Methotrexate is one of a group of drugs known as DMARDs, or disease modifying anti-rheumatic drug. This category of drug works by suppressing the immune system and is considered a first-line drug for treating Rheumatoid Arthritis.
Because inflammation is an overactivity of one part of the immune system, the intent of using the drug is to reduce inflammation in rheumatoid arthritis. The major side effects of Methotrexate, however, have everything to do with causing inflammation of the digestive tract. This is important to understand, because the integrity and function of the intestinal lining is quite central to controlling inflammation. The most recognized risk of Methotrexate is increased intestinal permeability; this leaks to what is known as leaky gut [i] [ii] [iii] [iv] [v] [vi] [vii] [viii] and is a cause of inflammation [ix]
Methotrexate also has been shown to reduce the number and diversity of gut microbiome [x] which has been shown to promote joint inflammation [xi]. Intestinal inflammation [xii] [xiii] and inflammatory bowel disease have also been found to promote rheumatoid arthritis [xiv]. Oxidative stress of intestinal lining [xv] from Methotrexate, and inflammation of the mucous lining of intestines (Intestinal mucositis) [xvi] also contribute to the side effects and immune dysfunction that can detract from it as a useful drug for many individuals. Some research has described the side effect as gastrointestinal toxicity with mitochondrial damage [xvii] which is what promotes oxidative stress of the intestinal lining, because the mitochondria are what produce energy for the columnar cells lining the gut. Because of this combination of factors, the side effects include diarrhea, anorexia, nausea, vomiting, abdominal pain, inflammation, ulcerations of the mucous membrane of mouth and throat [xviii].
[i] Meng Y, Zhang Y, Liu M, Huang YK, Zhang J, Yao Q, Zhao YL, Xiong JJ. Evaluating Intestinal Permeability by Measuring Plasma Endotoxin and Diamine Oxidase in Children with Acute Lymphoblastic Leukemia Treated with High-dose Methotrexate. Anticancer Agents Med Chem. 2016;16(3):387-92.
[ii] Beutheu S, Ouelaa W, Guérin C, Belmonte L, Aziz M, Tennoune N, Bôle-Feysot C, Galas L, Déchelotte P, Coëffier M. Glutamine supplementation, but not combined glutamine and arginine supplementation, improves gut barrier function during chemotherapy-induced intestinal mucositis in rats. Clin Nutr. 2014 Aug;33(4):694-701
[iii] Beutheu S, Ghouzali I, Galas L, Déchelotte P, Coëffier M. Glutamine and arginine improve permeability and tight junction protein expression in methotrexate-treated Caco-2 cells. Clin Nutr. 2013 Oct;32(5):863-9.
[iv] Beutheu Youmba S, Belmonte L, Galas L, Boukhettala N, Bôle-Feysot C, Déchelotte P, Coëffier M. Methotrexate modulates tight junctions through NF-κB, MEK, and JNK pathways. J Pediatr Gastroenterol Nutr. 2012 Apr;54(4):463-70
[v] Hamada K, Shitara Y, Sekine S, Horie T. Zonula Occludens-1 alterations and enhanced intestinal permeability in methotrexate-treated rats. Cancer Chemother Pharmacol. 2010 Nov;66(6):1031-8
[vi] Southcott E, Tooley KL, Howarth GS, Davidson GP, Butler RN. Yoghurts containing probiotics reduce disruption of the small intestinal barrier in methotrexate-treated rats. Dig Dis Sci. 2008 Jul;53(7):1837-41
[vii] Song WB, Zhang ZS, Xiao B. [Protective effect of curcumin against methotrexate-induced small intestinal damage in rats]. Nan Fang Yi Ke Da Xue Xue Bao. 2008 Jan;28(1):119-21
[viii] Song D, Shi B, Xue H, Li Y, Yang X, Yu B, Xu Z, Liu F, Li J. Confirmation and prevention of intestinal barrier dysfunction and bacterial translocation caused by methotrexate. Dig Dis Sci. 2006 Sep;51(9):1549-56
[ix] Sturgeon C, Fasano A. Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases. Tissue Barriers. 2016 Oct 21;4(4):e1251384. Doi: 10.1080/21688370.2016.1251384
[x] Fijlstra M, Ferdous M, Koning AM, Rings EH, Harmsen HJ, Tissing WJ. Substantial decreases in the number and diversity of microbiota during chemotherapy-induced gastrointestinal mucositis in a rat model. Support Care Cancer. 2015 Jun;23(6):1513-22
[xi] Breban M. Gut microbiota and inflammatory joint diseases. Joint Bone Spine. 2016 Dec;83(6):645-649.
[xii] Ahrne S, Hagslatt ML. Effect of lactobacilli on paracellular permeability in the gut. Nutrients. 2011 Jan;3(1):104-17.
[xiii] Nariya M, Shukla V, Jain S, Ravishankar B. Comparison of enteroprotective efficacy of triphala formulations (Indian Herbal Drug) on methotrexate-induced small intestinal damage in rats. Phytother Res. 2009 Aug;23(8):1092-8
[xiv] Rodríguez-Reyna TS, Martínez-Reyes C, Yamamoto-Furusho JK. Rheumatic manifestations of inflammatory bowel disease. World J Gastroenterol. 2009 Nov 28;15(44):5517-24
[xv] Maeda T, Miyazono Y, Ito K, Hamada K, Sekine S, Horie T. Oxidative stress and enhanced paracellular permeability in the small intestine of methotrexate-treated rats. Cancer Chemother Pharmacol. 2010 May;65(6):1117-23
[xvi] Tooley KL, Howarth GS, Lymn KA, Lawrence A, Butler RN. Oral ingestion of streptococcus thermophilus diminishes severity of small intestinal mucositis in methotrexate treated rats. Cancer Biol Ther. 2006 Jun;5(6):593-600
[xvii] Yáñez JA, Teng XW, Roupe KA, Fariss MW, Davies NM. Chemotherapy induced gastrointestinal toxicity in rats: involvement of mitochondrial DNA, gastrointestinal permeability and cyclooxygenase -2. J Pharm Pharm Sci. 2003 Sep-Dec;6(3):308-14