Duodenal Chemosensing of Short-Chain Fatty Acids: Implications for GI Diseases

  • Mari Iwasaki
  • Yasutada Akiba
  • Jonathan D. KaunitzEmail author
Stomach and Duodenum (J Pisegna and J Benhammou, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Stomach and Duodenum


Purpose of Review

Short-chain fatty acids (SCFAs), the main bacterial fermentation products in the hindgut of hindgut fermenters, are also present in the foregut lumen. We discuss the impact of SCFAs in the duodenal defense mechanisms and in the gastrointestinal (GI) pathogenesis.

Recent Findings

Luminal SCFAs augment the duodenal mucosal defenses via release of serotonin (5-HT) and glucagon-like peptide-2 (GLP-2) from enteroendocrine cells. Released GLP-2 protects the small intestinal mucosa from nonsteroidal anti-inflammatory drug-induced enteropathy. SCFAs are also rapidly absorbed via SCFA transporters and interact with afferent and myenteric nerves. Excessive SCFA signals with 5-HT3 receptor overactivation may be implicated in the pathogenesis of irritable bowel syndrome symptoms. SCFA production exhibits diurnal rhythms with host physiological responses, suggesting that oral SCFA treatment may adjust the GI clocks.


SCFAs are not only a source of energy but also signaling molecules for the local regulation of the GI tract and systemic regulation via release of gut hormones. Targeting SCFA signals may be a novel therapeutic for GI diseases and metabolic syndrome.


Short-chain fatty acid receptors Glucagon-like peptide-2 Serotonin Mucosal defense Nutrition sensing 


Funding Information

This work was supported by a Department of Veterans Affairs Merit Review Award and National Institute of Diabetes and Digestive and Kidney Diseases Grant R01-DK-54221.

