Skip to main content

Advertisement

Log in

Elemental diet moderates 5-fluorouracil-induced gastrointestinal mucositis through mucus barrier alteration

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

There are reports that elemental diet (ED) ameliorates oral mucositis caused by antineoplastic chemotherapy. Although this effectiveness may be partly due to high nutrient absorption, the effects of chemotherapy on mucosal defense mechanisms remain unclear. We investigated the effects of oral supplementation with ED on mucin in 5-fluorouracil (5-FU)-induced intestinal mucositis.

Methods

5-FU was administered to rats orally once daily, and ED was supplied orally twice daily for 5 days. The severity of mucositis was assessed by length, dry tissue weight, and villus height of the intestinal tract. Using anti-mucin monoclonal antibody, we compared the immunoreactivity in the gastrointestinal (GI) tract and mucin content by histological and biochemical examinations.

Results

Oral supplementation with ED reduced histological damage and loss of length, dry tissue weight, and villus height induced by 5-FU administration. ED markedly altered PGM34 antibody immunoreactivity and mucin contents in the small intestine of rats with 5-FU-induced mucositis.

Conclusions

ED may possibly be more effective for the prevention of antineoplastic chemotherapy-induced mucositis through the activation of GI mucus cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

ED:

Elemental diet

5-FU:

5-Fluorouracil

GI:

Gastrointestinal

References

  1. Sartori S, Trevisani L, Nielsen I, Tassinari D, Abbasciano V (1996) Misoprostol and omeprazole in the prevention of chemotherapy-induced acute gastroduodenal mucosal injury. A randomized, placebo-controlled pilot study. Cancer 78(7):1477–1482

    Article  CAS  PubMed  Google Scholar 

  2. Shirasaka T, Taguchi T (2006) Timeline from discovery of 5-FU to development of an oral anticancer agent S-1 and its drug concept. Gan To Kagaku Ryoho 33(Suppl 1):4–18

    CAS  PubMed  Google Scholar 

  3. Elting LS, Cooksley C, Chambers M, Cantor SB, Manzullo E, Rubenstein EB (2003) The burdens of cancer therapy. Clinical and economic outcomes of chemotherapy-induced mucositis. Cancer 98(7):1531–1539. doi:10.1002/cncr.11671

    Article  PubMed  Google Scholar 

  4. Slavin RE, Dias MA, Saral R (1978) Cytosine arabinoside induced gastrointestinal toxic alterations in sequential chemotherapeutic protocols: a clinical-pathologic study of 33 patients. Cancer 42(4):1747–1759

    Article  CAS  PubMed  Google Scholar 

  5. Saegusa Y, Ichikawa T, Iwai T, Goso Y, Ikezawa T, Nakano M, Shikama N, Saigenji K, Ishihara K (2008) Effects of acid antisecretory drugs on mucus barrier of the rat against 5-fluorouracil-induced gastrointestinal mucositis. Scand J Gastroenterol 43(5):531–537. doi:10.1080/00365520701811693

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Yamamoto H, Ishihara K, Takeda Y, Koizumi W, Ichikawa T (2013) Changes in the mucus barrier during cisplatin-induced intestinal mucositis in rats. BioMed Res Int 2013:276186. doi:10.1155/2013/276186

    PubMed Central  PubMed  Google Scholar 

  7. Rubenstein EB, Peterson DE, Schubert M, Keefe D, McGuire D, Epstein J, Elting LS, Fox PC, Cooksley C, Sonis ST (2004) Clinical practice guidelines for the prevention and treatment of cancer therapy-induced oral and gastrointestinal mucositis. Cancer 100(9 Suppl):2026–2046. doi:10.1002/cncr.20163

    Article  PubMed  Google Scholar 

  8. Sonis ST, Elting LS, Keefe D, Peterson DE, Schubert M, Hauer-Jensen M, Bekele BN, Raber-Durlacher J, Donnelly JP, Rubenstein EB (2004) Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 100(9 Suppl):1995–2025. doi:10.1002/cncr.20162

    Article  PubMed  Google Scholar 

  9. Andrianifahanana M, Moniaux N, Batra SK (2006) Regulation of mucin expression: mechanistic aspects and implications for cancer and inflammatory diseases. Biochim Biophys Acta 1765(2):189–222

