Exploration of pathogenesis of rheumatoid arthritis and efficacy of methotrexate based on intestinal microbiota_West China Medical Journal

Authors：

ZHANG Rui ¹ , ZHANG Li ² , MAO Jing ¹ , LI Wenhua ¹ , ZHANG Xianmeng ¹ ,  SHEN Haili ²

1. The Second Clinical Medical School of Lanzhou University, Lanzhou, Gansu 730000, P. R. China;
2. Department of Rheumatology and Immunology, the Second Hospital of Lanzhou University, Lanzhou, Gansu 730030, P. R. China;

Corresponding author：

SHEN Haili, Email: shenhl@lzu.edu.cn

Keywords：

Intestinal microbiota; methotrexate; rheumatoid arthritis; immune response

DOI：

10.7507/1002-0179.202405209

Video：

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Rheumatoid arthritis (RA) is one of the most common immune-mediated diseases, and the interaction between the intestinal microbiota and the patient’s immune system may play a role in the occurrence and development of RA. Methotrexate (MTX), as a first-line drug for the treatment of RA, can be directly and indirectly influenced by intestinal microbiota and its enzyme products to affect the bioavailability, clinical efficacy, and toxicity of the drug. Therefore, it is crucial to understand the mechanism by which intestinal microbiota affects RA and the impact of intestinal microbiota on the efficacy of MTX. This article provides a review of the mechanisms by which intestinal microbiota may contribute to the pathogenesis of RA, as well as the role and impact of intestinal microbiota in MTX drug metabolism and treatment response.

Citation： ZHANG Rui, ZHANG Li, MAO Jing, LI Wenhua, ZHANG Xianmeng, SHEN Haili. Exploration of pathogenesis of rheumatoid arthritis and efficacy of methotrexate based on intestinal microbiota. West China Medical Journal, 2024, 39(8): 1302-1307. doi: 10.7507/1002-0179.202405209 Copy

