Gastroparesis syndromes: emerging drug targets and potential therapeutic opportunities

References

• Camilleri M, Kuo B, Nguyen L, et al., ACG clinical guideline: gastroparesis. Am J Gastroenterol. 2022;117(8): 1197–1220.
   PubMedGoogle Scholar
• Horowitz M, AF M, JM W, et al. Relationships between oesophageal transit and solid and liquid gastric emptying in diabetes mellitus. Eur J Nucl Med. 1991;18(4):229–234.
   PubMedGoogle Scholar
• AR S, MM W, Calles-Escandon J. Epidemiology and diagnosis of gastroparesis in the United States: a population-based study. J Clin Gastroenterol. 2020;54(1):50–54.
   PubMedGoogle Scholar
• Krishnasamy S, Abell TL. Diabetic gastroparesis: principles and current trends in management. Diabetes Therapy. 2018 Jul;9(Suppl 1):1–42.
   PubMedGoogle Scholar
• Huang I-H, Schol J, Khatun R, et al. Worldwide prevalence and burden of gastroparesis-like symptoms as defined by the United European gastroenterology (UEG) and European society for neurogastroenterology and motility (ESNM) consensus on gastroparesis. United European Gastroenterology Journal.n/a(n/a).
   Google Scholar
• Stanghellini V, Chan FK, Hasler WL, et al. Gastroduodenal Disorders. Gastroenterology. 2016;150(6):1380–1392.
   PubMed Web of Science ®Google Scholar
• Pasricha PJ, Grover M, Yates KP, et al. Functional dyspepsia and gastroparesis in tertiary care are interchangeable syndromes with common clinical and pathologic features. Gastroenterology. 2021;160(6):2006–2017.
   PubMedGoogle Scholar
• Tansel A, Nguyen L, Abell T. Pathophysiology of Gastric neuromuscular disorders. The AFS Textbook of Foregut Disease: Springer Nature [IN PRESS].
   Google Scholar
• Gottfried-Blackmore A, Namkoong H, Adler E, et al. Gastric mucosal immune profiling and dysregulation in idiopathic gastroparesis. Clin Transl Gastroenterol. 2021;12(5):e00349–e00349.
   PubMedGoogle Scholar
• Shine A, Abell TL. Role of gastric electrical stimulation in the treatment of gastroparesis. Gastrointestinal Disorders. 2020;2(1):12–26.
   Google Scholar
• Abell TL, Kedar A, Stocker A, et al. Pathophysiology of gastroparesis syndromes includes anatomic and physiologic abnormalities. Dig Dis Sci. 2021 Apr;66(4):1127–1141.
   PubMedGoogle Scholar
• Pasricha PJ, Grover M, Yates KP, et al. Progress in gastroparesis - A narrative review of the work of the gastroparesis clinical research consortium. Clin Gastroenterol Hepatol. 2022 Dec;20(12):2684–2695.e3.
   PubMedGoogle Scholar
• Maurer AH, Abell T, Bennett P, et al. Appropriate use criteria for gastrointestinal transit scintigraphy. J Nucl Med. 2020;61(3):11N–17N.
   PubMed Web of Science ®Google Scholar
• Carson DA, Bhat S, Hayes TCL, et al. Abnormalities on electrogastrography in nausea and vomiting syndromes: a systematic review, meta-analysis, and comparison to other gastric disorders. Dig Dis Sci. 2022;67(3):773–785.
   PubMedGoogle Scholar
• DJ L. Slow wave(s) of enthusiasm: electrogastrography as an electrodiagnostic tool in clinical gastroenterology. Dig Dis Sci. 2022;67(3):737–738.
   PubMedGoogle Scholar
• Gharibans AA, Calder S, Varghese C, et al. Gastric dysfunction in patients with chronic nausea and vomiting syndromes defined by a novel non-invasive gastric mapping device. medRxiv. 2022;2022:2002.2007.22270514.
   Google Scholar
• Camilleri M, Parkman HP, Shafi MA, et al. Clinical guideline: management of gastroparesis. Am J Gastroenterol. 2013;108(1):18–37.
   PubMed Web of Science ®Google Scholar
• Mekaroonkamol P, Tiankanon K, Rerknimitr R. A new paradigm shift in gastroparesis management. Gut Liver. 2022 Nov 15;16(6):825–839.
   PubMedGoogle Scholar
• Belkacemi L, Darmani NA. Dopamine receptors in emesis: molecular mechanisms and potential therapeutic function. Pharmacol Res. 2020;161:105124.
   PubMed Web of Science ®Google Scholar
• Yoshikawa T, Yoshida N, Hosoki K. Involvement of dopamine D3 receptors in the area postrema in R(+)-7-OH-DPAT-induced emesis in the ferret. Eur J Pharmacol. 1996;301(1–3):143–149.
   PubMedGoogle Scholar
• Osinski MA, Uchic ME, Seifert T, et al. Dopamine D2, but not D4, receptor agonists are emetogenic in ferrets. Pharmacol Biochem Behav. 2005;81(1):211–219.
