Quercetin prevents small intestinal damage and enhances intestinal recovery during methotrexate-induced intestinal mucositis of rats

  • Igor Sukhotnik
  • Dalia Moati
  • Ron Shaoul
  • Boaz Loberman
  • Yulia Pollak
  • Betty Schwartz
Keywords: chemotherapy, methotrexate, mucositis, quercetin, enterocyte proliferation, enterocyte apoptosis


Background: Gastrointestinal mucositis occurs as a consequence of cytotoxic treatment. Quercetin (QCT) is a bioflavonoid that exerts significant antioxidant activity and anti-inflammatory as well as anti-malignancy properties.

Objective: To evaluate the effects of oral QCT consumption in preventing intestinal mucosal damage and stimulating intestinal recovery following methotrexate (MTX)-induced intestinal damage in a rat model.

Design: Male Sprague–Dawley rats were divided into four groups: Control Group A (CONTR) – rats were treated with 2 cc of saline given by gavage for 6 days. Group B (CONTR-QCT) – rats were treated with QCT (100 mg/kg in 2 ml saline) given by gavage 3 days before and 3 days after intraperitoneal (IP) injection of saline. Group C (MTX) – rats were injected a single dose (25 mg/kg) of MTX IP. Group D (MTX-QCT) rats were treated with QCT (similar to Group B) 3 days before and 3 days after IP MTX injection. Intestinal mucosal parameters (bowel and mucosal weight, mucosal DNA and protein content, and villus height and crypt depth), enterocytes proliferation, and enterocyte apoptosis degree were investigated at sacrifice on the 4th day after MTX or saline injection.

Results: Administration of QCT to MTX-treated rats resulted in: (1) significant decrease in intestinal injury score, (2) significant increase in intestinal and mucosal weight in jejunum and ileum, (3) increase on the protein content of the ileum, (4) increase in the villus height in the ileum, (5) increase of crypt depth of jejunum and ileum, and (6) increase in cell proliferation in the jejunum and ileum compared to MTX-nontreated group.

Conclusions: Administration of QCT prevents intestinal damage and improves intestinal recovery following MTX-induced intestinal damage in a rat. We surmise that the effect of QCT is based on induction of cell proliferation in the crypt rather than inhibition of apoptosis.


Download data is not yet available.


  1. Sonis ST. Complications of cancer and their treatment: oral complications. In: Holland JF, Frei E, Bast RC, eds. Cancer medicine. 3rd ed. Philadelphia, PA: Lea and Febiger; 1993, pp. 2381–8.

  2. Naidu MUR, Ramana GV, Rani PU, Mohan IK, Suman A, Roy P. Chemotherapy-induced and/or radiation therapy-induced oral mucositis? Complicating the treatment of cancer. Neoplasia. 2004;6:423–31.

  3. Mitchell EP, Schein PS. Gastrointestinal toxicity of chemotherapeutic agents. Semin Oncol. 1982;9:52–64.

  4. Sonis ST, Elting LS, Keefe DMK, Peterson DE, Schubert M, Hauer-Jensen M, et al. Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer. 2004;100:1995–2025.

  5. Goldman ID, Matherly LH. The cellular pharmacology of methotrexate. Pharmacol Ther. 1985;28:77–102.

  6. Keefe DM, Brealey J, Goland GJ, Cummins AG. Chemotherapy for cancer causes apoptosis that precedes hypoplasia in crypts of the small intestine in humans. Gut. 2000;47:632–7.

  7. Pinkerton CR, Cameron CH, Sloan JM, Glasgow JF, Gwevava NJ. Jejunal crypt cell abnormalities associated with methotrexate treatment in children with acute lymphoblastic leukaemia. J Clin Pathol. 1982;35:1272–7.

  8. Chen S, Jiang H, Wu X, Fang J. Therapeutic effects of quercetin on inflammation, obesity, and type 2 diabetes. Mediators Inflamm. 2016;2016:9340637.

  9. George VC, Dellaire G, Rupasinghe HP. Plant flavonoids in cancer chemoprevention: role in genome stability. J Nutr Biochem. 2016;45:1–14.