Compliance With Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, Tcheang L, Daniels D, et al. The orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem. 2003;278:11312–9.CrossRefGoogle Scholar
  2. 2.
    • Kaji I, Iwanaga T, Watanabe M, Guth PH, Engel E, Kaunitz JD, et al. SCFA transport in rat duodenum. Am J Physiol Gastrointest Liver Physiol. 2015;308:G188–97 This study provides the evidence of rapid, electrogenic SCFA absorption via apical SMCT-1 in the duodenal mucosa.CrossRefGoogle Scholar
  3. 3.
    Hoverstad T, Bjorneklett A, Midtvedt T, Fausa O, Bohmer T. Short-chain fatty acids in the proximal gastrointestinal tract of healthy subjects. Scand J Gastroenterol. 1984;19:1053–8.CrossRefGoogle Scholar
  4. 4.
    Botta GA, Radin L, Costa A, Schito G, Blasi G. Gas-liquid chromatography of the gingival fluid as an aid in periodontal diagnosis. J Periodontal Res. 1985;20:450–7.CrossRefGoogle Scholar
  5. 5.
    Iwanaga T, Kishimoto A. Cellular distributions of monocarboxylate transporters: a review. Biomed Res. 2015;36:279–301.CrossRefGoogle Scholar
  6. 6.
    •• Akiba Y, Inoue T, Kaji I, Higashiyama M, Narimatsu K, Iwamoto K, et al. Short-chain fatty acid sensing in rat duodenum. J Physiol. 2015;593:585–99 This study provides for the first time that luminal SCFAs stimulate duodenal mucosa to enhance mucosal defense via distinct 5-HT and GLP-2 pathways via SCFA receptors.CrossRefGoogle Scholar
  7. 7.
    •• Akiba Y, Maruta K, Narimatsu K, Said H, Kaji I, Kuri A, et al. FFA2 activation combined with ulcerogenic COX inhibition induces duodenal mucosal injury via the 5-HT pathway in rats. Am J Physiol Gastrointest Liver Physiol. 2017;313:G117–28 This study links 5-HT release via FFA2 activation to duodenal mucosal injury with indomethacin treatment, implicating in 5-HT-related IBS symptom generation.CrossRefGoogle Scholar
  8. 8.
    Said H, Akiba Y, Narimatsu K, Maruta K, Kuri A, Iwamoto K, et al. FFA3 activation stimulates duodenal bicarbonate secretion and prevents NSAID-induced enteropathy via the GLP-2 pathway in rats. Dig Dis Sci. 2017;62:1944–52.CrossRefGoogle Scholar
  9. 9.
    Illman RJ, Topping DL, Trimble RP. Effects of food restriction and starvation-refeeding on volatile fatty acid concentrations in the rat. J Nutr. 1986;116:1694–700.CrossRefGoogle Scholar
  10. 10.
    Cummings JH, Pomare EW, Branch WJ, Naylor CP, Macfarlane GT. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut. 1987;28:1221–7.CrossRefGoogle Scholar
  11. 11.
    Bergman EN. Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Physiol Rev. 1990;70:567–90.CrossRefGoogle Scholar
  12. 12.
    Skutches CL, Holroyde CP, Myers RN, Paul P, Reichard GA. Plasma acetate turnover and oxidation. J Clin Invest. 1979;64:708–13.CrossRefGoogle Scholar
  13. 13.
    Ostman E, Granfeldt Y, Persson L, Bjorck I. Vinegar supplementation lowers glucose and insulin responses and increases satiety after a bread meal in healthy subjects. Eur J Clin Nutr. 2005;59:983–8.CrossRefGoogle Scholar
  14. 14.
    Brighenti F, Castellani G, Benini L, Casiraghi MC, Leopardi E, Crovetti R, et al. Effect of neutralized and native vinegar on blood glucose and acetate responses to a mixed meal in healthy subjects. Eur J Clin Nutr. 1995;49:242–7.PubMedGoogle Scholar
  15. 15.
    Ruppin H, Bar-Meir S, Soergel KH, Wood CM, Schmitt MG Jr. Absorption of short-chain fatty acids by the colon. Gastroenterology. 1980;78:1500–7.CrossRefGoogle Scholar
  16. 16.
    Braden B, Adams S, Duan LP, Orth KH, Maul FD, Lembcke B, et al. The [13C]acetate breath test accurately reflects gastric emptying of liquids in both liquid and semisolid test meals. Gastroenterology. 1995;108:1048–55.CrossRefGoogle Scholar
  17. 17.