   PubMed Web of Science ®Google Scholar
• Acosta A, Camilleri M. Prokinetics in gastroparesis. Gastroenterol Clin North Am. 2015;44(1):97–111.
   PubMed Web of Science ®Google Scholar
• Heckroth M, Luckett RT, Moser C, et al. Nausea and vomiting in 2021: a comprehensive update. J Clin Gastroenterol. 2021;55(4):279–299.
   PubMedGoogle Scholar
• Claassen S, Zünkler BJ. Comparison of the effects of metoclopramide and domperidone on HERG channels. Pharmacology. 2005;74(1):31–36.
   PubMed Web of Science ®Google Scholar
• Field J, Wasilewski M, Bhuta R, et al. Effect of chronic domperidone use on QT interval: a large single center study. J Clin Gastroenterol. 2019;53(9):648–652.
   PubMedGoogle Scholar
• Sarosiek I, Van Natta M, Parkman HP, et al. Effect of domperidone therapy on gastroparesis symptoms: results of a dynamic cohort study by NIDDK gastroparesis consortium. Clin Gastroenterol Hepatol. 2022;20(3):e452–e464.
   PubMedGoogle Scholar
• Heckert J, Parkman HP. Therapeutic response to domperidone in gastroparesis: a prospective study using the GCSI-daily diary. Neurogastroenterol Motil. 2018;30:1.
   Google Scholar
• Bashashati M, Sarosiek I, Siddiqui T, et al. Adverse Effects of domperidone: prolonged quest for knowledge? Dig Dis Sci. 2016;61(12):3384–3386.
   PubMedGoogle Scholar
• Spiller R. Serotonergic modulating drugs for functional gastrointestinal diseases. Br J Clin Pharmacol. 2002;54(1):11–20.
   PubMedGoogle Scholar
• Racke K, Reimann A, Schworer H, et al. Regulation of 5-HT release from enterochromaffin cells. Behav Brain Res. 1996;73(1–2):83–87.
   PubMedGoogle Scholar
• Smith HS, Cox LR, Smith EJ. 5-HT3 receptor antagonists for the treatment of nausea/vomiting. Ann Palliat Med. 2012;1(2):115–120.
   PubMedGoogle Scholar
• Hoffman JM, Tyler K, MacEachern SJ, et al. Activation of colonic mucosal 5-HT(4) receptors accelerates propulsive motility and inhibits visceral hypersensitivity. Gastroenterology. 2012;142(4):844–854.e844.
   PubMed Web of Science ®Google Scholar
• Morganroth J, Rüegg PC, Dunger-Baldauf C, et al. Tegaserod, a 5-hydroxytryptamine type 4 receptor partial agonist, is devoid of electrocardiographic effects. Am J Gastroenterol. 2002;97(9):2321–2327.
   PubMedGoogle Scholar
• Li C, Micci MA, Murthy KS, et al. Substance P is essential for maintaining gut muscle contractility: a novel role for coneurotransmission revealed by botulinum toxin. Am J Physiol Gastrointest Liver Physiol. 2014;306(10):G839–848.
   PubMedGoogle Scholar
• Jacob D, Busciglio I, Burton D, et al. Effects of NK1 receptors on gastric motor functions and satiation in healthy humans: results from a controlled trial with the NK1 antagonist aprepitant. Am J Physiol Gastrointest Liver Physiol. 2017;313(5):G505–g510.
   PubMed Web of Science ®Google Scholar
• Parkman HP, Van Natta ML, Abell TL, et al. Effect of nortriptyline on symptoms of idiopathic gastroparesis: the NORIG randomized clinical trial. Jama. 2013;310(24):2640–2649.
   PubMed Web of Science ®Google Scholar
• Kim SW, Shin IS, Kim JM, et al. Mirtazapine for severe gastroparesis unresponsive to conventional prokinetic treatment. Psychosomatics. 2006;47(5):440–442.
   PubMed Web of Science ®Google Scholar
• Wu CY, Chou LT, Chen HP, et al. Effect of fluoxetine on symptoms and gastric dysrhythmia in patients with functional dyspepsia. Hepatogastroenterology. 2003;50(49):278–283.
   PubMedGoogle Scholar
• Ladabaum U, Sharabidze A, Levin TR, et al. Citalopram provides little or no benefit in nondepressed patients with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2010;8(1):42–48.e41.
   PubMedGoogle Scholar
• Whiting RL, Choppin A, Luehr G, et al. Preclinical evaluation of the effects of trazpiroben (TAK-906), a novel, potent dopamine D2/D3 receptor antagonist for the management of gastroparesis. J Pharmacol Exp Ther. 2021 Oct;379(1):85–95. JPET-AR-2021-000698.
   PubMed Web of Science ®Google Scholar
• De Colle C, van der Hart M, Chen J, et al. A Potent and selective dopamine d2 receptor antagonist as a potential alternative to metoclopramide and domperidone for the treatment of gastroparesis [ABSTRACT]. Gastroenterology. 2016;150(4):1079NG1101.