  10. Dodda D, Chhajed R, Mishra J, Padhy M. Targeting oxidative stress attenuates trinitrobenzene sulphonic acid induced inflammatory bowel disease like symptoms in rats: role of quercetin. Indian J Pharmacol. 2014;46:286–91.

  11. Kelly GS. Quercetin. Monograph. Altern Med Rev. 2011;16:172–94.

  12. Sangild PT, Shen RL, Pontoppidan PE, Rathe M. Animal models of chemotherapy-induced mucositis: translational relevance and challenges. Am J Physiol Gastrointest Liver Physiol. 2018;314(2):G231–46. doi: 10.1152/ajpgi.00204.2017.

  13. Singh DP, Borse SP, Nivsarkar M. Overcoming the exacerbating effects of ranitidine on NSAID-induced small intestinal toxicity with quercetIn: providing a complete GI solution. Chem Biol Interact. 2017;272:53–64.

  14. Chromozinski P. A reagent for the single-step simultaneous isolation of RNA, DNA and proteins from cell and tissue samples. BioTechniques. 1993;15:532–6.

  15. Kesik V, Uysal B, Kurt B, Kismet E, Koseoglu V. Ozone ameliorates methotrexate-induced intestinal injury in rats. Cancer Biol Ther. 2009;8:1623–8.

  16. Manach C, Scalbert A, Morand C, Rémésy C, Jiménez L. Polyphenols: food sources and bioavailability. Am J Clin Nutr. 2004;79:727–47.

  17. Romier B, Schneider YJ, Larondelle Y, During A. Dietary polyphenols can modulate the intestinal inflammatory response. Nutr Rev. 2009;67:363–78.

  18. Cutillo FD, DellaGreca M, Gionti M, Previtera L, Zarrelli A. Phenols and lignans from Chenopodium album. Phytochem Anal. 2006;17:344–9.

  19. Pandey KB, Rizvi SI. Plant polyphenols as dietary antioxidants in human health and disease. Oxid Med Cell Longev. 2009;2:270–8.

  20. Calixto JB, Campos MM, Otuki MF, et al. Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. Planta Med. 2004;70:93–103.

  21. Joven J, Micol V, Segura-Carretero A, Alonso-Villaverde C, Menéndez JA, Bioactive Food Components Platform. Polyphenols and the modulation of gene expression pathways: can we eat our way out of the danger of chronic disease? Crit Rev Food Sci Nutr. 2014;54:985–1001.

  22. Sarkar SMS, Saha SJ, Bandyopadhyay U. Management of inflammation by natural polyphenols: a comprehensive mechanistic update. Curr Med Chem. 2016;23:1657–95.

  23. Ruby AJ, Kuttan G, Babu KD, Rajasekharan KN, Kuttan R. Anti-tumor and antioxidant activity of natural curcuminoids. Cancer Lett. 1995;94:79–83.

  24. Martín-Peláez S, Covas MI, Fitó M, Kušar A, Pravst I. Health effects of olive oil polyphenols: recent advances and possibilities for the use of health claims. Mol Nutr Food Res. 2013;57:760–771.

  25. Kim GY, Kim KH, Lee SH, et al. Curcumin inhibits immunostimulatory function of dendritic cells: MAPKs and translocation of NF-kB as potential targets. J Immunol. 2005;174:8116–8124.

  26. Nam NH. Naturally occurring NF-kappaB inhibitors. Mini Rev Med Chem. 2006;6:945–951.

  27. Cavalcanti E, Vadrucci E, Delvecchio FR, Addabbo F, Bettini S, Liou R, et al. Administration of reconstituted polyphenol oil bodies efficiently suppresses dendritic cell inflammatory pathways and acute intestinal inflammation. PLoS One. 2014;9:e88898.

  28. Davis JM, Murphy EA, Carmichael MD. Effects of the dietary flavonoid quercetin upon performance and health. Curr Sports Med Rep. 2009;8:206–13.

