Clinical trial NCT06321237: Influence of Ear Vagus Nerve Stimulator on Patients With IBS
Official title: Effect of Ear Vagus Nerve Stimulator on Symptom Improvement and Intestinal Microbiome in Patients With Irritable Bowel
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Irritable Bowel Syndrome
Keywords: Ear nail stimulator
Gut microbiota
Vagus nerve stimulation
Lead sponsor: Tongji Hospital
Sponsor class: OTHER
First posted: 2024-03-20
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: Irritable bowel syndrome (IBS) is a very common functional digestive disorder characterized by chronic abdominal pain and altered bowel habits in the absence of biological or structural abnormalities. In the field of IBS, effective drug treatments are very limited, and patients are urgently looking for alternatives, including probiotics, hypnotherapy, osteopathy, dietary changes, and fecal microbiota transplants. In recent years, with the continuous elucidation of vagus nerve mechanisms, IBS patients are increasingly interested in bioelectrical regulation, and these patients are often skeptical of traditional drug treatment and believe that drugs are prone to side effects. For several reasons, vagus nerve stimulation (VNS) may be a promising option for improving IBS symptoms. In this experiment, the portable ear nail stimulator produced by Ruishen Medical can accurately stimulate the ear nail, transdermal stimulation of the ear vagus nerve, and give full play to its therapeutic effect. Therefore, the purpose of this clinical trial is to use ear nail stimulator in patients with IBS to explore whether it has therapeutic effects on patients with IBS. To explore the influence of tVNS therapy on irritable bowel syndrome compared with drug therapy, it is hoped that the use of TVNS therapy can reduce the use of related drugs, or even replace drugs. This study intends to recruit a group of patients with irritable bowel syndrome to use the portable ear nail stimulator, (1) to observe whether the symptoms of irritable bowel syndrome patients are improved; (2) To analyze the changes of intestinal microbes in patients with IBS; (3) Verify whether the level of intestinal inflammation is reduced and discover metabolic markers in the intestine.

Detailed description: The human gut microbiome is one of the most densely populated microbial communities on Earth and contains highly diverse microbial communities that provide metabolic, immune and protective functions and play a critical role in human health. The gastrointestinal microbiota is influenced by a variety of factors, including neurological stress, genetics, host physiology (host age, disease, etc.), and environmental factors such as living conditions and drug use. At the same time, the vagus nerve (VN) is considered a key component of the autonomic nervous system (ANS), which innervates most of the digestive tract and many gastrointestinal organs such as the esophagus, stomach, small intestine, and colon, as well as vital organs such as the liver, pancreas, and gallbladder in the digestive system. The vagus nerve transmits excitement to the corresponding brain region by sensing intestinal stimulation, and regulates the gut and brain bidirectionally through the "gut-brain axis". Recent studies have shown that VN has anti-inflammatory effects. This vagus function is mediated through a variety of pathways, some of which remain controversial. The first is the anti-inflammatory pathway of the hypothalamic-pituitary-adrenal axis, stimulated by the afferent fibers of the vagus nerve, where the adrenal glands release cortisol, which provides an important first innate defense against inflammatory infections and helps restore homeostasis in the body. The second, known as the cholinergic anti-inflammatory pathway, releases acetylcholine (ACh) at the synaptic junction with macrophages through the vagal efferent fibre-mediated synaptic connections of intestinal neurons. Acetylcholine binds to the α-7-nicotinic acetylcholine receptor of macrophages and inhibits the release of tumor necrosis (TNF)α, a pro-inflammatory cytokine. The final pathway is the splenic sympathetic anti-inflammatory pathway, where VN stimulates the splenic sympathetic nerve to release acetylcholine from norepinephrine (norepinephrine) at the distal end. Finally, ACh inhibits the release of TNF-α from splenic macrophages through the α-7-nicotinic ACh receptor. Irritable bowel syndrome (IBS) is a very common functional digestive disorder characterized by chronic abdominal pain and altered bowel habits in the absence of biological or structural abnormalities. In the field of IBS, effective drug treatments are very limited, and patients are urgently looking for alternatives, including probiotics, hypnotherapy, osteopathy, dietary changes, and fecal microbiota transplants. In