![[PDF]](/pb-assets/Icons/adobe-pdf-icon-1498649896243.png){kind=icon}
Abstract
Methotrexate (MTX)-induced intestinal mucosal injury in animals has been studied to understand how MTX can cause gastrointestinal disorders, but the pathogenesis of gastrointestinal disorders is still uncertain. We have attempted to reveal how dietary factors influence intestinal toxicity due to MTX. Mice were fed normal chow (NC) or a high-fat high-sucrose diet (HFHSD) before oral administration of MTX. While MTX significantly decreased the survival rates of mice fed HFHSD, the intestinal epithelial injury was detected. MTX excretion in the feces of mice fed HFHSD was reduced. Change of diets between NC and HFHSD influences the survival. The survival rates of the mice fed a high-sucrose diet or control diet were higher than those fed HFHSD. Higher survival rates were observed in mice fed a high-fat high-sucrose diet modified (HFHSD-M) in which casein was replaced by soybean-derived proteins. The survival rates of mice treated with vancomycin were lower than those administered neomycin. Microbiome and metabolome analyses on feces suggest a similarity of the intestinal environments of mice fed NC and HFHSD-M. HFHSD may modify MTX-induced toxicity in intestinal epithelia on account of an altered MTX distribution as a result of change in the intestinal environment.
References
| 1. |
Visser, K, van der Heijde, DM. Risk and management of liver toxicity during methotrexate treatment in rheumatoid and psoriatic arthritis: a systematic review of the literature. Clin Exp Rheumatol 2009; 27: 1017–1025. Google Scholar | Medline | ISI |
| 2. |
Kinder, AJ, Hassell, AB, Brand, J, et al. The treatment of inflammatory arthritis with methotrexate in clinical practice: treatment duration and incidence of adverse drug reactions. Rheumatology (Oxford) 2005; 44: 61–66. Google Scholar | Crossref | Medline |
| 3. |
Goldman, ID, Matherly, LH. Biochemical factors in the selectivity of leucovorin rescue: selective inhibition of leucovorin reactivation of dihydrofolate reductase and leucovorin utilization in purine and pyrimidine biosynthesis by methotrexate and dihydrofolate polyglutamates. NCI Monogr 1987; 5: 17–26. Google Scholar |
| 4. |
Pinkerton, CR, Welshman, SG, Glasgow, JF, et al. Can food influence the absorption of methotrexate in children with acute lymphoblastic leukaemia? Lancet 1980; 2: 944–946. Google Scholar | Crossref | Medline |
| 5. |
Madanat, F, Awidi, A, Shaheen, O, et al. Effects of food and gender on the pharmacokinetics of methotrexate in children. Res Commun Chem Pathol Pharmacol 1987; 55: 279–282. Google Scholar | Medline |
| 6. |
Kozloski, GD, De Vito, JM, Kisicki, JC, et al. The effect of food on the absorption of methotrexate sodium tablets in healthy volunteers. Arthritis Rheum 1992; 35: 761–764. Google Scholar | Crossref | Medline |
| 7. |
Suzuki, Y, Uehara, R, Tajima, C, et al. Elevation of serum hepatic aminotransferases during treatment of rheumatoid arthritis with low-dose methotrexate. Risk factors and response to folic acid. Scand J Rheumatol 1999; 28: 273–281. Google Scholar | Crossref | Medline |
| 8. |
McAnena, OJ, Rossi, M, Mehta, BM, et al. Alteration of methotrexate metabolism in rats by administration of an elemental liquid diet. I. Changes in drug enterohepatic circulation. Cancer 1987; 59: 31–37. Google Scholar | Crossref | Medline |
| 9. |
McAnena, OJ, Harvey, LP, Bonau, RA, et al. Alteration of methotrexate toxicity in rats by manipulation of dietary components. Gastroenterology 1987; 92: 354–360. Google Scholar | Crossref | Medline |
| 10. |
Mitsugi, K, Nakamura, T, Kashiwabara, N, et al. Protection against methotrexate toxicity by a soybean protein- and omega-3 fatty acid-containing diet: comparative study with a casein-containing diet. Oncol Rep 2004; 12: 41–45. Google Scholar | Medline |
| 11. |
Funk, MA, Baker, DH. Effect of fiber, protein source and time of feeding on methotrexate toxicity in rats. J Nutr 1991; 121: 1673–1683. Google Scholar | Crossref | Medline | ISI |
| 12. |
Funk, MA, Baker, DH. Effect of soy products on methotrexate toxicity in rats. J Nutr 1991; 121: 1684–1692. Google Scholar | Crossref | Medline | ISI |
| 13. |