    CAS  PubMed  Google Scholar 

  10. Azuumi Y, Ohara S, Ishihara K, Okabe H, Hotta K (1980) Correlation of quantitative changes of gastric mucosal glycoproteins with aspirin-induced gastric damage in rats. Gut 21(6):533–536

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Ikezawa T, Ichikawa T, Adachi K, Sugano S, Ojima T, Nakamura Y, Watanabe Y, Ishihara K (2005) Analysis of mucin composition in gastric juices of chronic rheumatic patients with upper gastrointestinal damage. Biomed Res 26(4):147–151

    Article  CAS  PubMed  Google Scholar 

  12. Kojima Y, Ishihara K, Ohara S, Saigenji K, Hotta K (1992) Effects of the M1 muscarinic receptor antagonist pirenzepine on gastric mucus glycoprotein in rats with or without ethanol-induced gastric damage. Scand J Gastroenterol 27(9):764–768

    Article  CAS  PubMed  Google Scholar 

  13. Ishihara K, Kurihara M, Goso Y, Ota H, Katsuyama T, Hotta K (1996) Establishment of monoclonal antibodies against carbohydrate moiety of gastric mucins distributed in the different sites and layers of rat gastric mucosa. Glycoconj J 13(5):857–864

    Article  CAS  PubMed  Google Scholar 

  14. Tsubokawa D, Goso Y, Sawaguchi A, Kurihara M, Ichikawa T, Sato N, Suganuma T, Hotta K, Ishihara K (2007) A monoclonal antibody, PGM34, against 6-sulfated blood-group H type 2 antigen, on the carbohydrate moiety of mucin. The FEBS journal 274(7):1833–1848. doi:10.1111/j.1742-4658.2007.05731.x

    Article  CAS  PubMed  Google Scholar 

  15. Lochs H, Dejong C, Hammarqvist F, Hebuterne X, Leon-Sanz M, Schutz T, van Gemert W, van Gossum A, Valentini L, Lubke H, Bischoff S, Engelmann N, Thul P (2006) ESPEN guidelines on enteral nutrition: gastroenterology. Clin Nutr 25(2):260–274. doi:10.1016/j.clnu.2006.01.007

    Article  CAS  PubMed  Google Scholar 

  16. Homan M, Baldassano RN, Mamula P (2005) Managing complicated Crohn’s disease in children and adolescents. Nat Clin Pract Gastroenterol Hepatol 2(12):572–579. doi:10.1038/ncpgasthep0338

    Article  PubMed  Google Scholar 

  17. Johnson T, Macdonald S, Hill SM, Thomas A, Murphy MS (2006) Treatment of active Crohn’s disease in children using partial enteral nutrition with liquid formula: a randomised controlled trial. Gut 55(3):356–361. doi:10.1136/gut.2004.062554

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Matsui T, Sakurai T, Yao T (2005) Nutritional therapy for Crohn’s disease in Japan. J Gastroenterol 40(Suppl 16):25–31

    PubMed  Google Scholar 

  19. Yamamoto T, Nakahigashi M, Umegae S, Kitagawa T, Matsumoto K (2005) Impact of elemental diet on mucosal inflammation in patients with active Crohn’s disease: cytokine production and endoscopic and histological findings. Inflamm Bowel Dis 11(6):580–588

    Article  PubMed  Google Scholar 

  20. Andou A, Hisamatsu T, Okamoto S, Chinen H, Kamada N, Kobayashi T, Hashimoto M, Okutsu T, Shimbo K, Takeda T, Matsumoto H, Sato A, Ohtsu H, Suzuki M, Hibi T (2009) Dietary histidine ameliorates murine colitis by inhibition of proinflammatory cytokine production from macrophages. Gastroenterology 136(2):564.e562–574.e562. doi:10.1053/j.gastro.2008.09.062

    Article  Google Scholar 

  21. Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H (1984) Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol 133(4):1710–1715

    CAS  PubMed  Google Scholar 

  22. Gerlach C, Golding M, Larue L, Alison MR, Gerdes J (1997) Ki-67 immunoexpression is a robust marker of proliferative cells in the rat. Lab Invest 77(6):697–698

    CAS  PubMed  Google Scholar 

  23. Gerlach C, Sakkab DY, Scholzen T, Dassler R, Alison MR, Gerdes J (1997) Ki-67 expression during rat liver regeneration after partial hepatectomy. Hepatology 26(3):573–578. doi:10.1002/hep.510260307

