Chemical Composition of Refluxate

  • Iain A. BrownleeEmail author


The reflux of gastric contents into the aerodigestive tract has been linked to a variety of oesophageal, oral, airways and respiratory diseases. The composition of refluxate is not merely secreted gastric juice and instead represents a complex mixture of gastrointestinal secretions and exogenous factors. Within the stomach, gastric juice mixes with proximal (saliva) and distal (pancreatic juice, bile) gastrointestinal secretions. New microbes enter the stomach via ingested food, saliva and other aerodigestive secretions and join the gastric microbial community. Ingestion of food may itself drive a number of physiological actions that are linked to the occurrence of reflux.

Digestive enzymes, acid and bile may cause direct damage to the unprotected mucosal tissues of the aerodigestive tract. Further from this, the processes of digestion within the stomach may release new antigen that have the potential to cause an immunological response. The gastric microbiome is largely similar to that of the aerodigestive tract, so its role in damage as a result of reflux is unclear. The complex interplay between all of the above factors is not currently well understood, although is likely to play a role both in the damaging potential of refluxate as well as the frequency and volume of reflux events.


  1. 1.
    Shafik A, El Sibai O, Shafik AA, Shafik IA. Mechanism of gastric emptying through the pyloric sphincter: a human study. Med Sci Monit. 2007;13(1):CR24–CR9.PubMedGoogle Scholar
  2. 2.
    Kidd M, Hauso Ø, Drozdov I, Gustafsson BI, Modlin IM. Delineation of the chemomechanosensory regulation of gastrin secretion using pure rodent G cells. Gastroenterology. 2009;137(1):231–41.e10.CrossRefPubMedGoogle Scholar
  3. 3.
    Lee CS, Perreault N, Brestelli JE, Kaestner KH. Neurogenin 3 is essential for the proper specification of gastric enteroendocrine cells and the maintenance of gastric epithelial cell identity. Genes Dev. 2002;16(12):1488–97. Scholar
  4. 4.
    Allen A, Flemström G. Gastroduodenal mucus bicarbonate barrier: protection against acid and pepsin. Am J Physiol Cell Physiol. 2005;288(1):C1–C19.CrossRefPubMedGoogle Scholar
  5. 5.
    Barker N, Huch M, Kujala P, van de Wetering M, Snippert HJ, van Es JH, et al. Lgr5+ve stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell. 2010;6(1):25–36. Scholar
  6. 6.
    Mills JC, Shivdasani RA. Gastric epithelial stem cells. Gastroenterology. 2011;140(2):412–24. Scholar
  7. 7.
    Barker N, Van Oudenaarden A, Clevers H. Identifying the stem cell of the intestinal crypt: strategies and pitfalls. Cell Stem Cell. 2012;11(4):452–60. Scholar
  8. 8.
    Pearson JP, Parikh S, Robertson AGN, Stovold R, Brownlee IA. Pepsins. In: Johnston N, Toohill RJ, editors. Effects, diagnosis and management of extra-esophageal reflux. New York: Nova Science Publishers; 2012. p. 29–41.Google Scholar
  9. 9.
    Howell MD, Novack V, Grgurich P, Soulliard D, Novack L, Pencina M, et al. Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Arch Intern Med. 2010;170(9):784–90.CrossRefPubMedGoogle Scholar
  10. 10.
    Lombardo L, Foti M, Ruggia O, Chiecchio A. Increased incidence of small intestinal bacterial overgrowth during proton pump inhibitor therapy. Clin Gastroenterol Hepatol. 2010;8(6):504–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Van Pinxteren B, Numans ME, Lau J, De Wit NJ, Hungin APS, Bonis PAL. Short-term treatment of gastroesophageal reflux disease: a systematic review and meta-analysis of the effect of acid-suppressant drugs in empirical treatment and in endoscopy-negative patients. J Gen Intern Med. 2003;18(9):755–63. Scholar
  12. 12.
    Ali T, Roberts DN, Tierney WM. Long-term safety concerns with proton pump inhibitors. Am J Med. 2009;122(10):896–903. Scholar
  13. 13.
    Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease (Gerd): a clinical investigation of 225 patients using ambulatory 24-hour pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury. Laryngoscope. 1991;101(4):1–78.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Bulmer DM, Ali MS, Brownlee IA, Dettmar PW, Pearson JP. Laryngeal mucosa: its susceptibility to damage by acid and pepsin. Laryngoscope. 2010;120(4):777–82. Scholar