  29. Portillo MP. Beneficial effects of quercetin on obesity and diabetes. Open Nutraceuticals J. 2011;4:189–98.

  30. D’Andrea G. QuercetIn: a flavonol with multifaceted therapeutic applications? Fitoterapia. 2015;106:256–71.

  31. European Food Safety Agency (EFSA) NDA Panel (Dietetic Products, Nutrition and Allergies). Scientific opinion on the substantiation of health claims related to quercetin and protection of DNA, proteins and lipids from oxidative damage (ID 1647), “cardiovascular system” (ID 1844), “mental state and performance” (ID 1845), and “liver, kidneys” (ID 1846) pursuant to Article 13(1) of Regulation (EC) No 1924/2006. EFSA J. 2011;9:2067–82.

  32. Singh DP, Borse SP, Nivsarkar M. Co-administration of quercetin with pantoprazole sodium prevents NSAID-induced severe gastroenteropathic damage efficiently: evidence from a preclinical study in rats. Exp Toxicol Pathol. 2017;69:17–26.

  33. Kooshyar MM, Mozafari PM, Amirchaghmaghi M, Pakfetrat A, Karoos P, Mohasel MR, et al. A randomized placebo-controlled double blind clinical trial of quercetin in the prevention and treatment of chemotherapy-induced oral mucositis. J Clin Diagn Res. 2017;11:ZC46–50.

  34. Verburg M, Renes IB, Meijer HP, Taminiau JA, Büller HA, Einerhand AW, et al. Selective sparing of goblet cells and paneth cells in the intestine of methotrexate-treated rats. Am J Physiol Gastrointest Liver Physiol. 2000;279:G1037–47.

  35. Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, et al. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature. 1995;376:37–43.

  36. Sonis ST. The pathobiology of mucositis. Nat Rev Cancer. 2004;4:277–284.

  37. Generoso Sde V, Rodrigues NM, Trindade LM, Paiva NC, Cardoso VN, Carneiro CM, et al. Dietary supplementation with omega-3 fatty acid attenuates 5-fluorouracil induced mucositis in mice. Lipids Health Dis. 2015;14:54.

  38. Li Y, Wang J, Chen G, Feng S, Wang P, Zhu X, et al. Quercetin promotes the osteogenic differentiation of rat mesenchymal stem cells via mitogen-activated protein kinase signaling. Exp Ther Med. 2015;9:2072–80.

  39. Lee DY, Choi BK, Lee DG, Kim YH, Kim CH, Lee SJ, et al. 4-1BB signaling activates the T-cell factor 1 effector/β-catenin pathway with delayed kinetics via ERK signaling and delayed PI3K/AKT activation to promote the proliferation of CD8+ T cells. PLoS One. 2013;8:e69677.

  40. Ben Salem I, Prola A, Boussabbeh M, Guilbert A, Bacha H, Abid-Essefi S, et al. Crocin and Quercetin protect HCT116 and HEK293 cells from Zearalenone-induced apoptosis by reducing endoplasmic reticulum stress. Cell Stress Chaperones. 2015;20:927–38.

  41. Marchionatti AM, Pacciaroni A, Tolosa de Talamoni NG. Effects of quercetin and menadione on intestinal calcium absorption and the underlying mechanisms. Comp Biochem Physiol A Mol Integr Physiol. 2013;164:215–20.

  42. Chiang HM, Fang SH, Wen KC, et al. Life-threatening interaction between the root extract of Pueraria lobata and methotrexate in rats. Toxicol Appl Pharmacol. 2005;209:263–8.

  43. Shia CS, Juang SH, Tsai SY, Lee Chao PD, Hou YC. Interaction of rhubarb and methotrexate in rats: in vivo and ex vivo approaches. Am J Chin Med. 2013;41:1427–38.

How to Cite
Sukhotnik I., Moati D., Shaoul R., Loberman B., Pollak Y., & Schwartz B. (2018). Quercetin prevents small intestinal damage and enhances intestinal recovery during methotrexate-induced intestinal mucositis of rats. Food & Nutrition Research, 62. https://doi.org/10.29219/fnr.v62.1327
Original Articles