Vanderhoof, JA, Blackwood, DJ, Mohammadpour, H, et al. Effect of dietary menhaden oil on normal growth and development and on ameliorating mucosal injury in rats. Am J Clin Nutr 1991; 54: 346–350. Google Scholar | Crossref | Medline |
| 14. |
Hardwick, RN, Clarke, JD, Lake, AD, et al. Increased susceptibility to methotrexate-induced toxicity in nonalcoholic steatohepatitis. Toxicol Sci 2014; 142: 45–55. Google Scholar | Crossref | Medline |
| 15. |
Zaharko, DS, Bruckner, H, Oliverio, VT. Antibiotics alter methotrexate metabolism and excretion. Science 1969; 166: 887–888. Google Scholar | Crossref | Medline |
| 16. |
Alexander, JL, Wilson, ID, Teare, J, et al. Gut microbiota modulation of chemotherapy efficacy and toxicity. Nat Rev Gastroenterol Hepatol 2017; 14: 356–365. Google Scholar | Crossref | Medline |
| 17. |
Kehoe, JE, Harvey, LP, Daly, JM. Alteration of chemotherapy toxicity using a chemically defined liquid diet in rats. Cancer Res 1986; 46: 4047–4052. Google Scholar | Medline | ISI |
| 18. |
Maeda, N, Shimomura, I, Kishida, K, et al. Diet-induced insulin resistance in mice lacking adiponectin/ACRP30. Nat Med 2002; 8: 731–737. Google Scholar | Crossref | Medline | ISI |
| 19. |
Ohbayashi, M, Suzuki, M, Yashiro, Y, et al. Induction of pulmonary fibrosis by methotrexate treatment in mice lung in vivo and in vitro. J Toxicol Sci 2010; 35: 653–661. Google Scholar | Crossref | Medline |
| 20. |
Chiu, CJ, McArdle, AH, Brown, R, et al. Intestinal mucosal lesion in low-flow states. I. A morphological, hemodynamic, and metabolic reappraisal. Arch Surg 1970; 101: 478–483. Google Scholar | Crossref | Medline |
| 21. |
Kolli, VK, Kanakasabapathy, I, Faith, M, et al. A preclinical study on the protective effect of melatonin against methotrexate-induced small intestinal damage: effect mediated by attenuation of nitrosative stress, protein tyrosine nitration, and PARP activation. Cancer Chemother Pharmacol 2013; 71: 1209–1218. Google Scholar | Crossref | Medline | ISI |
| 22. |
Kolli, VK, Natarajan, K, Isaac, B, et al. Mitochondrial dysfunction and respiratory chain defects in a rodent model of methotrexate-induced enteritis. Hum Exp Toxicol 2014; 33: 1051–1065. Google Scholar | SAGE Journals | ISI |
| 23. |
Aronesty, E . Comparison of sequencing utility programs. Open Bioinforma J 2013; 7: 1–8. Google Scholar | Crossref |
| 24. |
Martin, M . Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet J 2011; 17: 10–12. Google Scholar | Crossref |
| 25. |
Edgar, RC . UPARSE: highly accurate OTU sequences from microbial amplicon reads. Nat Methods 2013; 10: 996–998. Google Scholar | Crossref | Medline | ISI |
| 26. |
Camacho, C, Coulouris, G, Avagyan, V, et al. BLAST+: architecture and applications. BMC Bioinformatics 2009; 10: 421. Google Scholar | Crossref | Medline | ISI |
| 27. |
Knight, R, Maxwell, P, Birmingham, A, et al. PyCogent: a toolkit for making sense from sequence. Genome Biol 2007; 8: R171. Google Scholar | Crossref | Medline |
| 28. |
Ohashi, Y, Hirayama, A, Ishikawa, T, et al. Depiction of metabolome changes in histidine-starved Escherichia coli by CE-TOFMS. Mol Biosyst 2008; 4: 135–147. Google Scholar | Crossref | Medline |
| 29. |
Ooga, T, Sato, H, Nagashima, A, et al. Metabolomic anatomy of an animal model revealing homeostatic imbalances in dyslipidaemia. Mol Biosyst 2011; 7: 1217–1223. Google Scholar | Crossref | Medline |
| 30. |
Sugimoto, M, Wong, DT, Hirayama, A, et al. Capillary electrophoresis mass spectrometry-based saliva metabolomics identified oral, breast and pancreatic cancer-specific profiles. Metabolomics 2010; 6: 78–95. Google Scholar | Crossref | Medline | ISI |
| 31. |
Chong, J, Soufan, O, Li, C, et al. MetaboAnalyst 4.0: towards more transparent and integrative metabolomics analysis. Nucleic Acids Res 2018; 46: W486–W494. Google Scholar | Crossref | Medline |
| 32. |
Thaiss, CA, Itav, S, Rothschild, D, et al. Persistent microbiome alterations modulate the rate of post-dieting weight regain. Nature 2016; 540: 544–551. Google Scholar | Crossref | Medline | ISI |
| 33. |
Qiu, A, Jansen, M, Sakaris, A, et al. Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 2006; 127: 917–928. Google Scholar | Crossref | Medline | ISI |
| 34. |
Yokooji, T . Role of ABC efflux transporters in the oral bioavailability and drug-induced intestinal toxicity. Yakugaku Zasshi 2013; 133: 815–822. Google Scholar | Crossref | Medline |