recent years, with the continuous elucidation of vagus nerve mechanisms, IBS patients are increasingly interested in bioelectrical regulation, and these patients are often skeptical of traditional drug treatment and believe that drugs are prone to side effects. For several reasons, vagus nerve stimulation (VNS) may be a promising option for improving IBS symptoms. Vagus nerve stimulation (VNS) is currently used as a treatment option for many clinical conditions, such as heart failure, migraines, and inflammatory bowel disease. VNS techniques are mainly divided into invasive (surgical implantation) and non-invasive (percutaneous)VNS techniques. Invasive VNS (iVNS) involve implanting a programmable pulse generator device in the chest wall and placing electrodes around the left (typical) cervical vagus nerve. As it stands, iVNS has several potential risks, such as bradycardia and cardiac arrest, and localized infections around the wound. The transcutaneous VNS (tVNS) delivery system relies on the skin distribution of the afferent nerve of the vagus nerve to intervene in the outer ear (the auricular branch of the vagus nerve) or the neck (the cervical branch of the vagus nerve), thereby avoiding the risk of surgical implantation of the VNS delivery device and promoting further research on the application of tVNS. In this experiment, the portable ear nail stimulator produced by Ruishen Medical can accurately stimulate the ear nail, transdermal stimulation of the ear vagus nerve, and give full play to its therapeutic effect. Therefore, the purpose of this clinical trial is to use ear nail stimulator in patients with IBS to explore whether it has therapeutic effects on patients with IBS. To explore the influence of tVNS therapy on irritable bowel syndrome compared with drug therapy, it is hoped that the use of TVNS therapy can reduce the use of related drugs, or even replace drugs. This study intends to recruit a group of patients with IBS to use the portable ear nail stimulator. The purpose of the study is (1) to observe whether the symptoms of IBS patients are improved; (2) To analyze the changes of intestinal microbes in patients with IBS; (3) Verify whether the level of intestinal inflammation is reduced and discover metabolic markers in the intestine. This was a randomized, double-blind study with no placebo group and enrolled 40 patients diagnosed with diarrheal irritable bowel syndrome. The enrolled patients were randomly assigned to tVNS true stimulation (real transcutaneous vagal stimulation) and false stimulation (same instrument but no vagal stimulation) at different times. This study does not require recruitment advertisements, and subjects are recruited on a completely voluntary basis. Possible risks during the experiment are explained to subjects and informed consent is signed after they agree to join the study. The volunteers who agreed to join the experiment were surveyed by questionnaire to obtain their intestinal health and other health conditions, and screened according to the above research object selection criteria and exclusion criteria. The collected samples are named by number, which will not disclose the personal information of the subjects. The identity of the subjects is kept secret throughout the study process, and only the number and disease phenotype are visible. Subjects may withdraw from the study at any time. This study will analyze the composition and structure of the gut microbiota of the subjects, and the subjects can keep abreast of the progress of the testing and analysis and obtain their own relevant data. In this study, the Ruishenan auricular vagus nerve stimulator is used directly without installation. Easy to carry, can be opened at any time stimulation, does not affect daily work and life. Currently approved indications are: adjuvant therapy for sleep disorders, anxiety, loss of appetite, fatigue, and adjuvant therapy for diabetes. In this study, ear nail stimulation with a pulse width of 200μs and a frequency of 30Hz was used for 3 hours a day for 8 weeks to improve the clinical symptoms of patients with irritable bowel syndrome. The experimental plan was to collect stool samples from the recruited patients with diarrheal irritable bowel syndrome, and use the ear conchal stimulator for 3h every day with pulse width of 200μs and frequency of 30Hz. The treatment lasted for 8 weeks \[28\], and each patient was randomly selected as true or false stimulus every 4 weeks, and a total of 4 groups were generated, namely true-true, true-false, false-true, and false-false (Figure 2). The volunteers' stool samples were collected on days 0, 28 and 56. Stool samples were collected two weeks after treatment. On day 0 and every 7 days thereafter, the patients filled in the questionnaire, and a total of 11 questionnaires were collected.