    Sjölund K, Sandén G, Håkanson R, Sundler F. Endocrine cells in human intestine: an immunocytochemical study. Gastroenterology. 1983;85:1120–30.PubMedGoogle Scholar
  18. 18.
    Akiba Y, Kaunitz JD. Duodenal luminal chemosensing; acid, ATP, and nutrients. Curr Pharm Des. 2014;20:2760–5.CrossRefGoogle Scholar
  19. 19.
    Akiba Y, Guth PH, Engel E, Nastaskin I, Kaunitz JD. Acid-sensing pathways of rat duodenum. Am J Physiol Gastrointest Liver Physiol. 1999;277:G268–74.CrossRefGoogle Scholar
  20. 20.
    Akiba Y, Ghayouri S, Takeuchi T, Mizumori M, Guth PH, Engel E, et al. Carbonic anhydrases and mucosal vanilloid receptors help mediate the hyperemic response to luminal CO2 in rat duodenum. Gastroenterology. 2006;131:142–52.CrossRefGoogle Scholar
  21. 21.
    Mizumori M, Ham M, Guth PH, Engel E, Kaunitz JD, Akiba Y. Intestinal alkaline phosphatase regulates protective surface microclimate pH in rat duodenum. J Physiol. 2009;587:3651–63.CrossRefGoogle Scholar
  22. 22.
    Engelstoft MS, Egerod KL, Holst B, Schwartz TW. A gut feeling for obesity: 7TM sensors on enteroendocrine cells. Cell Metab. 2008;8:447–9.CrossRefGoogle Scholar
  23. 23.
    Tazoe H, Otomo Y, Karaki S, Kato I, Fukami Y, Terasaki M, et al. Expression of short-chain fatty acid receptor GPR41 in the human colon. BiomedRes. 2009;30:149–56.Google Scholar
  24. 24.
    Karaki S, Tazoe H, Hayashi H, Kashiwabara H, Tooyama K, Suzuki Y, et al. Expression of the short-chain fatty acid receptor, GPR43, in the human colon. J Mol Histol. 2008;39:135–42.CrossRefGoogle Scholar
  25. 25.
    Akiba Y, Inoue T, Kaji I, Higashiyama M, Guth PH, Engel E, et al. Short-chain fatty acid sensing in rat duodenum. J Physiol. 2014;593:585–99.CrossRefGoogle Scholar
  26. 26.
    •• Wan Saudi WS, Sjöblom M. Short-chain fatty acids augment rat duodenal mucosal barrier function. Exp Physiol. 2017;102:791–803 This study provides that luminal SCFAs rather than IV SCFAs enhance duodenal defense mechanisms.CrossRefGoogle Scholar
  27. 27.
    Wang JH, Inoue T, Higashiyama M, Guth PH, Engel E, Kaunitz JD, et al. Umami receptor activation increases duodenal bicarbonate secretion via glucagon-like peptide-2 release in rats. J Pharmacol Exp Ther. 2011;339:464–73.CrossRefGoogle Scholar
  28. 28.
    Guan X, Karpen HE, Stephens J, Bukowski JT, Niu S, Zhang G, et al. GLP-2 receptor localizes to enteric neurons and endocrine cells expressing vasoactive peptides and mediates increased blood flow. Gastroenterology. 2006;130:150–64.CrossRefGoogle Scholar
  29. 29.
    Kaji I, Iwanaga T, Watanabe M, Guth PH, Engel E, Kaunitz JD, et al. SCFA transport in rat duodenum. Am J Physiol Gastrointest Liver Physiol. 2014;308:G188–97.CrossRefGoogle Scholar
  30. 30.
    Kaji I, Akiba Y, Konno K, Watanabe M, Kimura S, Iwanaga T, et al. Neural FFA3 activation inversely regulates anion secretion evoked by nicotinic ACh receptor activation in rat proximal colon. J Physiol. 2016;594:3339–52.CrossRefGoogle Scholar
  31. 31.
    Rowland KJ, Brubaker PL. The “cryptic” mechanism of action of glucagon-like peptide-2. Am J Physiol Gastrointest Liver Physiol. 2011;301:G1–8.CrossRefGoogle Scholar
  32. 32.
    Jeppesen PB, Gilroy R, Pertkiewicz M, Allard JP, Messing B, O'Keefe SJ. Randomised placebo-controlled trial of teduglutide in reducing parenteral nutrition and/or intravenous fluid requirements in patients with short bowel syndrome. Gut. 2011;60:902–14.CrossRefGoogle Scholar
  33. 33.
    Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696–705.CrossRefGoogle Scholar
  34. 34.
    Inoue T, Wang JH, Higashiyama M, Rudenkyy S, Higuchi K, Guth PH, et al. Dipeptidyl peptidase IV inhibition potentiates amino acid- and bile acid-induced bicarbonate secretion in rat duodenum. Am J Physiol Gastrointest Liver Physiol. 2012;303:G810–6.CrossRefGoogle Scholar
  35. 35.