    Article  CAS  PubMed  Google Scholar 

  24. Ichikawa T, Ito Y, Saegusa Y, Iwai T, Goso Y, Ikezawa T, Ishihara K (2009) Effects of combination treatment with famotidine and methylmethionine sulfonium chloride on the mucus barrier of rat gastric mucosa. J Gastroenterol Hepatol 24(3):488–492. doi:10.1111/j.1440-1746.2008.05667.x

    Article  CAS  PubMed  Google Scholar 

  25. Saegusa Y, Ichikawa T, Iwai T, Goso Y, Okayasu I, Ikezawa T, Shikama N, Saigenji K, Ishihara K (2008) Changes in the mucus barrier of the rat during 5-fluorouracil-induced gastrointestinal mucositis. Scand J Gastroenterol 43(1):59–65

    Article  CAS  PubMed  Google Scholar 

  26. Ogata Y, Takeuchi M, Ishibashi N, Kibe S, Takahashi K, Uchida S, Murakami N, Yahara T, Shirouzu K (2012) Efficacy of Elental on prevention for chemotherapy-induced oral mucositis in colorectal cancer patients. Gan To Kagaku Ryoho 39(4):583–587

    PubMed  Google Scholar 

  27. Fukui T, Itoh Y, Orihara M, Yoshizawa K, Takeda H, Kawada S, Yoshioka T (2011) Elental prevented and reduced oral mucositis during chemotherapy in patients esophageal cancer. Gan To Kagaku Ryoho 38(13):2597–2601

    PubMed  Google Scholar 

  28. Tobisawa Y, Imai Y, Fukuda M, Kawashima H (2010) Sulfation of colonic mucins by N-acetylglucosamine 6-O-sulfotransferase-2 and its protective function in experimental colitis in mice. J Biol Chem 285(9):6750–6760. doi:10.1074/jbc.M109.067082

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Sukhotnik I, Mogilner JG, Karry R, Shamian B, Lurie M, Kokhanovsky N, Ure BM, Coran AG (2009) Effect of oral glutamine on enterocyte turnover during methotrexate-induced mucositis in rats. Digestion 79(1):5–13. doi:10.1159/000191209

    Article  CAS  PubMed  Google Scholar 

  30. Jebb SA, Osborne RJ, Maughan TS, Mohideen N, Mack P, Mort D, Shelley MD, Elia M (1994) 5-Fluorouracil and folinic acid-induced mucositis: no effect of oral glutamine supplementation. Br J Cancer 70(4):732–735

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Leitao RF, Ribeiro RA, Lira AM, Silva LR, Bellaguarda EA, Macedo FD, Sousa RB, Brito GA (2008) Glutamine and alanyl-glutamine accelerate the recovery from 5-fluorouracil-induced experimental oral mucositis in hamster. Cancer Chemother Pharmacol 61(2):215–222. doi:10.1007/s00280-007-0463-2

    Article  CAS  PubMed  Google Scholar 

  32. Okuno SH, Woodhouse CO, Loprinzi CL, Sloan JA, LaVasseur BI, Clemens-Schutjer D, Swan D, Axvig C, Ebbert LP, Tirona MR, Michalak JC, Pierson N (1999) Phase III controlled evaluation of glutamine for decreasing stomatitis in patients receiving fluorouracil (5-FU)-based chemotherapy. Am J Clin Oncol 22(3):258–261

    Article  CAS  PubMed  Google Scholar 

  33. Fonnum F (1984) Glutamate: a neurotransmitter in mammalian brain. J Neurochem 42(1):1–11

    Article  CAS  PubMed  Google Scholar 

  34. Rothman S (1984) Synaptic release of excitatory amino acid neurotransmitter mediates anoxic neuronal death. J Neurosci 4(7):1884–1891

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We express our sincere appreciation to S.Sugawara for technical assistance. This study was supported by a grant from the School of Allied Health Sciences, Kitasato University. Grant from Kitasato University (Kitasato University Research Grant for Young Researchers) supported this research.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Takafumi Ichikawa.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kawashima, R., Kawakami, F., Maekawa, T. et al. Elemental diet moderates 5-fluorouracil-induced gastrointestinal mucositis through mucus barrier alteration. Cancer Chemother Pharmacol 76, 269–277 (2015). https://doi.org/10.1007/s00280-015-2790-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-015-2790-z

Keywords

Navigation