   Web of Science ®Google Scholar
• Carbone F, Van den Houte K, Clevers E, et al. Prucalopride in gastroparesis: a randomized placebo-controlled crossover study. Am J Gastroenterol. 2019;114(8):1265–1274.
   PubMed Web of Science ®Google Scholar
• Vijayvargiya P, Camilleri M. Use of prucalopride in adults with chronic idiopathic constipation. Expert Rev Clin Pharmacol. 2019;12(7):579–589.
   PubMed Web of Science ®Google Scholar
• Hongo M, Harasawa S, Mine T, et al. Large-scale randomized clinical study on functional dyspepsia treatment with mosapride or teprenone: Japan mosapride mega-study (JMMS). J Gastroenterol Hepatol. 2012;27(1):62–68.
   PubMedGoogle Scholar
• He J. A meta-analysis of mosapride in the treatment of diabetic gastroparesis. Chinese Journal of Gastroenterology. 2011;16:2.
   Google Scholar
• Bang CS, Kim JH, Baik GH, et al. Mosapride treatment for functional dyspepsia: a meta-analysis. J Gastroenterol Hepatol. 2015;30(1):28–42.
   PubMed Web of Science ®Google Scholar
• Jalleh RJ, Marathe CS, Jones KL, et al. Digesting the pathogenesis of diabetic gastroparesis. J Diabetes Complications. 2021;35(10):107992.
   PubMedGoogle Scholar
• Abell TL, Garcia LM, Wiener GJ, et al. Effect of Oral CNSA-001 (sepiapterin, PTC923) on gastric accommodation in women with diabetic gastroparesis: a randomized, placebo-controlled, Phase 2 trial. J Diabetes Complications. 2021;35(9):107961.
   PubMedGoogle Scholar
• Hobson R, Farmer AD, Dewit OE, et al. The effects of camicinal, a novel motilin agonist, on gastro-esophageal function in healthy humans-a randomized placebo controlled trial. Neurogastroenterol Motil. 2015;27(11):1629–1637.
   PubMedGoogle Scholar
• Deloose E, Depoortere I, de Hoon J, et al. Manometric evaluation of the motilin receptor agonist camicinal (GSK962040) in humans. Neurogastroenterol Motil. 2018;30:1.
   Google Scholar
• Hellstrom PM, Tack J, Barton ME, et al. A double-blind, randomized placebo-controlled phase II study of the pharmacokinetics of single doses of the motilin agonist GSK962040, in patients with type I diabetes mellitus (TIDM) and gastroparesis. Gastroenterology. 2011;140(5):S–813.
   Google Scholar
• Dukes GE, Barton ME, Dewit OE, et al. Safety/tolerability, pharmacokinetics (PK), and effect on gastric emptying(GE) with 14-days repeat oral dosing of the motilin receptor agonist, GSK962040, in healthy male and female volunteers. Neurogastroenterol Motility. 2010;22:14–15.
   Google Scholar
• Tack J, Janssen P, Masaoka T, et al. Efficacy of buspirone, a fundus-relaxing drug, in patients with functional dyspepsia. Clin Gastroenterol Hepatol. 2012;10(11):1239–1245.
   PubMed Web of Science ®Google Scholar
• Caviglia GP, Sguazzini C, Cisarò F, et al. Gastric emptying and related symptoms in patients treated with buspirone, amitriptyline or clebopride: a “real world” study by 13C-octanoic acid breath test. Minerva Medicine. 2017;108:489–495.
   PubMedGoogle Scholar
• Van Oudenhove L, Kindt S, Vos R, et al. Influence of buspirone on gastric sensorimotor function in man. Aliment Pharmacol Ther. 2008;28(11–12):1326–1333.
   PubMed Web of Science ®Google Scholar
• The complex interplay between gut-brain, gut-liver, and liver-brain axes. Cambridge, Massachusetts: Academic Press; 2021.
   Google Scholar
• Yamawaki H, Futagami S, Kawagoe T, et al. Improvement of meal-related symptoms and epigastric pain in patients with functional dyspepsia treated with acotiamide was associated with acylated ghrelin levels in Japan. Neurogastroenterol Motility. 2016;28(7):1037–1047.
   PubMedGoogle Scholar
• Nakamura K, Tomita T, Oshima T, et al. A double-blind placebo controlled study of acotiamide hydrochloride for efficacy on gastrointestinal motility of patients with functional dyspepsia. J Gastroenterol. 2017;52(5):602–610.
   PubMedGoogle Scholar
• Tack J, Masclee A, Heading R, et al. A dose-ranging, placebo-controlled, pilot trial of Acotiamide in patients with functional dyspepsia. Neurogastroenterol Motil. 2009;21(3):272–280.
   PubMed Web of Science ®Google Scholar
• Sinha S, Chary S, Thakur P, et al. Efficacy and safety of acotiamide versus mosapride in patients with functional dyspepsia associated with meal-induced postprandial distress syndrome: a phase III randomized clinical trial. Cureus. 2021;13(9):e18109.
   PubMedGoogle Scholar
• Shinozaki S, Osawa H, Sakamoto H, et al. Timing and predictors of recurrence of dyspepsia symptoms after cessation of acotiamide therapy for functional dyspepsia: a long-term observational study. Digestion. 2020;101(4):382–390.