  15. 15.
    Johnston N, Dettmar PW, Bishwokarma B, Lively MO, Koufman JA. Activity/stability of human pepsin: implications for reflux attributed laryngeal disease. Laryngoscope. 2007;117(6):1036–9. Scholar
  16. 16.
    Johnston N, Yan JC, Hoekzema CR, Samuels TL, Stoner GD, Blumin JH, et al. Pepsin promotes proliferation of laryngeal and pharyngeal epithelial cells. Laryngoscope. 2012;122(6):1317–25.CrossRefPubMedGoogle Scholar
  17. 17.
    Kelly EA, Samuels TL, Johnston N. Chronic pepsin exposure promotes anchorage-independent growth and migration of a hypopharyngeal squamous cell line. Otolaryngol Head Neck Surg. 2014;150(4):618–24. Scholar
  18. 18.
    Harada S, Tanaka S, Takahashi Y, Matsumura H, Shimamoto C, Nakano T, et al. Inhibition of Ca2+-regulated exocytosis by levetiracetam, a ligand for SV2A, in antral mucous cells of guinea pigs. Eur J Pharmacol. 2013;721(1–3):185–92.CrossRefPubMedGoogle Scholar
  19. 19.
    Phillipson M, Johansson MEV, Henriksnäs J, Petersson J, Gendler SJ, Sandler S, et al. The gastric mucus layers: constituents and regulation of accumulation. Am J Physiol Gastrointest Liver Physiol. 2008;295(4):G806–G12.CrossRefPubMedGoogle Scholar
  20. 20.
    Younan F, Pearson J, Allen A, Venables C. Changes in the structure of the mucous gel on the mucosal surface of the stomach in association with peptic ulcer disease. Gastroenterology. 1982;82(5 Pt 1):827–31.PubMedGoogle Scholar
  21. 21.
    Goudra BG, Singh PM, Carlin A, Manjunath AK, Reihmer J, Gouda GB, et al. Effect of gum chewing on the volume and pH of gastric contents: a prospective randomized study. Dig Dis Sci. 2015;60(4):979–83. Scholar
  22. 22.
    Hirschowitz BI. Gastric acid and pepsin secretion in patients with Barrett’s esophagus and appropriate controls. Dig Dis Sci. 1996;41(7):1384–91. Scholar
  23. 23.
    Janssen P, Vanden Berghe P, Verschueren S, Lehmann A, Depoortere I, Tack J. Review article: the role of gastric motility in the control of food intake. Aliment Pharmacol Ther. 2011;33(8):880–94.CrossRefPubMedGoogle Scholar
  24. 24.
    Beaumont H, Bennink RJ, De Jong J, Boeckxstaens GE. The position of the acid pocket as a major risk factor for acidic reflux in healthy subjects and patients with GORD. Gut. 2010;59(4):441–51. Scholar
  25. 25.
    Brownlee IA. The impact of dietary fibre intake on the physiology and health of the stomach and upper gastrointestinal tract. Bioact Carbohydr Diet Fibre. 2014;4(2):155–69. Scholar
  26. 26.
    Schubert ML, Peura DA. Control of gastric acid secretion in health and disease. Gastroenterology. 2008;134(7):1842–60.CrossRefPubMedGoogle Scholar
  27. 27.
    Isackson H, Ashley CC. Secretory functions of the gastrointestinal tract. Surgery (United Kingdom). 2014;32(8):396–403.Google Scholar
  28. 28.
    Brownlee IA. The physiological roles of dietary fibre. Food Hydrocoll. 2011;25(2):238–50.CrossRefGoogle Scholar
  29. 29.
    Saqui-Salces M, Dowdle WE, Reiter JF, Merchant JL. A high-fat diet regulates gastrin and acid secretion through primary cilia. FASEB J. 2012;26(8):3127–39.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Torii K, Uneyama H, Nakamura E. Physiological roles of dietary glutamate signaling via gut-brain axis due to efficient digestion and absorption. J Gastroenterol. 2013;48(4):442–51.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Fiorucci S, Distrutti E, Federici B, Palazzetti B, Baldoni M, Morelli A, et al. PAR-2 modulates pepsinogen secretion from gastric-isolated chief cells. Am J Physiol Gastrointest Liver Physiol. 2003;285(3):G611–G20.CrossRefPubMedGoogle Scholar
  32. 32.
    Lopetuso LR, Scaldaferri F, Franceschi F, Gasbarrini A. The gastrointestinal microbiome - functional interference between stomach and intestine. Best Pract Res Clin Gastroenterol. 2014;28(6):995–1002. Scholar
  33. 33.
    Bassis CM, Erb-Downward JR, Dickson RP, Freeman CM, Schmidt TM, Young VB, et al. Analysis of the upper respiratory tract microbiotas as the source of the lung and gastric microbiotas in healthy individuals. mBio. 2015;6(2):e00037-15. Scholar
  34. 34.
    Wang ZK, Yang YS. Upper gastrointestinal microbiota and digestive diseases. World J Gastroenterol. 2013;19(10):1541–50. Scholar