1.	Romero-Figueroa MDS, Ramírez-Durán N, Montiel-Jarquín AJ, et al. Gut-joint axis: gut dysbiosis can contribute to the onset of rheumatoid arthritis via multiple pathways. Front Cell Infect Microbiol, 2023, 13: 1092118.
2.	Attur M, Scher JU, Abramson SB, et al. Role of intestinal dysbiosis and nutrition in rheumatoid arthritis. Cells, 2022, 11(15): 2436.
3.	Gilbert BTP, Tadeo RYT, Lamacchia C, et al. Gut microbiome and intestinal inflammation in preclinical stages of rheumatoid arthritis. RMD Open, 2024, 10(1): e003589.
4.	Holers VM, Demoruelle MK, Kuhn KA, et al. Rheumatoid arthritis and the mucosal origins hypothesis: protection turns to destruction. Nat Rev Rheumatol, 2018, 14(9): 542-557.
5.	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.
6.	Fan J, Jiang T, He D. Advances in the implications of the gut microbiota on the treatment efficacy of disease-modifying anti-rheumatic drugs in rheumatoid arthritis. Front Immunol, 2023, 14: 1189036.
7.	Arumugam M, Raes J, Pelletier E, et al. Enterotypes of the human gut microbiome. Nature, 2011, 473(7346): 174-180.
8.	Rooney CM, Mankia K, Emery P. The role of the microbiome in driving RA-related autoimmunity. Front Cell Dev Biol, 2020, 8: 538130.
9.	Mangalea MR, Paez-Espino D, Kieft K, et al. Individuals at risk for rheumatoid arthritis harbor differential intestinal bacteriophage communities with distinct metabolic potential. Cell Host Microbe, 2021, 29(5): 726-739.e5.
10.	Wang X, Yuan W, Yang C, et al. Emerging role of gut microbiota in autoimmune diseases. Front Immunol, 2024, 15: 1365554.
11.	Shin C, Kim YK. Autoimmunity in microbiome-mediated diseases and novel therapeutic approaches. Curr Opin Pharmacol, 2019, 49: 34-42.
12.	Zhang X, Chen BD, Zhao LD, et al. The gut microbiota: emerging evidence in autoimmune diseases. Trends Mol Med, 2020, 26(9): 862-873.
13.	Wang Y, Yin Y, Chen X, et al. Induction of intestinal Th17 cells by flagellins from segmented filamentous bacteria. Front Immunol, 2019, 10: 2750.
14.	Li Y, Zhang SX, Yin XF, et al. The gut microbiota and its relevance to peripheral lymphocyte subpopulations and cytokines in patients with rheumatoid arthritis. J Immunol Res, 2021, 2021: 6665563.
15.	Marazzato M, Iannuccelli C, Guzzo MP, et al. Gut microbiota structure and metabolites, before and after treatment in early rheumatoid arthritis patients: a pilot study. Front Med (Lausanne), 2022, 9: 921675.
16.	Zhao T, Wei Y, Zhu Y, et al. Gut microbiota and rheumatoid arthritis: from pathogenesis to novel therapeutic opportunities. Front Immunol, 2022, 13: 1007165.
17.	Sun Y, Chen Q, Lin P, et al. Characteristics of gut microbiota in patients with rheumatoid arthritis in Shanghai, China. Front Cell Infect Microbiol, 2019, 9: 369.
18.	Narushima S, Sugiura Y, Oshima K, et al. Characterization of the 17 strains of regulatory T cell-inducing human-derived Clostridia. Gut Microbes, 2014, 5(3): 333-339.
19.	Chiang HI, Li JR, Liu CC, et al. An association of gut microbiota with different phenotypes in Chinese patients with rheumatoid arthritis. J Clin Med, 2019, 8(11): 1770.
20.	Cheng H, Guan X, Chen D, et al. The Th17/Treg cell balance: a gut microbiota-modulated story. Microorganisms, 2019, 7(12): 583.
21.	Wu R, Wang D, Cheng L, et al. Impaired immune tolerance mediated by reduced Tfr cells in rheumatoid arthritis linked to gut microbiota dysbiosis and altered metabolites. Arthritis Res Ther, 2024, 26(1): 21.
22.	Xu X, Wang M, Wang Z, et al. The bridge of the gut-joint axis: gut microbial metabolites in rheumatoid arthritis. Front Immunol, 2022, 13: 1007610.
23.	Foster KR, Schluter J, Coyte KZ, et al. The evolution of the host microbiome as an ecosystem on a leash. Nature, 2017, 548(7665): 43-51.
24.	Audo R, Sanchez P, Rivière B, et al. Rheumatoid arthritis is associated with increased gut permeability and bacterial translocation which are reversed by inflammation control. Rheumatology (Oxford), 2022, 10: keac454.
25.	Tajik N, Frech M, Schulz O, et al. Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis. Nat Commun, 2020, 11(1): 1995.
26.	Litvak Y, Byndloss MX, Bäumler AJ. Colonocyte metabolism shapes the gut microbiota. Science, 2018, 362(6418): eaat9076.
27.	Opoku YK, Asare KK, Ghartey-Quansah G, et al. Intestinal microbiome-rheumatoid arthritis crosstalk: the therapeutic role of probiotics. Front Microbiol, 2022, 13: 996031.
28.	Brandl C, Bucci L, Schett G, et al. Crossing the barriers: revisiting the gut feeling in rheumatoid arthritis. Eur J Immunol, 2021, 51(4): 798-810.
29.	Pacifici R. T cells, osteoblasts, and osteocytes: interacting lineages key for the bone anabolic and catabolic activities of parathyroid hormone. Ann N Y Acad Sci, 2016, 1364(1): 11-24.