    Higuchi K, Umegaki E, Watanabe T, Yoda Y, Morita E, Murano M, et al. Present status and strategy of NSAIDs-induced small bowel injury. J Gastroenterol. 2009;44:879–88.CrossRefGoogle Scholar
  36. 36.
    Inoue T, Higashiyama M, Kaji I, Rudenkyy S, Higuchi K, Guth PH, et al. Dipeptidyl peptidase IV inhibition prevents the formation and promotes the healing of indomethacin-induced intestinal ulcers in rats. Dig Dis Sci. 2014;59:1286–95.CrossRefGoogle Scholar
  37. 37.
    Kaji I, Akiba Y, Furuyama T, Adelson DW, Iwamoto K, Watanabe M, et al. Free fatty acid receptor 3 activation suppresses neurogenic motility in rat proximal colon. Neurogastroenterol Motil, in press. 2017.Google Scholar
  38. 38.
    Fujimiya M, Okumiya K, Kuwahara A. Immunoelectron microscopic study of the luminal release of serotonin from rat enterochromaffin cells induced by high intraluminal pressure. Histochem Cell Biol. 1997;108:105–13.CrossRefGoogle Scholar
  39. 39.
    Kellum JM, Albuquerque FC, Stoner MC, Harris RP. Stroking human jejunal mucosa induces 5-HT release and Cl- secretion via afferent neurons and 5-HT4 receptors. Am J Phys. 1999;277:G515–20.Google Scholar
  40. 40.
    Braun T, Voland P, Kunz L, Prinz C, Gratzl M. Enterochromaffin cells of the human gut: sensors for spices and odorants. Gastroenterology. 2007;132:1890–901.CrossRefGoogle Scholar
  41. 41.
    Kellum JM, Donowitz M, Cerel A, Wu J. Acid and isoproterenol cause serotonin release by acting on opposite surfaces of duodenal mucosa. J Surg Res. 1984;36:172–6.CrossRefGoogle Scholar
  42. 42.
    Fukumoto S, Tatewaki M, Yamada T, Fujimiya M, Mantyh C, Voss M, et al. Short-chain fatty acids stimulate colonic transit via intraluminal 5-HT release in rats. Am J Physiol Regul Integr Comp Physiol. 2003;284:R1269–76.CrossRefGoogle Scholar
  43. 43.
    Turvill JL, Connor P, Farthing MJ. The inhibition of cholera toxin-induced 5-HT release by the 5-HT3 receptor antagonist, granisetron, in the rat. Br J Pharmacol. 2000;130:1031–6.CrossRefGoogle Scholar
  44. 44.
    Hagbom M, Istrate C, Engblom D, Karlsson T, Rodriguez-Diaz J, Buesa J, et al. Rotavirus stimulates release of serotonin (5-HT) from human enterochromaffin cells and activates brain structures involved in nausea and vomiting. PLoS Pathog. 2011;7:e1002115.CrossRefGoogle Scholar
  45. 45.
    Cubeddu LX. Serotonin mechanisms in chemotherapy-induced emesis in cancer patients. Oncology. 1996;53(Suppl 1):18–25.CrossRefGoogle Scholar
  46. 46.
    Lee KJ, Tack J. Duodenal implications in the pathophysiology of functional dyspepsia. J Neurogastroenterol Motil. 2010;16:251–7.CrossRefGoogle Scholar
  47. 47.
    Beattie DT, Smith JA. Serotonin pharmacology in the gastrointestinal tract: a review. Naunyn Schmiedeberg's Arch Pharmacol. 2008;377:181–203.CrossRefGoogle Scholar
  48. 48.
    Bharucha AE, Camilleri M, Burton DD, Thieke SL, Feuerhak KJ, Basu A, et al. Increased nutrient sensitivity and plasma concentrations of enteral hormones during duodenal nutrient infusion in functional dyspepsia. Am J Gastroenterol. 2014;109:1910–20.CrossRefGoogle Scholar
  49. 49.
    van Boxel OS, ter Linde JJ, Siersema PD, Smout AJ. Role of chemical stimulation of the duodenum in dyspeptic symptom generation. Am J Gastroenterol. 2010;105:803–11.CrossRefGoogle Scholar
  50. 50.
    Glisic R, Koko V, Todorovic V, Drndarevic N, Cvijic G. Serotonin-producing enterochromaffin (EC) cells of gastrointestinal mucosa in dexamethasone-treated rats. Regul Pept. 2006;136:30–9.CrossRefGoogle Scholar
  51. 51.
    Fukudo S, Kinoshita Y, Okumura T, Ida M, Akiho H, Nakashima Y, et al. Ramosetron reduces symptoms of irritable bowel syndrome with diarrhea and improves quality of life in women. Gastroenterology. 2016;150:358–66.CrossRefGoogle Scholar
  52. 52.