Eligibility criteria: Inclusion Criteria:

1、All patients were excluded from colorectal tumors by colonoscopy within two years, and their clinical manifestations were diarrheal irritable bowel syndrome, which met the diagnostic criteria of Rome IV

Exclusion Criteria:

1. Colonoscopy excludes patients with colorectal tumors within one or two years
2. Patients with other gastrointestinal disorders
3. Patients with a history of prior abdominal surgery, cardiovascular disease, or serious illness
4. In the past month, participants had used drugs that could have affected the study results (e.g., probiotics, prebiotics, antibiotics, laxatives, motility agents).
5. Patients participating in other clinical studies

Primary outcomes:
measure: Changes in irritable bowel symptoms
timeFrame: 90 days
measure: Changes in the diversity of intestinal flora
timeFrame: 90 days
measure: Changes in the relative abundance of species of intestinal flora
timeFrame: 90 days
measure: Changes in the number of intestinal flora
timeFrame: 90 days
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: Tongji Medical College of Huazhong University of Science and Technology
name: ping h Xie
role: STUDY_CHAIR
affiliation: Tongji Medical College of Huazhong University of Science and Technology
name: qiang Ding
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jumpertz R, Le DS, Turnbaugh PJ, Trinidad C, Bogardus C, Gordon JI, Krakoff J. Energy-balance studies reveal associations between gut microbes, caloric load, and nutrient absorption in humans. Am J Clin Nutr. 2011 Jul;94(1):58-65. doi: 10.3945/ajcn.110.010132. Epub 2011 May 4.
citation: Wang Z, Klipfell E, Bennett BJ, Koeth R, Levison BS, Dugar B, Feldstein AE, Britt EB, Fu X, Chung YM, Wu Y, Schauer P, Smith JD, Allayee H, Tang WH, DiDonato JA, Lusis AJ, Hazen SL. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011 Apr 7;472(7341):57-63. doi: 10.1038/nature09922.
citation: Goldsmith JR, Sartor RB. The role of diet on intestinal microbiota metabolism: downstream impacts on host immune function and health, and therapeutic implications. J Gastroenterol. 2014 May;49(5):785-98. doi: 10.1007/s00535-014-0953-z. Epub 2014 Mar 21.
citation: Bonaz B, Sinniger V, Pellissier S. Anti-inflammatory properties of the vagus nerve: potential therapeutic implications of vagus nerve stimulation. J Physiol. 2016 Oct 15;594(20):5781-5790. doi: 10.1113/JP271539. Epub 2016 May 1.
citation: Yu CD, Xu QJ, Chang RB. Vagal sensory neurons and gut-brain signaling. Curr Opin Neurobiol. 2020 Jun;62:133-140. doi: 10.1016/j.conb.2020.03.006. Epub 2020 May 4.
citation: Johnston GR, Webster NR. Cytokines and the immunomodulatory function of the vagus nerve. Br J Anaesth. 2009 Apr;102(4):453-62. doi: 10.1093/bja/aep037. Epub 2009 Mar 3.
citation: Pavlov VA, Wang H, Czura CJ, Friedman SG, Tracey KJ. The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation. Mol Med. 2003 May-Aug;9(5-8):125-34.
citation: Matteoli G, Gomez-Pinilla PJ, Nemethova A, Di Giovangiulio M, Cailotto C, van Bree SH, Michel K, Tracey KJ, Schemann M, Boesmans W, Vanden Berghe P, Boeckxstaens GE. A distinct vagal anti-inflammatory pathway modulates intestinal muscularis resident macrophages independent of the spleen. Gut. 2014 Jun;63(6):938-48. doi: 10.1136/gutjnl-2013-304676. Epub 2013 Aug 8.
citation: Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology. 2006 Apr;130(5):1480-91. doi: 10.1053/j.gastro.2005.11.061.
citation: Wang Y, Zheng F, Liu S, Luo H. Research Progress in Fecal Microbiota Transplantation as Treatment for Irritable Bowel Syndrome. Gastroenterol Res Pract. 2019 Dec 1;2019:9759138. doi: 10.1155/2019/9759138. eCollection 2019.
citation: Shah K, Ramos-Garcia M, Bhavsar J, Lehrer P. Mind-body treatments of irritable bowel syndrome symptoms: An updated meta-analysis. Behav Res Ther. 2020 May;128:103462. doi: 10.1016/j.brat.2019.103462. Epub 2019 Nov 12.