   PubMedGoogle Scholar
• Shinozaki S, Osawa H, Sakamoto H, et al. Adherence to an acotiamide therapeutic regimen improves long-term outcomes in patients with functional dyspepsia. J Gastrointestin Liver Dis. 2017;26(4):345–350.
   PubMedGoogle Scholar
• Tack J, Pokrotnieks J, Urbonas G, et al. Long-term safety and efficacy of acotiamide in functional dyspepsia (postprandial distress syndrome)—results from the European phase 3 open-label safety trial. Neurogastroenterol Motility. 2018;30(6):e13284.
   PubMed Web of Science ®Google Scholar
• Shrestha DB, Budhathoki P, Subedi P, et al. Acotiamide and functional dyspepsia: a systematic review and meta-analysis. Cureus. 2021;13(12):e20532.
   PubMedGoogle Scholar
• Iwasaki H, Kajimura M, Osawa S, et al. A deficiency of gastric interstitial cells of Cajal accompanied by decreased expression of neuronal nitric oxide synthase and substance P in patients with type 2 diabetes mellitus. J Gastroenterol. 2006;41(11):1076–1087.
   PubMedGoogle Scholar
• Grover M, Bernard CE, Pasricha PJ, et al. Diabetic and idiopathic gastroparesis is associated with loss of CD206-positive macrophages in the gastric antrum. Neurogastroenterol Motil. 2017;29(6).
   PubMed Web of Science ®Google Scholar
• Grover M, Farrugia G, Lurken MS, et al. Cellular changes in diabetic and idiopathic gastroparesis. Gastroenterology. 2011;140(5):1575–1585e1578.
   PubMed Web of Science ®Google Scholar
• Herring BP, Hoggatt AM, Gupta A, et al. Idiopathic gastroparesis is associated with specific transcriptional changes in the gastric muscularis externa. Neurogastroenterol Motility. 2018;30(4):e13230.
   PubMedGoogle Scholar
• Herring BP, Hoggatt AM, Gupta A, et al. Gastroparesis is associated with decreased FOXF1 and FOXF2 in humans, and loss of FOXF1 and FOXF2 results in gastroparesis in mice. Neurogastroenterol Motility. 2019;31(3):e13528.
   PubMedGoogle Scholar
• Soota K, Kedar A, Nikitina Y, et al. Immunomodulation for treatment of drug and device refractory gastroparesis. Results Immunol. 2016;6:11–14.
   PubMedGoogle Scholar
• Flanagan EP, Saito YA, Lennon VA, et al. Immunotherapy trial as diagnostic test in evaluating patients with presumed autoimmune gastrointestinal dysmotility. Neurogastroenterol Motil. 2014;26(9):1285–1297.
   PubMed Web of Science ®Google Scholar
• Ashat M, Lewis A, Liaquat H, et al. Intravenous immunoglobulin in drug and device refractory patients with the symptoms of gastroparesis-an open-label study. Neurogastroenterol Motil. 2018;30:3.
   Google Scholar
• Gala K, Stocker A, Tu Y, et al. Baseline characteristics and predictive factors of intravenous immunoglobulin response in drug and device refractory gastroparesis symptoms. J Clin Gastroenterol. 2023 Feb 1;57(2):172–177.
   PubMedGoogle Scholar
• Choi KM, Gibbons SJ, Nguyen TV, et al. Heme oxygenase-1 protects interstitial cells of Cajal from oxidative stress and reverses diabetic gastroparesis. Gastroenterology. 2008;135(6):2055–2064, 2064.e2051–2052.
   Google Scholar
• Bernard CE, Gibbons SJ, Mann IS, et al. Association of low numbers of CD206-positive cells with loss of ICC in the gastric body of patients with diabetic gastroparesis. Neurogastroenterol Motil. 2014;26(9):1275–1284.
   PubMedGoogle Scholar
• Bharucha AE, Daley SL, Low PA, et al. Effects of hemin on heme oxygenase-1, gastric emptying, and symptoms in diabetic gastroparesis. Neurogastroenterol Motil. 2016;28(11):1731–1740.
   PubMedGoogle Scholar
• Acosta A, Camilleri M, Kolar G, et al. Relamorelin relieves constipation and accelerates colonic transit in a phase 2, placebo-controlled, randomized trial. Clin Gastroenterol Hepatol. 2015;13(13):2312–2319.e2311.
   PubMed Web of Science ®Google Scholar
• Pasha SF, Lunsford TN, Lennon VA. Autoimmune gastrointestinal dysmotility treated successfully with pyridostigmine. Gastroenterology. 2006;131(5):1592–1596.
   PubMed Web of Science ®Google Scholar
• Lembo A, Camilleri M, McCallum R, et al. Relamorelin reduces vomiting frequency and severity and accelerates gastric emptying in adults with diabetic gastroparesis. Gastroenterology. 2016;151(1):87–96.e86.
