Hepatology. The cost of constipation. Lancet Gastroenterol Hepatol 2019;4:811.

Liu B, Wu J, Yan S, et al. Electroacupuncture vs prucalopride for severe chronic constipation: a multicenter, randomized, controlled, noninferiority trial. Am J Gastroenterol 2021;116:1024-1035.

Wang X, Yang B, Yin J, et al. Electroacupuncture via chronically implanted electrodes improves gastrointestinal motility by balancing sympathovagal activities in a rat model of constipation. Am J Physiol Gastrointest Liver Physiol 2019;316:G797-G805.

Liang C, Wang KY, Gong MR, et al. Electro-acupuncture at ST37 and ST25 induce different effects on colonic motility via the enteric nervous system by affecting excitatory and inhibitory neurons. Neurogastroenterol Motil 2018;30:e13318.

Ge Z, Duan Z, Yang H, et al. Home-based transcutaneous neuromodulation improved constipation via modulating gastrointestinal hormones and bile acids. Evid Based Complement Alternat Med 2018;2018:2086163.

Jin X, Guan Y, Bai H, et al. Effects of sEA on slow transit constipation through the microbiota-gut-brain axis in rats. Evid Based Complement Alternat Med 2020;2020:8828846.

Zhu D, Hu J, Chi Z, et al. Effectiveness and safety of acupuncture in the treatment of chronic severe functional constipation: a protocol for systematic review and meta-analysis. Medicine (Baltimore) 2021;100:e24589.

Xu J, Chen Y, Liu S, et al. Electroacupuncture regulates apoptosis/proliferation of intramuscular interstitial cells of cajal and restores colonic motility in diabetic constipation rats. Evid Based Complement Alternat Med 2013;2013:584179.

Dikic I, Elazar Z. Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol 2018;19:349-364.

Zhang LM, Zeng LJ, Deng J, et al. Investigation of autophagy and differentiation of myenteric interstitial cells of Cajal in the pathogenesis of gastric motility disorders in rats with functional dyspepsia. Biotechnol Appl Biochem 2018;65:533-539.

Wei X, Lin Y, Zhao D, et al. Electroacupuncture relieves suppression of autophagy in interstitial cells of Cajal of diabetic gastroparesis rats. Can J Gastroenterol Hepatol 2020;2020:7920715.

Zheng H, Liu YJ, Chen ZC, et al. miR-222 regulates cell growth, apoptosis, and autophagy of interstitial cells of Cajal isolated from slow transit constipation rats by targeting c-kit. Indian J Gastroenterol 2021;40:198-208.

Zhang W. Research on GDNF-PI3K-AKT signal pathway in FC mice with acupuncture Back-shu and Front-mu points improving gastrointestinal transmitting function [Dissertation]. Chengdu:Chengdu University of Traditional Chinese Medicine;2016.

Seguella L, Gulbransen BD. Enteric glial biology, intercellular signalling and roles in gastrointestinal disease. Nat Rev Gastroenterol Hepatol 2021;18:571-587.

Chow AK, Grubisic V, Gulbransen BD. Enteric glia regulate lymphocyte activation via autophagy-mediated MHC-Ⅱ expression. Cell Mol Gastroenterol Hepatol 2021;12:1215-1237.

Duan Y, Haybaeck J, Yang Z. Therapeutic potential of PI3K/AKT/mTOR pathway in gastrointestinal stromal tumors:rationale and progress. Cancers (Basel) 2020;12:2972.

Zhang MH, Jiang JZ, Cai YL, et al. Significance of dynamic changes in gastric smooth muscle cell apoptosis, PI3K-AKT-mTOR and AMPK-mTOR signaling in a rat model of diabetic gastroparesis. Mol Med Rep 2017;16:1530-1536.

Wen Y, Zhan Y, Tang SY, et al. Zhizhu Decoction alleviates intestinal barrier damage via regulating SIRT1/FoxO1 signaling pathway in slow transit constipation model mice. Chin J Integr Med 2022. Epub ahead of print

Wang XM, Lv LX, Qin YS, et al. Ji-Chuan Decoction ameliorates slow transit constipation via regulation of intestinal glial cell apoptosis. World J Gastroenterol 2022;28:5007-5022.