citation: Muller A, Franke H, Resch KL, Fryer G. Effectiveness of osteopathic manipulative therapy for managing symptoms of irritable bowel syndrome: a systematic review. J Am Osteopath Assoc. 2014 Jun;114(6):470-9. doi: 10.7556/jaoa.2014.098.
citation: Ford AC, Harris LA, Lacy BE, Quigley EMM, Moayyedi P. Systematic review with meta-analysis: the efficacy of prebiotics, probiotics, synbiotics and antibiotics in irritable bowel syndrome. Aliment Pharmacol Ther. 2018 Nov;48(10):1044-1060. doi: 10.1111/apt.15001. Epub 2018 Oct 8.
citation: Bonaz B, Picq C, Sinniger V, Mayol JF, Clarencon D. Vagus nerve stimulation: from epilepsy to the cholinergic anti-inflammatory pathway. Neurogastroenterol Motil. 2013 Mar;25(3):208-21. doi: 10.1111/nmo.12076. Epub 2013 Jan 29.
citation: Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000 May 25;405(6785):458-62. doi: 10.1038/35013070.
citation: Bonaz B, Bazin T, Pellissier S. The Vagus Nerve at the Interface of the Microbiota-Gut-Brain Axis. Front Neurosci. 2018 Feb 7;12:49. doi: 10.3389/fnins.2018.00049. eCollection 2018.
citation: Foster JA, Rinaman L, Cryan JF. Stress & the gut-brain axis: Regulation by the microbiome. Neurobiol Stress. 2017 Mar 19;7:124-136. doi: 10.1016/j.ynstr.2017.03.001. eCollection 2017 Dec.
citation: De Ferrari GM, Crijns HJ, Borggrefe M, Milasinovic G, Smid J, Zabel M, Gavazzi A, Sanzo A, Dennert R, Kuschyk J, Raspopovic S, Klein H, Swedberg K, Schwartz PJ; CardioFit Multicenter Trial Investigators. Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure. Eur Heart J. 2011 Apr;32(7):847-55. doi: 10.1093/eurheartj/ehq391. Epub 2010 Oct 28.
citation: Botha C, Farmer AD, Nilsson M, Brock C, Gavrila AD, Drewes AM, Knowles CH, Aziz Q. Preliminary report: modulation of parasympathetic nervous system tone influences oesophageal pain hypersensitivity. Gut. 2015 Apr;64(4):611-7. doi: 10.1136/gutjnl-2013-306698. Epub 2014 May 28.
citation: Ghia JE, Blennerhassett P, Kumar-Ondiveeran H, Verdu EF, Collins SM. The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model. Gastroenterology. 2006 Oct;131(4):1122-30. doi: 10.1053/j.gastro.2006.08.016. Epub 2006 Aug 15.
citation: Asconape JJ, Moore DD, Zipes DP, Hartman LM, Duffell WH Jr. Bradycardia and asystole with the use of vagus nerve stimulation for the treatment of epilepsy: a rare complication of intraoperative device testing. Epilepsia. 1999 Oct;40(10):1452-4. doi: 10.1111/j.1528-1157.1999.tb02019.x.
citation: Fahy BG. Intraoperative and perioperative complications with a vagus nerve stimulation device. J Clin Anesth. 2010 May;22(3):213-22. doi: 10.1016/j.jclinane.2009.10.002.
citation: Lacy BE, Patel NK. Rome Criteria and a Diagnostic Approach to Irritable Bowel Syndrome. J Clin Med. 2017 Oct 26;6(11):99. doi: 10.3390/jcm6110099.
citation: Wiklund IK, Fullerton S, Hawkey CJ, Jones RH, Longstreth GF, Mayer EA, Peacock RA, Wilson IK, Naesdal J. An irritable bowel syndrome-specific symptom questionnaire: development and validation. Scand J Gastroenterol. 2003 Sep;38(9):947-54. doi: 10.1080/00365520310004209.
citation: Travers P, Lacy BE, Cangemi DJ. Irritable bowel syndrome - less irritable, or better treatments? Curr Opin Gastroenterol. 2024 Jan 1;40(1):27-33. doi: 10.1097/MOG.0000000000000987. Epub 2023 Oct 19.