Abstract
The sucrose breath test (SBT) was employed to noninvasively assess the efficacy of probiotics in 5-fluorouracil (5-FU)-induced intestinal mucositis. Dark Agouti rats were allocated to 5 groups (n=10): 5-FU+L. fermentum BR11, 5-FU+L. rhamnosus GG, 5-FU+B. lactis BB12, 5-FU+skim milk (SM), and saline+SM. Probiotics were administered by oral gavage for 10 days. Mucositis was induced on day 7 by intraperitoneal injection of 5-FU (150 mg/kg) or vehicle (saline). Rats were sacrificed 72 h after 5-FU injection. The SBT measured breath 13CO2 (expressed as percentage cumulative dose at 90 min; %CD90) on days 0, 7, and 10. %CD90 was significantly lower in 5-FU-treated controls compared with that in saline-treated controls on day 10. 5-FU caused an 83% reduction in sucrase and a 510% increase in MPO activity. The SBT detected damage induced by 5-FU and is a simple, noninvasive indicator of small bowel injury. The probiotics assessed offered no protection from mucositis at the dose tested.
Similar content being viewed by others
References
Sonis ST, Eilers JP, Epstein JB, LeVeque FG, Liggett Jr WH, Mulagha MT, Peterson DE, Rose AH, Schubert MM, Spijkervet FK, et al. (1999) Validation of a new scoring system for the assessment of clinical trial research of oral mucositis induced by radiation or chemotherapy. Cancer 85:2103–2113
Pico J-L, Avila-Garavito A, Naccache P (1998) Mucositis: its occurrence, consequences, and treatment in the oncology setting. Oncologist 3:446–451
Khan SA, Wingard JR (2001) Infection and mucosal injury in cancer treatment. J Natl Cancer Inst Monogr 31–36
Keefe DMK (2004) Gastrointestinal mucositis: a new biological model. Support Care Cancer 12:6–9
Clarke J, Butler R, Howarth G, Read L, Regester G (2002) Exposure of oral mucosa to bioactive milk factors reduces severity of chemotherapy-induced mucositis in the hamster. Oral Oncol 38:478–485
Sonis ST (2004) A biological approach to mucositis. J Support Oncol 2:21–32; discussion 35–36
Freytes CO, Ratanatharathorn V, Taylor C, Abboud C, Chesser N, Restrepo A, Arango J, Odenheimer D (2004) Phase I/II randomized trial evaluating the safety and clinical effects of repifermin administered to reduce mucositis in patients undergoing autologous hematopoietic stem cell transplantation. Clin Cancer Res 10:8318–8324
Spielberger R, Stiff P, Bensinger W, Gentile T, Weisdorf D, Kewalramani T, Shea T, Yanovich S, Hansen K, Noga S, et al. (2004) Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med 351:2590–2598
Howarth GS (2003) Insulin-like growth factor-I and the gastrointestinal system: therapeutic indications and safety implications. J Nutr 133:2109–2112
Howarth GS, Francis GL, Cool JC, Xu X, Byard RW, Read LC (1996) Milk growth factors enriched from cheese whey ameliorate intestinal damage by methotrexate when administered orally to rats. J Nutr 126:2519–2530
Harsha WT, Kalandarova E, McNutt P, Irwin R, Noel J (2006) Nutritional supplementation with transforming growth factor-beta, glutamine, and short chain fatty acids minimizes methotrexate-induced injury. J Pediatr Gastroenterol Nutr 42:53–58
O’Mahony L, McCarthy J, Kelly P, Hurley G, Luo F, Chen K, O’Sullivan GC, Kiely B, Collins JK, Shanahan F, et al. (2005) Lactobacillus and Bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology 128:541–551
Isolauri E (2001) Probiotics in human disease. Am J Clin Nutr 73:1142S–1146S
Mombelli B, Gismondo MR (2000) The use of probiotics in medical practice. Int J Antimicrob Agents 16:531–536
Madsen K, Cornish A, Soper P, McKaigney C, Jijon H, Yachimec C, Doyle J, Jewell L, De Simone C (2001) Probiotic bacteria enhance murine and human intestinal epithelial barrier function. Gastroenterology 121:580–591
Park SY, Ji GE, Ko YT, Jung HK, Ustunol Z, Pestka JJ (1999) Potentiation of hydrogen peroxide, nitric oxide, and cytokine production in RAW 264.7 macrophage cells exposed to human and commercial isolates. Int J Food Microbiol 46:231–241
Bezkorovainy A (2001) Probiotics: determinants of survival and growth in the gut. Am J Clin Nutr 73:S399–S405
Ruiz PA, Hoffmann M, Szency S, Blaut M, Haller D (2005) Innate mechanisms of Bifidobacterium lactis to activate transient pro-inflammatory host response in intestinal epithelial cells after the colonization of germ-free rats. Immunology 115:441–450
Kullisaar T, Zilmer M, Mikelsaar M, Vihalemm T, Annuk H, Kairane C, Kilk A (2002) Two antioxidative lactobacilli strains as promising probiotics. Int J Food Microbiol 72:215–224
Hung J, Cooper D, Turner MS, Walsh T, Giffard PM (2003) Cystine up take prevents production of hydrogen peroxide by Lactobacillus fermentum BR11. FEMS Microbiol Lett 69:5855–5863