| 35. |
Harvey, LP, McAnena, OJ, Mehta, BM, et al. Reversibility of elemental liquid diet-enhanced methotrexate toxicity by refeeding with chow. J Parenter Enteral Nutr 1987; 11: 119–123. Google Scholar | Crossref | Medline | ISI |
| 36. |
Dunki Jacobs, PB, Ruevekamp, M, Varossiau, FJ, et al. Alterations in serum levels, anti-tumor activity and toxicity of methotrexate in rats after a short period of nutritional depletion. Eur J Cancer Clin Oncol 1989; 25: 415–422. Google Scholar | Crossref | Medline |
| 37. |
Horie, T, Nakamaru, M, Masubuchi, Y. Docosahexaenoic acid exhibits a potent protection of small intestine from methotrexate-induced damage in mice. Life Sci 1998; 62: 1333–1338. Google Scholar | Crossref | Medline |
| 38. |
Frank, M, Hennenberg, EM, Eyking, A, et al. TLR signaling modulates side effects of anticancer therapy in the small intestine. J Immunol 2015; 194: 1983–1995. Google Scholar | Crossref | Medline |
| 39. |
Goldman, P, Levy, CC. The enzymatic hydrolysis of folate analogues. Biochem Pharmacol 1968; 17: 2265–2270. Google Scholar | Crossref | Medline |
| 40. |
Shane, B, Stokstad, EL. Transport and metabolism of folates by bacteria. J Biol Chem 1975; 250: 2243–2253. Google Scholar | Medline |
| 41. |
Nayak, RR, O’Loughlin, C, Fischbach, M, et al. Methotrexate is an antibacterial drug metabolized by human gut bacteria. Arthritis Rheum 2016; 68: 1536. Google Scholar |
| 42. |
Zhou, B, Xia, X, Wang, P, et al. Induction and amelioration of methotrexate-induced gastrointestinal toxicity are related to immune response and gut microbiota. EBioMedicine 2018; 33: 122–133. Google Scholar | Crossref | Medline |
| 43. |
Fijlstra, M, Ferdous, M, Koning, AM, et al. Substantial decreases in the number and diversity of microbiota during chemotherapy-induced gastrointestinal mucositis in a rat model. Support Care Cancer 2015; 23: 1513–1522. Google Scholar | Crossref | Medline |
| 44. |
de Koning, BA, van Dieren, JM, Lindenbergh-Kortleve, DJ, et al. Contributions of mucosal immune cells to methotrexate-induced mucositis. Int Immunol 2006; 18: 941–949. Google Scholar | Crossref | Medline | ISI |
| 45. |
Atarashi, K, Tanoue, T, Shima, T, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 2011; 331: 337–341. Google Scholar | Crossref | Medline | ISI |
| 46. |
Furusawa, Y, Obata, Y, Fukuda, S, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 2013; 504: 446–450. Google Scholar | Crossref | Medline | ISI |
| 47. |
Kinoshita, M, Kayama, H, Kusu, T, et al. Dietary folic acid promotes survival of Foxp3+ regulatory T cells in the colon. J Immunol 2012; 189: 2869–2878. Google Scholar | Crossref | Medline |
| 48. |
Mao, Y, Nobaek, S, Kasravi, B, et al. The effects of Lactobacillus strains and oat fiber on methotrexate-induced enterocolitis in rats. Gastroenterology 1996; 111: 334–344. Google Scholar | Crossref | Medline | ISI |
| 49. |
Duman, DG, Kumral, ZN, Ercan, F, et al. Saccharomyces boulardii ameliorates clarithromycin- and methotrexate-induced intestinal and hepatic injury in rats. Br J Nutr 2013; 110: 493–499. Google Scholar | Crossref | Medline |
| 50. |
Shou, J, Lieberman, MD, Hofmann, K, et al. Dietary manipulation of methotrexate-induced enterocolitis. J Parenter Enteral Nutr 1991; 15: 307–312. Google Scholar | Crossref | Medline | ISI |
| 51. |
Warden, RA, Noltorp, RS, Francis, JL, et al. Vitamin A deficiency exacerbates methotrexate-induced jejunal injury in rats. J Nutr 1997; 127: 770–776. Google Scholar | Crossref | Medline | ISI |
| 52. |
Sukhotnik, I, Mogilner, JG, Karry, R, et al. Effect of oral glutamine on enterocyte turnover during methotrexate-induced mucositis in rats. Digestion 2009; 79: 5–13. Google Scholar | Crossref | Medline |
| 53. |
Sukhotnik, I, Pollak, Y, Coran, AG, et al. Glutamine attenuates the inhibitory effect of methotrexate on TLR signaling during intestinal chemotherapy-induced mucositis in a rat. Nutr Metab (Lond) 2014; 11: 17. Google Scholar | Crossref | Medline |
| 54. |
Cetiner, M, Sener, G, Sehirli, AO, et al. Taurine protects against methotrexate-induced toxicity and inhibits leukocyte death. Toxicol Appl Pharmacol 2005; 209: 39–50. Google Scholar | Crossref | Medline | ISI |