Xu M, Wang L, Guo Y, et al. Corrigendum to "Positive effect of electro-acupuncture treatment on gut motility in constipated mice is related to rebalancing the gut microbiota". Evid Based Complement Alternat Med 2021;2021:9835654.

Su H, Chen J, Miao S, et al. Lotus seed oligosaccharides at various dosages with prebiotic activity regulate gut microbiota and relieve constipation in mice. Food Chem Toxicol 2019;134:110838.

Yan S, Yue YZ, Wang XP, et al. Aqueous extracts of herba cistanche promoted intestinal motility in loperamide-induced constipation rats by ameliorating the interstitial cells of Cajal. Evid Based Complement Alternat Med 2017;2017:6236904.

Khan I, Khan K. Uncoupling of carbonic anhydrase from Na-H exchanger-1 in experimental colitis: a possible mechanistic link with Na-H exchanger. Biomolecules 2019;9:700.

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001;25:402-408.

Liu Z, Yan S, Wu J, et al. Acupuncture for chronic severe functional constipation: a randomized trial. Ann Intern Med 2016;165:761-769.

Wang L, Xu M, Zheng Q, et al. The effectiveness of acupuncture in management of functional constipation:a systematic review and meta-analysis. Evid Based Complement Alternat Med 2020;2020:6137450.

Sun F, Liu Z, Zhang W. Clinical acupoint selection for the treatment of functional constipation by massage and acupuncture based on smart medical big data analysis. J Healthc Eng 2021;2021:9930412.

Zhu X, Liu Z, Qu H, et al. The effect and mechanism of electroacupuncture at LI11 and ST37 on constipation in a rat model. Acupunct Med 2016;34:194-200.

Jain M, Wylie WP, eds. Diphenoxylate and atropine. Updated 2022 Jun 26. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan. PMID: 32644726.

Tang L, Zeng Y, Li L, et al. Correction to: electroacupuncture upregulated ghrelin in rats with functional dyspepsia via AMPK/TSC2/Rheb-mediated mTOR inhibition. Dig Dis Sci 2020;65:2148.

Wu M, Li Y, Gu Y. Hesperidin improves colonic motility in loeramide-induced constipation rat model via 5-hydroxytryptamine 4R/cAMP signaling pathway. Digestion 2020;101:692-705.

Di Meco A, Curtis ME, Lauretti E, et al. Autophagy dysfunction in Alzheimer's disease: mechanistic insights and new therapeutic opportunities. Biol Psychiatry 2020;87:797-807.

Hong Y, Ren X, Liu W, et al. miR-128 participates in the pathogenesis of chronic constipation by regulating the p38alpha/M-CSF inflammatory signaling pathway. Am J Physiol Gastrointest Liver Physiol 2021;321:G436-G447.

Liu S, Wang Z, Su Y, et al. A neuroanatomical basis for electroacupuncture to drive the vagal-adrenal axis. Nature 2021;598:641-645.

Oh JE, Kim SN. Anti-inflammatory effects of acupuncture at ST36 point: a literature review in animal studies. Front Immunol 2021;12:813748.

Yang NN, Yang JW, Ye Y, et al. Electroacupuncture ameliorates intestinal inflammation by activating alpha7nAChR-mediated JAK2/STAT3 signaling pathway in postoperative ileus. Theranostics 2021;11:4078-4089.

Bianco F, Lattanzio G, Lorenzini L, et al. Novel understanding on genetic mechanisms of enteric neuropathies leading to severe gut dysmotility. Eur J Histochem 2021;65:3289.

Spencer NJ, Hu H. Enteric nervous system: sensory transduction, neural circuits and gastrointestinal motility. Nat Rev Gastroenterol Hepatol 2020;17:338-351.