Rush CM, Hafner LM, Timms P (1994) Genetic modification of a vaginal strain of Lactobacillus fermentum and its maintenance within the reproductive tract after intravaginal administration. J Med Microbiol 41:272–278
Geier MS, Butler RN, Howarth GS (2005) Differential efficacy of probiotic species in amelioration of dextran sulphate sodium-induced colitis in rats. Gastroenterology 128:A603–A604
Pelton NS, Tivey DR, Howarth GS, Davidson GP, Butler RN (2004) A novel breath test for the non-invasive assessment of small intestinal mucosal injury following methotrexate administration in the rat. Scand J Gastroenterol 39:1015–1016
Semenza G, Dahlqvist A (1985) Disaccharides of small-intestinal mucosa. J Pediatr Gastroenterol Nutr 4:857–867
Clarke JM, Pelton NC, Bajka BH, Howarth GS, Read LC, Butler RN (2006) Use of the (13)c-sucrose breath test to assess chemotherapy-induced small intestinal mucositis in the rat. Cancer Biol Ther 5:34–38
McCarthy GM, Awde JD, Ghandi H, Vincent M, Kocha WI (1998) Risk factors associated with mucositis in cancer patients receiving 5-fluorouracil. Oral Oncol 34:484–490
Tomas FM, Knowles SE, Owens PC, Read LC, Chandler CS, Gargosky SE, Bllard FJ (1991) Effects of full-length and truncated insulin-like growth factor-I on nitrogen balance and muscle protein metabolism in nitrogen-restricted rats. J Endocrinol 128:97–105
Xian CJ, Howarth GS, Cool JC, Foster BK (2004) Effects of acute 5-fluorouracil chemotherapy and insulin-like growth factor-I pretreament on growth plate cartilage and metaphyseal bone in rats. Bone 35:739–749
Cool JC, Dyer JL, Xian CJ, Butler RN, Geier MS, Howarth GS (2005) Pre-treatment with insulin-like growth factor-I partially ameliorates 5-fluorouracil-induced intestinal mucositis in rats. Growth Horm IGF Res 15:72–82
Dahlqvist A (1968) Assay of intestinal disaccharides. Anal Biochem 22:99–107
Krawisz JE, Sharon P, Stenson WF (1984) Quantitative assay for acute intestinal inflammation based on myeloperoxidase activity. Gastroenterology 87:1344–1350
Geier MS, Tenikoff D, Yazbeck R, McCaughan GW, Abbott CA, Howarth GS (2005) Development and resolution of experimental colitis in mice with targeted deletion of dipeptidyl peptidase IV. J Cell Physiol 204:687–692
Howarth GS, Xian CJ, Read LC (2000) Predisposition to colonic dysplasia is unaffected by continuous administration of insulin-like growth factor-I for twenty weeks in a rat model of chronic inflammatory bowel disease. Growth Factors 18:119–133
Shibolet O, Karmeli F, Eliakim R, Swennen E, Brigidi P, Gionchetti P, Campieri M, Morgenstern S, Rachmilewitz D (2002) Variable response to probiotics in two models of experimental colitis in rats. Inflammatory Bowel Dis 8:399–406
Dieleman LA, Goerres MS, Arends A, Sprengers D, Torrice C, Hoentjen F, Grenther WB, Sartor RB (2003) Lactobacillus GG prevents recurrence of colitis in HLA-B27 transgenic rats after antibiotic treatment. Gut 52:370–376
Di Stefano M, Miceli E, Armellini E, Missanelli A, Corazza GR (2004) Probiotics and functional abdominal bloating. J Clin Gastroenterol 38:S102–S103
Kajander K, Hatakka K, Poussa T, Farkkila M, Korpela R (2005) A probiotic mixture alleviates symptoms in irritable bowel syndrome patients: a controlled 6-month intervention. Aliment Pharmacol Ther 22:387–394
Hawrelak JA, Whitten DL, Myers SP (2005) Is Lactobacillus rhamnosus GG effective in preventing the onset of antibiotic-associated diarrhoea: a systematic review. Digestion 72:51–56
Myllyluoma E, Veijola L, Ahlroos T, Tynkkynen S, Kankuri E, Vapaatalo H, Rautelin H, Korpela R (2005) Probiotic supplementation improves tolerance to Helicobacter pylori eradication therapy—a placebo-controlled, double-blind randomized pilot study. Aliment Pharmacol Ther 21:1263–1272
Tooley K, Howarth G, Lymn K, Lawrence A, Butler R (2006) Oral ingestion of Streptococcus thermophilus diminishes severity of small intestinal mucositis in methotrexate treated rats. Cancer Biol Ther 5(6):593–600
Acknowledgments
The authors thank Kerry Lymn, Roger Yazbeck, Joanne Ball, Stamatiki Kritas, Geoffrey Matthews, Lynn Scarman, and Dr. Coung Tran for assistance with the animal experiments, histologic processing, biochemical analyses, and proofreading. Dr. Andrew Lawrence and the staff of the CYWHS Microbiology Department are thanked for their assistance with microbial culture. Thanks are also extended to Inpak Foods, Royal Park, South Australia, for their generous donation of Bonlac® skim milk powder.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Mauger, C.A., Butler, R.N., Geier, M.S. et al. Probiotic Effects on 5-Fluorouracil-Induced Mucositis Assessed by the Sucrose Breath Test in Rats. Dig Dis Sci 52, 612–619 (2007). https://doi.org/10.1007/s10620-006-9464-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10620-006-9464-y