30.	Zhou L, Zhang M, Wang Y, et al. Faecalibacterium prausnitzii produces butyrate to maintain Th17/Treg balance and to ameliorate colorectal colitis by inhibiting histone deacetylase 1. Inflamm Bowel Dis, 2018, 24(9): 1926-1940.
31.	Zhang M, Zhou L, Wang Y, et al. Faecalibacterium prausnitzii produces butyrate to decrease c-Myc-related metabolism and Th17 differentiation by inhibiting histone deacetylase 3. Int Immunol, 2019, 31(8): 499-514.
32.	Matei DE, Menon M, Alber DG, et al. Intestinal barrier dysfunction plays an integral role in arthritis pathology and can be targeted to ameliorate disease. Med, 2021, 2(7): 864-883.e9.
33.	Rashid T, Ebringer A. Autoimmunity in rheumatic diseases is induced by microbial infections via crossreactivity or molecular mimicry. Autoimmune Dis, 2012, 2012: 539282.
34.	Garabatos N, Santamaria P. Gut microbial antigenic mimicry in autoimmunity. Front Immunol, 2022, 13: 873607.
35.	Zhou C, Zhao H, Xiao XY, et al. Metagenomic profiling of the pro-inflammatory gut microbiota in ankylosing spondylitis. J Autoimmun, 2020, 107: 102360.
36.	Pianta A, Arvikar SL, Strle K, et al. Two rheumatoid arthritis-specific autoantigens correlate microbial immunity with autoimmune responses in joints. J Clin Invest, 2017, 127(8): 2946-2956.
37.	方灵芝, 曹格溪, 关丽叶, 等. 某院门诊甲氨蝶呤片超说明书使用的循证医学分析与管理. 中国现代应用药学, 2020, 37(16): 1993-1997.
38.	Schiff MH, Sadowski P. Oral to subcutaneous methotrexate dose-conversion strategy in the treatment of rheumatoid arthritis. Rheumatol Int, 2017, 37(2): 213-218.
39.	Cronstein BN, Aune TM. Methotrexate and its mechanisms of action in inflammatory arthritis. Nat Rev Rheumatol, 2020, 16(3): 145-154.
40.	Maksimovic V, Pavlovic-Popovic Z, Vukmirovic S, et al. Molecular mechanism of action and pharmacokinetic properties of methotrexate. Mol Biol Rep, 2020, 47(6): 4699-4708.
41.	Zaragoza-García O, Castro-Alarcón N, Pérez-Rubio G, et al. DMARDs-gut microbiota feedback: implications in the response to therapy. Biomolecules, 2020, 10(11): 1479.
42.	Nayak RR, Alexander M, Deshpande I, et al. Methotrexate impacts conserved pathways in diverse human gut bacteria leading to decreased host immune activation. Cell Host Microbe, 2021, 29(3): 362-377.e11.
43.	Tang D, Zeng T, Wang Y, et al. Dietary restriction increases protective gut bacteria to rescue lethal methotrexate-induced intestinal toxicity. Gut Microbes, 2020, 12(1): 1714401.
44.	Neumann VC, Shinebaum R, Cooke EM, et al. Effects of sulphasalazine on faecal flora in patients with rheumatoid arthritis: a comparison with penicillamine. Br J Rheumatol, 1987, 26(5): 334-337.
45.	Rodrigues GSP, Cayres LCF, Gonçalves FP, et al. Detection of increased relative expression units of bacteroides and prevotella, and decreased Clostridium leptum in stool samples from brazilian rheumatoid arthritis patients: a pilot study. Microorganisms, 2019, 7(10): 413.
46.	Gargaro AR, Soteriou A, Frenkiel TA, et al. The solution structure of the complex of Lactobacillus casei dihydrofolate reductase with methotrexate. J Mol Biol, 1998, 277(1): 119-134.
47.	Huang X, Fang Q, Rao T, et al. Leucovorin ameliorated methotrexate induced intestinal toxicity via modulation of the gut microbiota. Toxicol Appl Pharmacol, 2020, 391: 114900.
48.	Scher JU, Sczesnak A, Longman RS, et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. Elife, 2013, 2: e01202.
49.	Artacho A, Isaac S, Nayak R, et al. The pretreatment gut microbiome is associated with lack of response to methotrexate in new-onset rheumatoid arthritis. Arthritis Rheumatol, 2021, 73(6): 931-942.
50.	Han M, Zhang N, Mao Y, et al. The potential of gut microbiota metabolic capability to detect drug response in rheumatoid arthritis patients. Front Microbiol, 2022, 13: 839015.
51.	Pannu AK. Methotrexate overdose in clinical practice. Curr Drug Metab, 2019, 20(9): 714-719.
52.	Yan H, Su R, Xue H, et al. Pharmacomicrobiology of methotrexate in rheumatoid arthritis: gut microbiome as predictor of therapeutic response. Front Immunol, 2021, 12: 789334.
53.	Touchefeu Y, Montassier E, Nieman K, et al. Systematic review: the role of the gut microbiota in chemotherapy- or radiation-induced gastrointestinal mucositis - current evidence and potential clinical applications. Aliment Pharmacol Ther, 2014, 40(5): 409-421.
54.	Letertre MPM, Munjoma N, Wolfer K, et al. A two-way interaction between methotrexate and the gut microbiota of male Sprague-Dawley rats. J Proteome Res, 2020, 19(8): 3326-3339.
55.	Higuchi T, Yoshimura M, Oka S, et al. Modulation of methotrexate-induced intestinal mucosal injury by dietary factors. Hum Exp Toxicol, 2020, 39(4): 500-513.
56.	Scher JU, Nayak RR, Ubeda C, et al. Pharmacomicrobiomics in inflammatory arthritis: gut microbiome as modulator of therapeutic response. Nat Rev Rheumatol, 2020, 16(5): 282-292.
57.	Maier L, Pruteanu M, Kuhn M, et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature, 2018, 555(7698): 623-628.