   PubMed Web of Science ®Google Scholar
• Altarifi AA, David B, Muchhala KH, et al. Effects of acute and repeated treatment with the biased mu opioid receptor agonist TRV130 (oliceridine) on measures of antinociception, gastrointestinal function, and abuse liability in rodents. J Psychopharmacol. 2017;31(6):730–739.
   PubMed Web of Science ®Google Scholar
• Singla NK, Skobieranda F, Soergel DG, et al. APOLLO-2: a randomized, placebo and active-controlled phase III study investigating oliceridine (TRV130), a G protein-biased ligand at the μ-opioid receptor, for management of moderate to severe Acute pain following abdominoplasty. Pain Pract. 2019;19(7):715–731.
   PubMed Web of Science ®Google Scholar
• Bergese SD, Brzezinski M, Hammer GB, et al. ATHENA: a phase 3, open-label study of the safety and effectiveness of oliceridine (TRV130), A G-protein selective agonist at the µ-opioid receptor, in patients with moderate to severe acute pain requiring parenteral opioid therapy. J Pain Res. 2019;12:3113–3126.
   PubMed Web of Science ®Google Scholar
• Castro J, Garcia-Caraballo S, Maddern J, et al. Olorinab (APD371), a peripherally acting, highly selective, full agonist of the cannabinoid receptor 2, reduces colitis-induced acute and chronic visceral hypersensitivity in rodents. Pain. 2022;163(1):e72–e86.
   PubMedGoogle Scholar
• Wouters MM, Balemans D, Van Wanrooy S, et al. Histamine receptor H1-mediated sensitization of TRPV1 mediates visceral hypersensitivity and symptoms in patients with irritable bowel syndrome. Gastroenterology. 2016;150(4):875–887.e879.
   PubMed Web of Science ®Google Scholar
• Schwetz I, McRoberts JA, Coutinho SV, et al. Corticotropin-releasing factor receptor 1 mediates acute and delayed stress-induced visceral hyperalgesia in maternally separated Long-Evans rats. Am J Physiol Gastrointest Liver Physiol. 2005;289(4):G704–G712.
   PubMedGoogle Scholar
• Barbash B, Mehta D, Siddiqui MT, et al. Impact of cannabinoids on symptoms of refractory gastroparesis: a single-center experience. Cureus. 2019;11(12):e6430.
   PubMedGoogle Scholar
• Lacy BE, Saito YA, Camilleri M, et al. Effects of antidepressants on gastric function in patients with functional dyspepsia. Am J Gastroenterol. 2018;113(2):216–224.
   PubMed Web of Science ®Google Scholar
• Liberski SM, Koch KL, Atnip RG, et al. Ischemic gastroparesis: resolution after revascularization. Gastroenterology. 1990;99(1):252–257.
   PubMedGoogle Scholar
• Koch KL, Stern RM, Stewart WR, et al. Gastric emptying and gastric myoelectrical activity in patients with diabetic gastroparesis: effect of long-term domperidone treatment. Am J Gastroenterol. 1989;84(9):1069–1075.
   PubMed Web of Science ®Google Scholar
• Jonderko K, Kwiecień J, Kasicka-Jonderko A, et al. The effect of drugs and stimulants on gastric myoelectrical activity. Prz Gastroenterol. 2014;9(3):130–135.
   PubMedGoogle Scholar
• Acosta A, Camilleri M. Elobixibat and its potential role in chronic idiopathic constipation. Therap Adv Gastroenterol. 2014;7(4):167–175.
   PubMed Web of Science ®Google Scholar
• Chiang JYL, Ferrell JM. Up to date on cholesterol 7 alpha-hydroxylase (CYP7A1) in bile acid synthesis. Liver Res. 2020;4(2):47–63.
   PubMedGoogle Scholar
• Wong BS, Camilleri M, McKinzie S, et al. Effects of A3309, an ileal bile acid transporter inhibitor, on colonic transit and symptoms in females with functional constipation. Am J Gastroenterol. 2011;106(12):2154–2164.
   PubMed Web of Science ®Google Scholar
• Chey WD, Camilleri M, Chang L, et al. A randomized placebo-controlled phase IIb trial of a3309, a bile acid transporter inhibitor, for chronic idiopathic constipation. Am J Gastroenterol. 2011;106(10):1803–1812.
   PubMed Web of Science ®Google Scholar
• Walters JRF, Johnston IM, Nolan JD, et al. The response of patients with bile acid diarrhoea to the farnesoid X receptor agonist obeticholic acid. Aliment Pharmacol Ther. 2014;41(1):54–64.
   PubMedGoogle Scholar
• Camilleri M, Nord SL, Burton D, et al. Randomised clinical trial: significant biochemical and colonic transit effects of the farnesoid X receptor agonist tropifexor in patients with primary bile acid diarrhoea. Aliment Pharmacol Ther. 2020;52(5):808–820.
   PubMed Web of Science ®Google Scholar
• Lete I, Allué J. The effectiveness of ginger in the prevention of nausea and vomiting during pregnancy and chemotherapy. Integr Med Insights. 2016;11:11–17.
