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Oral Supplementation of Butyrate Reduces Mucositis and Intestinal Permeability Associated with 5-Fluorouracil Administration


Mucositis affects about 40 % of patients undergoing chemotherapy. Short chain fatty acids (SCFA), mainly butyrate, are claimed to improve mucosal integrity, reduce intestinal permeability and act as anti-inflammatory agents for the colon mucosa. We evaluated the effects of oral administration of SCFA or butyrate in the 5FU-induced mucositis. Mice received water, SCFA or butyrate during all experiment (10 days) and a single dose of 5FU (200 mg/kg) 3 days before euthanasia. We evaluated inflammatory and histological score by morphometry, and by activity of enzymes specific to neutrophil, eosinophil and macrophage and TLR-4, TNF-alpha and IL6 expressions. Intestinal permeability and tight junction protein ZO-1 expression were evaluated. Mice from the 5FU (5-Fluorouracil) group presented weight loss, ulcerations and inflammatory infiltration of neutrophils and eosinophils, increased expression of IL6 and TNF-alpha and increased intestinal permeability. SCFA minimized intestinal damage, reduced ulcerations without affecting intestinal permeability. Butyrate alone was more efficient at improving those parameters than in SCFA solution and also reduced intestinal permeability. The expression of pro-inflammatory cytokines and ZO-1 tended to be higher in the SCFA supplemented but not in the butyrate supplemented group. We showed the beneficial effects of butyrate on intestinal mucositis and its promising function as an adjuvant in the treatment of diseases not only of the colon, but also of the small intestine.

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Monocyte chemotactic protein-1


Dimethyl sulfoxide


Diethyleneaminopentacetic acid


Eosinophil peroxidase


Glucagon-like peptide-2


Monocarboxylate transporters






Short-chain fatty acid


Tight junctions


Zonula occludens-1


  1. 1.

    Bergman EN (1990) Energy contributions of volatile fatty acids from the gastrointestinal tract in various species. Physiol Rev 70:567–590

    PubMed  CAS  Google Scholar 

  2. 2.

    Blijlevens NM, Van’t Land B, Donnelly JP, M’Rabet L, de Pauw BE (2004) Measuring mucosal damage induced by cytotoxic therapy. Support Care Cancer 12:227–233

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Broughton G 2nd, Janis JE, Attinger CE (2006) The basic science of wound healing. Plast Reconstr Surg 117:12S–34S

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Chu E, Sartorelli AC (2012) Cancer chemotherapy. In: Katzung BG, Masters SB, Trevor AJ (eds) Basic and clinical pharmacology, chap 54, 12th edn. McGraw-Hill, New York

  5. 5.

    Desmoulin F, Canioni P, Cozzone PJ (1985) Glutamate–glutamine metabolism in the perfused rat liver. 13C-NMR study using (2-13C)-enriched acetate. FEBS Lett 185:29–32

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Duee PH, Darcy-Vrillon B, Blachier F, Morel MT (1995) Fuel selection in intestinal cells. Proc Nutr Soc 54:83–94

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Generoso SV, Viana M, Santos R, Martins FS, Machado JA, Arantes RM, Nicoli JR, Correia MI, Cardoso VN (2010) Saccharomyces cerevisiae strain UFMG 905 protects against bacterial translocation, preserves gut barrier integrity and stimulates the immune system in a murine intestinal obstruction model. Arch Microbiol 192:477–484

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Guilloteau P, Martin L, Eeckhaut V, Ducatelle R, Zabielski R, Van Immerseel F (2010) From the gut to the peripheral tissues: the multiple effects of butyrate. Nutr Res Rev 23:366–384

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Guilloteau P, Savary G, Jaguelin-Peyrault Y, Rome V, Le Normand L, Zabielski R (2010) Dietary sodium butyrate supplementation increases digestibility and pancreatic secretion in young milk-fed calves. J Dairy Sci 93:5842–5850

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Hamer HM, Jonkers D, Venema K, Vanhoutvin S, Troost FJ, Brummer RJ (2008) Review article: the role of butyrate on colonic function. Aliment Pharmacol Ther 27:104–119

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Hinnebusch BF, Meng S, Wu JT, Archer SY, Hodin RA (2002) The effects of short-chain fatty acids on human colon cancer cell phenotype are associated with histone hyperacetylation. J Nutr 132:1012–1017

    PubMed  CAS  Google Scholar 

  12. 12.

    Hornby PJ, Moore BA (2011) The therapeutic potential of targeting the glucagon-like peptide-2 receptor in gastrointestinal disease. Expert Opin Ther Targets 15:637–646

    PubMed  CAS  Google Scholar 

  13. 13.

    Hudcovic T, Kolinska J, Klepetar J, Stepankova R, Rezanka T, Srutkova D, Schwarzer M, Erban V, Du Z, Wells JM, Hrncir T, Tlaskalova-Hogenova H, Kozakova H (2012) Protective effect of Clostridium tyrobutyricum in acute dextran sodium sulphate-induced colitis: differential regulation of tumour necrosis factor-alpha and interleukin-18 in BALB/c and severe combined immunodeficiency mice. Clin Exp Immunol 167:356–365

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Kinoshita M, Suzuki Y, Saito Y (2002) Butyrate reduces colonic paracellular permeability by enhancing PPARgamma activation. Biochem Biophys Res Commun 293:827–831

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Luhrs H, Gerke T, Muller JG, Melcher R, Schauber J, Boxberge F, Scheppach W, Menzel T (2002) Butyrate inhibits NF-kappaB activation in lamina propria macrophages of patients with ulcerative colitis. Scand J Gastroenterol 37:458–466

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Martinez C, Vicario M, Ramos L, Lobo B, Mosquera JL, Alonso C, Sanchez A, Guilarte M, Antolin M, de Torres I, Gonzalez-Castro AM, Pigrau M, Saperas E, Azpiroz F, Santos J (2012) The jejunum of diarrhea-predominant irritable bowel syndrome shows molecular alterations in the tight junction signaling pathway that are associated with mucosal pathobiology and clinical manifestations. Am J Gastroenterol

  17. 17.