    Garsed K, Chernova J, Hastings M, Lam C, Marciani L, Singh G, et al. A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea. Gut. 2014;63:1617–25.CrossRefGoogle Scholar
  53. 53.
    Ghoshal UC, Srivastava D, Misra A, Ghoshal U. A proof-of-concept study showing antibiotics to be more effective in irritable bowel syndrome with than without small-intestinal bacterial overgrowth: a randomized, double-blind, placebo-controlled trial. Eur J Gastroenterol Hepatol. 2016;28:281–9.CrossRefGoogle Scholar
  54. 54.
    Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol. 2000;95:3503–6.CrossRefGoogle Scholar
  55. 55.
    Bohn L, Storsrud S, Liljebo T, Collin L, Lindfors P, Tornblom H, et al. Diet low in FODMAPs reduces symptoms of irritable bowel syndrome as well as traditional dietary advice: a randomized controlled trial. Gastroenterology. 2015;149:1399–407.CrossRefGoogle Scholar
  56. 56.
    Barreto JC, Smith GS, Tornwall MS, Miller TA. Protective action of oral N-acetylcysteine against gastric injury: role of hypertonic sodium. Am J Physiol. 1993;264:G422–6.PubMedGoogle Scholar
  57. 57.
    Aihara E, Sasaki Y, Ise F, Kita K, Nomura Y, Takeuchi K. Distinct mechanisms of acid-induced HCO3 - secretion in normal and slightly permeable stomachs. Am J Physiol Gastrointest Liver Physiol. 2006;291:G464–71.CrossRefGoogle Scholar
  58. 58.
    Black JW, Fisher EW, Smith AN. The effects of 5-hydroxytryptamine on gastric secretion in anaesthetized dogs. J Physiol. 1958;141:27–34.CrossRefGoogle Scholar
  59. 59.
    Canfield SP, Spencer JE. The inhibitory effects of 5-hydroxytryptamine on gastric acid secretion by the rat isolated stomach. Br J Pharmacol. 1983;78:123–9.CrossRefGoogle Scholar
  60. 60.
    Kaji I, Akiba Y, Kaunitz JD, Karaki S, Kuwahara A. Differential expression of short-chain fatty acid receptor FFA2 and FFA3 in foregut. Gastroenterology. 2012;142:S494.CrossRefGoogle Scholar
  61. 61.
    Said HM, Akiba Y, Kaji I, Narimatsu K, Kaunitz JD. FFA2 activation suppresses basal and stimulated gastric acid secretion via 5-HT3 receptor activation in rats. Gastroenterology. 2015;148:S-315.CrossRefGoogle Scholar
  62. 62.
    Lai YC, Ho Y, Huang KH, Tsai LH. Effects of serotonin on acid secretion in isolated rat stomach: the role of 5-HT3 receptors. Chin J Physiol. 2009;52:395–405.CrossRefGoogle Scholar
  63. 63.
    • Segers A, Desmet L, Thijs T, Verbeke K, Tack J, Depoortere I. The circadian clock regulates the diurnal levels of microbial short-chain fatty acids and their rhythmic effects on colon contractility in mice. Acta Physiol (Oxf). 2018:e13193 This study reports diurnal fluctuation of fecal SCFAs synchronized with colonic myenteric neural FFA3 expression, suggesting that luminal SCFA production regulates SCFA receptor expression.Google Scholar
  64. 64.
    •• Tahara Y, Yamazaki M, Sukigara H, Motohashi H, Sasaki H, Miyakawa H, et al. Gut microbiota-derived short chain fatty acids induce circadian clock entrainment in mouse peripheral tissue. Sci Rep. 2018;8:1395 This study provides a new concept that oral SCFA treatment facilitates peripheral clock adjustment, suggesting that the microbiome and host organs are communicating with circadian rhythmicity.CrossRefGoogle Scholar

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© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2019

Authors and Affiliations

  • Mari Iwasaki
    • 1
  • Yasutada Akiba
    • 1
    • 2
  • Jonathan D. Kaunitz
    • 1
    • 2
    • 3
    Email author
  1. 1.West Los Angeles VAMCLos AngelesUSA
  2. 2.Department of Medicine, The David Geffen School of MedicineUniversity of CaliforniaLos AngelesUSA
  3. 3.Department of Surgery, The David Geffen School of MedicineUniversity of CaliforniaLos AngelesUSA

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