   PubMedGoogle Scholar
• Lazzini S, Polinelli W, Riva A, et al. The effect of ginger (Zingiber officinalis) and artichoke (Cynara cardunculus) extract supplementation on gastric motility: a pilot randomized study in healthy volunteers. Eur Rev Med Pharmacol Sci. 2016;20(1):146–149.
   PubMed Web of Science ®Google Scholar
• Giacosa A, Guido D, Grassi M, et al. The effect of ginger (Zingiber officinalis) and artichoke (Cynara cardunculus) extract supplementation on functional dyspepsia: a randomised, double-blind, and placebo-controlled clinical trial. Evid Based Complement Alternat Med. 2015;2015:915087.
   PubMedGoogle Scholar
• Hu ML, Rayner CK, Wu KL, et al. Effect of ginger on gastric motility and symptoms of functional dyspepsia. World J Gastroenterol. 2011;17(1):105–110.
   PubMed Web of Science ®Google Scholar
• Viljoen E, Visser J, Koen N, et al. A systematic review and meta-analysis of the effect and safety of ginger in the treatment of pregnancy-associated nausea and vomiting. Nutr J. 2014;13:20.
   PubMed Web of Science ®Google Scholar
• Firouzbakht M, Nikpour M, Jamali B, et al. Comparison of ginger with vitamin B6 in relieving nausea and vomiting during pregnancy. Ayu. 2014;35(3):289–293.
   PubMedGoogle Scholar
• Chittumma P, Kaewkiattikun K, Wiriyasiriwach B. Comparison of the effectiveness of ginger and vitamin B6 for treatment of nausea and vomiting in early pregnancy: a randomized double-blind controlled trial. J Med Assoc Thai. 2007;90(1):15–20.
   PubMedGoogle Scholar
• Pakniat H, Lalooha F, Movahed F, et al. The effect of ginger and metoclopramide in the prevention of nausea and vomiting during and after surgery in cesarean section under spinal anesthesia. Obstet Gynecol Sci. 2020;63(2):173–180.
   PubMedGoogle Scholar
• Mohammadbeigi R, Shahgeibi S, Soufizadeh N, et al. Comparing the effects of ginger and metoclopramide on the treatment of pregnancy nausea. Pak J Biol Sci. 2011;14(16):817–820.
   PubMedGoogle Scholar
• Unuofin JO, Masuku NP, Paimo OK, et al. Ginger from farmyard to town: nutritional and pharmacological applications. Front Pharmacol. 2021;12:779352.
   PubMedGoogle Scholar
• Kamali A, Beigi S, Shokrpour M, et al. The efficacy of ginger and doxedetomidine in reducing postoperative nausea and vomiting in patients undergoing abdominal hysterectomy. Altern Ther Health Med. 2020;26(2):28–33.
   PubMedGoogle Scholar
• Fitriyanti D, Sulung R. Effectiveness of ginger to overcome nausea and vomiting caused by chemotherapy in breast cancer patients. Can Oncol Nurs J. 2020;30(1):3–5.
   PubMedGoogle Scholar
• Melzer J, Iten F, Reichling J, et al. Iberis amara L. and Iberogast–results of a systematic review concerning functional dyspepsia. J Herb Pharmacother. 2004;4(4):51–59.
   PubMedGoogle Scholar
• Saller R, Pfister-Hotz G, Iten F, et al. Iberogast(r): eine moderne phytotherapeutische Arzneimittelkombination zur Behandlung funktioneller Erkrankungen des Magen-Darm-Trakts (Dyspepsie, Colon irritabile) – von der Pflanzenheilkunde zur «Evidence Based Phytotherapy».Eine systematische Übersicht. Complement Med Res. 2002;9(suppl1):1–20.
   Google Scholar
• Melzer J, Rösch W, Reichling J, et al. Meta-analysis: phytotherapy of functional dyspepsia with the herbal drug preparation STW 5 (Iberogast). Aliment Pharmacol Ther. 2004;20(11–12):1279–1287.
   PubMed Web of Science ®Google Scholar
• Rösch W, Vinson B, Sassin I. A randomised clinical trial comparing the efficacy of a herbal preparation STW 5 with the prokinetic drug cisapride in patients with dysmotility type of functional dyspepsia. Z Gastroenterol. 2002;40(6):401–408.
   PubMed Web of Science ®Google Scholar
• Braden B, Caspary W, Börner N, et al. Clinical effects of STW 5 (Iberogast®) are not based on acceleration of gastric emptying in patients with functional dyspepsia and gastroparesis. Neurogastroenterol Motility. 2009;21(6):632–e625.
   PubMed Web of Science ®Google Scholar
• Goerg KJ, Spilker T. Effect of peppermint oil and caraway oil on gastrointestinal motility in healthy volunteers: a pharmacodynamic study using simultaneous determination of gastric and gall-bladder emptying and orocaecal transit time. Aliment Pharmacol Ther. 2003;17(3):445–451.
   PubMed Web of Science ®Google Scholar
• Papathanasopoulos A, Rotondo A, Janssen P, et al. Effect of acute peppermint oil administration on gastric sensorimotor function and nutrient tolerance in health. Neurogastroenterol Motility. 2013;25(4):e263–e271.