    Melo ML, Brito GA, Soares RC, Carvalho SB, Silva JV, Soares PM, Vale ML, Souza MH, Cunha FQ, Ribeiro RA (2008) Role of cytokines (TNF-alpha, IL-1beta and KC) in the pathogenesis of CPT-11-induced intestinal mucositis in mice: effect of pentoxifylline and thalidomide. Cancer Chemother Pharmacol 61(5):775–784

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Ohata A, Usami M, Miyoshi M (2005) Short-chain fatty acids alter tight junction permeability in intestinal monolayer cells via lipoxygenase activation. Nutrition 21:838–847

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Peng L, He Z, Chen W, Holzman IR, Lin J (2007) Effects of butyrate on intestinal barrier function in a Caco-2 cell monolayer model of intestinal barrier. Pediatr Res 61:37–41

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Ramos MG, Bambirra EA, Cara DC, Vieira EC, Alvarez-Leite JI (1997) Oral administration of short-chain fatty acids reduces the intestinal mucositis caused by treatment with Ara-C in mice fed commercial or elemental diets. Nutr Cancer 28:212–217

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Rothenberg ME (2004) Eosinophilic gastrointestinal disorders (EGID). J Allergy Clin Immunol 113:11–28 quiz 29

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Sanderson IR (2007) Dietary modulation of GALT. J Nutr 137:2557S–2562S

    PubMed  CAS  Google Scholar 

  23. 23.

    Sappington PL, Han X, Yang R, Delude RL, Fink MP (2003) Ethyl pyruvate ameliorates intestinal epithelial barrier dysfunction in endotoxemic mice and immunostimulated caco-2 enterocytic monolayers. J Pharmacol Exp Ther 304:464–476

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Soares PM, Mota JM, Gomes AS, Oliveira RB, Assreuy AM, Brito GA, Santos AA, Ribeiro RA, Souza MH (2008) Gastrointestinal dysmotility in 5-fluorouracil-induced intestinal mucositis outlasts inflammatory process resolution. Cancer Chemother Pharmacol 63:91–98

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Souba WW, Scott TE, Wilmore DW (1985) Intestinal consumption of intravenously administered fuels. JPEN J Parenter Enteral Nutr 9:18–22

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Turner JR (2009) Intestinal mucosal barrier function in health and disease. Nat Rev Immunol 9:799–809

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Van Deun K, Pasmans F, Van Immerseel F, Ducatelle R, Haesebrouck F (2008) Butyrate protects Caco-2 cells from Campylobacter jejuni invasion and translocation. Br J Nutr 100:480–484

    PubMed  Article  Google Scholar 

  28. 28.

    Vieira EL, Leonel AJ, Sad AP, Beltrao NR, Costa TF, Ferreira TM, Gomes-Santos AC, Faria AM, Peluzio MC, Cara DC, Alvarez-Leite JI (2012) Oral administration of sodium butyrate attenuates inflammation and mucosal lesion in experimental acute ulcerative colitis. J Nutr Biochem (in press)

  29. 29.

    Windmueller HG, Spaeth AE (1978) Identification of ketone bodies and glutamine as the major respiratory fuels in vivo for postabsorptive rat small intestine. J Biol Chem 253:69–76

    PubMed  CAS  Google Scholar 

  30. 30.

    Xavier RJ, Podolsky DK (2007) Unravelling the pathogenesis of inflammatory bowel disease. Nature 448:427–434

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Yan BM, Shaffer EA (2009) Primary eosinophilic disorders of the gastrointestinal tract. Gut 58:721–732

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    Yazbeck R, Howarth GS, Abbott CA (2009) Growth factor based therapies and intestinal disease: is glucagon-like peptide-2 the new way forward? Cytokine Growth Factor Rev 20:175–184

    PubMed  Article  CAS  Google Scholar 

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This study was supported by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnologico (CNPq); Coordenação de Aperfeiçoamento de Nível Superior (CAPES), Fundação de Amparo a Pesquisa de Minas Gerais (FAPEMIG) e Pro-Reitoria de Pesquisa (PRPq) da UFMG. The authors are grateful to Maria Helena Alves, for taking care of the animals.

Conflict of interest

The authors declare that they have no conflict of interest.

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Corresponding author

Correspondence to Jacqueline I. Alvarez-Leite.

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Ferreira, T.M., Leonel, A.J., Melo, M.A. et al. Oral Supplementation of Butyrate Reduces Mucositis and Intestinal Permeability Associated with 5-Fluorouracil Administration. Lipids 47, 669–678 (2012).

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  • Mucositis
  • Inflammation
  • Short-chain fatty acids
  • Butyrate
  • 5-Fluorouracil
  • Lipids