Ye L, Li G, Goebel A, et al. Caspase-11-mediated enteric neuronal pyroptosis underlies Western diet-induced colonic dysmotility. J Clin Invest 2020;130:3621-3636.

Chen F, Yu Y, Wang P, et al. Brain-derived neurotrophic factor accelerates gut motility in slow-transit constipation. Acta Physiol (Oxf) 2014;212:226-238.

Costa M, Spencer NJ, Brookes SJH. The role of enteric inhibitory neurons in intestinal motility. Auton Neurosci 2021;235:102854.

Kitada M, Koya D. Autophagy in metabolic disease and ageing. Nat Rev Endocrinol 2021;17:647-661.

Kang R, Zeh HJ, Lotze MT, et al. The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ 2011;18:571-580.

Abada A, Elazar Z. Getting ready for building: signaling and autophagosome biogenesis. EMBO Rep 2014;15:839-852.

Lamb CA, Yoshimori T, Tooze SA. The autophagosome:origins unknown, biogenesis complex. Nat Rev Mol Cell Biol 2013;14:759-774.

Wang T, Liu K, Wen L, et al. Autophagy and gastrointestinal diseases. Adv Exp Med Biol 2020;1207:529-556.

Camilleri M, Sanders KM. Gastroparesis. Gastroenterology 2022;162:68-87.e1.

Jaeger PA, Wyss-Coray T. All-you-can-eat: autophagy in neurodegeneration and neuroprotection. Mol Neurodegener 2009;4:16.

Marino G, Niso-Santano M, Baehrecke EH, et al. Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol 2014;15:81-94.

Hu S, Du MH, Luo HM, et al. Electroacupuncture at Zusanli(ST36) prevents intestinal barrier and remote organ dysfunction following gut ischemia through activating the cholinergic anti-inflammatory-dependent mechanism. Evid Based Complement Alternat Med 2013;2013:592127.

Cao Y, Zhong F, Wen Q, et al. Effect of electroacupuncture on gastrointestinal motility in rats with slow transit constipation based on GDNF methylation modification. Acupunct Res (Chin) 2022;47:141-147.

Yu JS, Cui W. Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination. Development 2016;143:3050-3060.

Xu Z, Han X, Ou D, et al. Targeting PI3K/AKT/mTOR-mediated autophagy for tumor therapy. Appl Microbiol Biotechnol 2020;104:575-587.

More>

Views

Downloads

CSCD

Alert me when the article has been cited

Submit

Tools

Publicity Resources

Electroacupuncture Promotes Functional Recovery after Facial Nerve Injury in Rats by Regulating Autophagy via GDNF and PI3K/mTOR Signaling Pathway

Protective Mechanism of Cordyceps sinensis Treatment on Acute Kidney Injury-Induced Acute Lung Injury through AMPK/mTOR Signaling Pathway

Electroacupuncture Improves Blood-Brain Barrier and Hippocampal Neuroinflammation in SAMP8 Mice by Inhibiting HMGB1/TLR4 and RAGE/NADPH Signaling Pathways

Effect of Electro-acupuncture on Vasomotor Symptoms in Rats with Acute Cerebral Infarction Based on Phosphatidylinositol System

Related Author

No data

Related Institution

Department of Rehabilitation Medicine, Guanghan People's Hospital

Academic Affairs Office, Chengdu University of Traditional Chinese Medicine

Nephropathy Department, Shenzhen Hospital (Futian)of Guangzhou University of Chinese Medicine

The Third Clinical Medical School, Guangzhou University of Chinese Medicine

College of Acu-moxibustion and Massage, Shaanxi University of Chinese Medicine

Address：1 Caochang, xiyuan, Beijing, People's Republic of China Postal code：100091
Tel：010-62886827, 62877592 Fax：010-62874291
Technical support is provided by Beijing Founder electronics co., LTD 京ICP备05067934号-1 京公网安备11010802024621
It is recommended to read the content of this site in Chrome&IE9+. Please switch to extreme mode in browser 360.
Cookies We use cookies to help provide and enhance our service and tailor content. By continuing, you agree to the use of cookies.

⁰