   PubMed Web of Science ®Google Scholar
• Xiong G, Liu H, Li W, et al. Spray of peppermint oil on papilla shortens the cannulation time of endoscopic retrograde cholangiopancreatography (ERCP): a randomized study. Int J Clin Exp Med. 2019;12:3.
   Google Scholar
• Yamamoto N, Nakai Y, Sasahira N, et al. Efficacy of peppermint oil as an antispasmodic during endoscopic retrograde cholangiopancreatography. J Gastroenterol Hepatol. 2006;21(9):1394–1398.
   PubMed Web of Science ®Google Scholar
• You Q, Li L, Chen H, et al. L-menthol for gastrointestinal endoscopy: a systematic review and meta-analysis. Clin Transl Gastroenterol. 2020;11(10):e00252.
   PubMedGoogle Scholar
• Rich G, Shah A, Koloski N, et al. A randomized placebo-controlled trial on the effects of Menthacarin, a proprietary peppermint- and caraway-oil-preparation, on symptoms and quality of life in patients with functional dyspepsia. Neurogastroenterol Motility. 2017;29(11):e13132.
   Web of Science ®Google Scholar
• May B, Köhler S, Schneider B. Efficacy and tolerability of a fixed combination of peppermint oil and caraway oil in patients suffering from functional dyspepsia. Aliment Pharmacol Ther. 2000;14(12):1671–1677.
   PubMed Web of Science ®Google Scholar
• Chey WD, Lacy BE, Cash BD, et al. A novel, duodenal-release formulation of a combination of caraway oil and l-menthol for the treatment of functional dyspepsia: a randomized controlled trial. Clin Transl Gastroenterol. 2019;10(4):e00021.
   PubMedGoogle Scholar
• Li J, Lv L, Zhang J, et al. A combination of peppermint oil and caraway oil for the treatment of functional dyspepsia: a systematic review and meta-analysis. Evid Based Complement Alternat Med. 2019;2019:7654947.
   PubMedGoogle Scholar
• Yang M, Li X, Liu S, et al. Meta-analysis of acupuncture for relieving non-organic dyspeptic symptoms suggestive of diabetic gastroparesis. BMC Complement Altern Med. 2013;13(1):311.
   PubMedGoogle Scholar
• Ho RST, Chung VCH, Wong CHL, et al. Acupuncture and related therapies used as add-on or alternative to prokinetics for functional dyspepsia: overview of systematic reviews and network meta-analysis. Sci Rep. 2017;7(1):10320.
   PubMedGoogle Scholar
• Li G, Huang C, Zhang X, et al. The short-term effects of acupuncture on patients with diabetic gastroparesis: a randomised crossover study. Acupuncture Med. 2015;33(3):204–209.
   PubMedGoogle Scholar
• Sun B-M, Luo M, Wu S-B, et al. Acupuncture versus metoclopramide in treatment of postoperative gastroparesis syndrome in abdominal surgical patients: a randomized controlled trial. Zhong Xi Yi Jie He Xue Bao. 2010;8(7):641–644.
   PubMedGoogle Scholar
• Cheong KB, Zhang J-p HY. The effectiveness of acupuncture in postoperative gastroparesis syndrome – a systematic review and meta-analysis. Complement Ther Med. 2014;22(4):767–786.
   PubMedGoogle Scholar
• Marathe CS, Rayner CK, Jones KL, et al. Relationships between gastric emptying, postprandial glycemia, and incretin hormones. Diabetes Care. 2013;36(5):1396–1405.
   PubMed Web of Science ®Google Scholar
• Linnebjerg H, Park S, Kothare PA, et al. Effect of exenatide on gastric emptying and relationship to postprandial glycemia in type 2 diabetes. Regul Pept. 2008;151(1):123–129.
   PubMedGoogle Scholar
• Nakatani Y, Maeda M, Matsumura M, et al. Effect of GLP-1 receptor agonist on gastrointestinal tract motility and residue rates as evaluated by capsule endoscopy. Diabetes Metab. 2017;43(5):430–437.
   PubMedGoogle Scholar
• Suganuma Y, Shimizu T, Sato T, et al. Magnitude of slowing gastric emptying by glucagon-like peptide-1 receptor agonists determines the amelioration of postprandial glucose excursion in Japanese patients with type 2 diabetes. J Diabetes Investig. 2020;11(2):389–399.
   PubMedGoogle Scholar
• Jonderko G, Jonderko K, Gołab T. Effect of glucagon on gastric emptying and on postprandial gastrin and insulin release in man. Mater Med Pol. 1989;21(2):92–96.
   PubMedGoogle Scholar
• Patel GK, Whalen GE, Soergel KH, et al. Glucagon effects on the human small intestine. Dig Dis Sci. 1979;24(7):501–508.
   PubMedGoogle Scholar
• Abell TL, Malagelada JRM. Glucagon evoked gastric dysrhythmias in healthy humans demonstrated by an improved electrogastrographic method. Gastroenterology. 1984;86:1011.