  35. 35.
    Deng B, Li Y, Zhang Y, Bai L, Yang P. Helicobacter pylori infection and lung cancer: a review of an emerging hypothesis. Carcinogenesis. 2013;34(6):1189–95. Scholar
  36. 36.
    Scarpellini E, Ianiro G, Attili F, Bassanelli C, De Santis A, Gasbarrini A. The human gut microbiota and virome: potential therapeutic implications. Dig Liver Dis. 2015;47(12):1007–12. Scholar
  37. 37.
    Gong YB, Zheng JL, Jin B, Zhuo DX, Huang ZQ, Qi H, et al. Particular Candida albicans strains in the digestive tract of dyspeptic patients, identified by multilocus sequence typing. PLoS One. 2012;7(4):e35311. Scholar
  38. 38.
    Lundberg JO, Weitzberg E, Gladwin MT. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov. 2008;7(2):156–67. Scholar
  39. 39.
    Kessing BF, Conchillo JM, Bredenoord AJ, Smout AJPM, Masclee AAM. Review article: the clinical relevance of transient lower oesophageal sphincter relaxations in gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2011;33(6):650–61. Scholar
  40. 40.
    Seenan JP, Wirz AA, Robertson EV, Clarke AT, Manning JJ, Kelman AW, et al. Effect of nitrite delivered in saliva on postprandial gastro-esophageal function. Scand J Gastroenterol. 2012;47(4):387–96. Scholar
  41. 41.
    Piche T, Zerbib F, Bruley Des Varannes S, Cherbut C, Anini Y, Roze C, et al. Modulation by colonic fermentation of LES function in humans. Am J Physiol Gastrointest Liver Physiol. 2000;278(4):G578–G84.CrossRefPubMedGoogle Scholar
  42. 42.
    Fuchs KH, Maroske J, Fein M, Tigges H, Ritter MP, Heimbucher J, et al. Variability in the composition of physiologic duodenogastric reflux. J Gastrointest Surg. 1999;3(4):389–96.CrossRefPubMedGoogle Scholar
  43. 43.
    D’Ovidio F, Mura M, Ridsdale R, Takahashi H, Waddell TK, Hutcheon M, et al. The effect of reflux and bile acid aspiration on the lung allograft and its surfactant and innate immunity molecules SP-A and SP-D. Am J Transplant. 2006;6(8):1930–8. Scholar
  44. 44.
    Koufman JA. Low-acid diet for recalcitrant laryngopharyngeal reflux: therapeutic benefits and their implications. Ann Otol Rhinol Laryngol. 2011;120(5):281–7.CrossRefPubMedGoogle Scholar
  45. 45.
    Singh M, Lee J, Gupta N, Gaddam S, Smith BK, Wani SB, et al. Weight loss can lead to resolution of gastroesophageal reflux disease symptoms: a prospective intervention trial. Obesity. 2013;21(2):284–90. Scholar
  46. 46.
    Smith JE, Morjaria JB, Morice AH. Dietary intervention in the treatment of patients with cough and symptoms suggestive of airways reflux as determined by hull airways reflux questionnaire. Cough. 2013;9(1):27. Scholar
  47. 47.
    Kaltenbach T, Crockett S, Gerson LB. Are lifestyle measures effective in patients with gastroesophageal reflux disease? An evidence-based approach. Arch Intern Med. 2006;166(9):965–71.CrossRefPubMedGoogle Scholar
  48. 48.
    Kubo A, Block G, Quesenberry CP, Buffler P, Corley DA. Dietary guideline adherence for gastroesophageal reflux disease. BMC Gastroenterol. 2014;14(1):144. Scholar
  49. 49.
    Kristal AR, Blount PL, Schenk JM, Sanchez CA, Rabinovitch PS, Odze RD, et al. Low-fat, high fruit and vegetable diets and weight loss do not affect biomarkers of cellular proliferation in Barrett esophagus. Cancer Epidemiol Biomarkers Prev. 2005;14(10):2377–83. Scholar
  50. 50.
    Corvaglia L, Aceti A, Mariani E, Legnani E, Ferlini M, Raffaeli G, et al. Lack of efficacy of a starch-thickened preterm formula on gastro-oesophageal reflux in preterm infants: a pilot study. J Matern Fetal Neonatal Med. 2012;25(12):2735–8. Scholar
  51. 51.
    Xinias I, Mouane N, Le Luyer B, Spiroglou K, Demertzidou V, Hauser B, et al. Cornstarch thickened formula reduces oesophageal acid exposure time in infants. Dig Liver Dis. 2005;37(1):23–7. Scholar
  52. 52.
    Delgado-Aros S, Camilleri M, Cremonini F, Ferber I, Stephens D, Burton DD. Contributions of gastric volumes and gastric emptying to meal size and postmeal symptoms in functional dyspepsia. Gastroenterology. 2004;127(6):1685–94. Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Newcastle Research and Innovation InstituteNewcastle UniversitySingaporeSingapore

Personalised recommendations