   PubMedGoogle Scholar
• Taylor I, Duthie HL, Cumberland DC, et al. Glucagon and the colon. Gut. 1975;16(12):973–978.
   PubMedGoogle Scholar
• Abell TL, Kedar A, Stocker A, et al. Gastroparesis syndromes: response to electrical stimulation. Neurogastroenterol Motil. 2019;31(3):e13534.
   PubMedGoogle Scholar
• Reigstad CS, Salmonson CE, Rainey JF 3rd, et al. Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. Faseb J. 2015;29(4):1395–1403.
   PubMed Web of Science ®Google Scholar
• Bhattarai Y, Williams BB, Battaglioli EJ, et al. Gut microbiota-produced tryptamine activates an epithelial g-protein-coupled receptor to increase colonic secretion. Cell Host Microbe. 2018;23(6):775–785.e775.
   PubMedGoogle Scholar
• Hasler WL, Wilson LA, Parkman HP, et al. Bloating in gastroparesis: severity, impact, and associated factors. Am J Gastroenterol. 2011;106(8):1492–1502.
   PubMedGoogle Scholar
• Chandrasekharan B, Saeedi BJ, Alam A, et al. Interactions between commensal bacteria and enteric neurons, via FPR1 induction of ROS, increase gastrointestinal motility in mice. Gastroenterology. 2019;157(1):179–192.e172.
   PubMedGoogle Scholar
• Xu D, Gao J, Gillilland M 3rd, et al. Rifaximin alters intestinal bacteria and prevents stress-induced gut inflammation and visceral hyperalgesia in rats. Gastroenterology. 2014;146(2):484–496.e484.
   PubMed Web of Science ®Google Scholar
• Lovino P, Bucci C, Tremolaterra F, et al. Bloating and functional gastro-intestinal disorders: where are we and where are we going? World J Gastroenterol. 2014;20(39):14407–14419.
   PubMedGoogle Scholar
• Feuerstadt P, Louie TJ, Lashner B, et al. SER-109, an oral microbiome therapy for recurrent clostridioides difficile infection. N Engl J Med. 2022;386(3):220–229.
   PubMed Web of Science ®Google Scholar
• Gatarek P, Trimethylamine N-oxide K-CJ. (TMAO) in human health. Excli J. 2021;20:301–319.
   PubMedGoogle Scholar
• Chou R-H, Chen C-Y, Chen IC, et al. Trimethylamine N-oxide, circulating endothelial progenitor cells, and endothelial function in patients with stable angina. Sci Rep. 2019;9(1):4249.
   PubMed Web of Science ®Google Scholar
• Yang S, Li X, Yang F, et al. Gut microbiota-dependent marker TMAO in promoting cardiovascular disease: inflammation mechanism, clinical prognostic, and potential as a therapeutic target. Front Pharmacol. 2019;10:1360.
   PubMed Web of Science ®Google Scholar
• Janeiro MH, Ramírez MJ, Milagro FI, et al. Implication of Trimethylamine N-Oxide (TMAO) in disease: potential biomarker or new therapeutic target. Nutrients. 2018;10:10.
   Google Scholar
• Kim CH, Hanson RB, Abell TL, et al. Effect of inhibition of prostaglandin synthesis on epinephrine-induced gastroduodenal electromechanical changes in humans. Mayo Clin Proc. 1989;64(2):149–157.
   PubMedGoogle Scholar
• Mishra S. Electroceuticals in medicine – the brave new future. Indian Heart J. 2017;69(5):685–686.
   PubMedGoogle Scholar
• Payne SC, Furness JB, Stebbing MJ. Bioelectric neuromodulation for gastrointestinal disorders: effectiveness and mechanisms. Nat Clin Pract Gastroenterol Hepatol. 2019;16(2):89–105.
   Google Scholar
• Abell TL, Yamada G, McCallum RW, et al. Effectiveness of gastric electrical stimulation in gastroparesis: results from a large prospectively collected database of national gastroparesis registries. Neurogastroenterol Motil. 2019;31(12):e13714.
   PubMed Web of Science ®Google Scholar
• Abell TL, Johnson WD, Kedar A, et al. A double-masked, randomized, placebo-controlled trial of temporary endoscopic mucosal gastric electrical stimulation for gastroparesis. Gastrointest Endosc. 2011;74(3):496–503.e493.
   PubMedGoogle Scholar
• Liu X, Steiger C, Lin S, et al. Ingestible hydrogel device. Nat Commun. 2019;10(1):493.
   PubMedGoogle Scholar
• Karamanolis G, Caenepeel P, Arts J, et al. Determinants of symptom pattern in idiopathic severely delayed gastric emptying: gastric emptying rate or proximal stomach dysfunction? Gut. 2007;56(1):29–36.
   PubMed Web of Science ®Google Scholar
• Khayyam U, Sachdeva P, Gomez J, et al. Assessment of symptoms during gastric emptying scintigraphy to correlate symptoms to delayed gastric emptying. Neurogastroenterol Motil. 2010;22(5):539–545.
   PubMed Web of Science ®Google Scholar