1. Romero-Figueroa MDS, Ramírez-Durán N, Montiel-Jarquín AJ, et al. Gut-joint axis: gut dysbiosis can contribute to the onset of rheumatoid arthritis via multiple pathways. Front Cell Infect Microbiol, 2023, 13: 1092118.
2. Attur M, Scher JU, Abramson SB, et al. Role of intestinal dysbiosis and nutrition in rheumatoid arthritis. Cells, 2022, 11(15): 2436.
3. Gilbert BTP, Tadeo RYT, Lamacchia C, et al. Gut microbiome and intestinal inflammation in preclinical stages of rheumatoid arthritis. RMD Open, 2024, 10(1): e003589.
4. Holers VM, Demoruelle MK, Kuhn KA, et al. Rheumatoid arthritis and the mucosal origins hypothesis: protection turns to destruction. Nat Rev Rheumatol, 2018, 14(9): 542-557.
5. 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.
6. Fan J, Jiang T, He D. Advances in the implications of the gut microbiota on the treatment efficacy of disease-modifying anti-rheumatic drugs in rheumatoid arthritis. Front Immunol, 2023, 14: 1189036.
7. Arumugam M, Raes J, Pelletier E, et al. Enterotypes of the human gut microbiome. Nature, 2011, 473(7346): 174-180.
8. Rooney CM, Mankia K, Emery P. The role of the microbiome in driving RA-related autoimmunity. Front Cell Dev Biol, 2020, 8: 538130.
9. Mangalea MR, Paez-Espino D, Kieft K, et al. Individuals at risk for rheumatoid arthritis harbor differential intestinal bacteriophage communities with distinct metabolic potential. Cell Host Microbe, 2021, 29(5): 726-739.e5.
10. Wang X, Yuan W, Yang C, et al. Emerging role of gut microbiota in autoimmune diseases. Front Immunol, 2024, 15: 1365554.
11. Shin C, Kim YK. Autoimmunity in microbiome-mediated diseases and novel therapeutic approaches. Curr Opin Pharmacol, 2019, 49: 34-42.
12. Zhang X, Chen BD, Zhao LD, et al. The gut microbiota: emerging evidence in autoimmune diseases. Trends Mol Med, 2020, 26(9): 862-873.
13. Wang Y, Yin Y, Chen X, et al. Induction of intestinal Th17 cells by flagellins from segmented filamentous bacteria. Front Immunol, 2019, 10: 2750.
14. Li Y, Zhang SX, Yin XF, et al. The gut microbiota and its relevance to peripheral lymphocyte subpopulations and cytokines in patients with rheumatoid arthritis. J Immunol Res, 2021, 2021: 6665563.
15. Marazzato M, Iannuccelli C, Guzzo MP, et al. Gut microbiota structure and metabolites, before and after treatment in early rheumatoid arthritis patients: a pilot study. Front Med (Lausanne), 2022, 9: 921675.
16. Zhao T, Wei Y, Zhu Y, et al. Gut microbiota and rheumatoid arthritis: from pathogenesis to novel therapeutic opportunities. Front Immunol, 2022, 13: 1007165.
17. Sun Y, Chen Q, Lin P, et al. Characteristics of gut microbiota in patients with rheumatoid arthritis in Shanghai, China. Front Cell Infect Microbiol, 2019, 9: 369.
18. Narushima S, Sugiura Y, Oshima K, et al. Characterization of the 17 strains of regulatory T cell-inducing human-derived Clostridia. Gut Microbes, 2014, 5(3): 333-339.
19. Chiang HI, Li JR, Liu CC, et al. An association of gut microbiota with different phenotypes in Chinese patients with rheumatoid arthritis. J Clin Med, 2019, 8(11): 1770.
20. Cheng H, Guan X, Chen D, et al. The Th17/Treg cell balance: a gut microbiota-modulated story. Microorganisms, 2019, 7(12): 583.
21. Wu R, Wang D, Cheng L, et al. Impaired immune tolerance mediated by reduced Tfr cells in rheumatoid arthritis linked to gut microbiota dysbiosis and altered metabolites. Arthritis Res Ther, 2024, 26(1): 21.
22. Xu X, Wang M, Wang Z, et al. The bridge of the gut-joint axis: gut microbial metabolites in rheumatoid arthritis. Front Immunol, 2022, 13: 1007610.
23. Foster KR, Schluter J, Coyte KZ, et al. The evolution of the host microbiome as an ecosystem on a leash. Nature, 2017, 548(7665): 43-51.
24. Audo R, Sanchez P, Rivière B, et al. Rheumatoid arthritis is associated with increased gut permeability and bacterial translocation which are reversed by inflammation control. Rheumatology (Oxford), 2022, 10: keac454.
25. Tajik N, Frech M, Schulz O, et al. Targeting zonulin and intestinal epithelial barrier function to prevent onset of arthritis. Nat Commun, 2020, 11(1): 1995.
26. Litvak Y, Byndloss MX, Bäumler AJ. Colonocyte metabolism shapes the gut microbiota. Science, 2018, 362(6418): eaat9076.
27. Opoku YK, Asare KK, Ghartey-Quansah G, et al. Intestinal microbiome-rheumatoid arthritis crosstalk: the therapeutic role of probiotics. Front Microbiol, 2022, 13: 996031.
28. Brandl C, Bucci L, Schett G, et al. Crossing the barriers: revisiting the gut feeling in rheumatoid arthritis. Eur J Immunol, 2021, 51(4): 798-810.
29. Pacifici R. T cells, osteoblasts, and osteocytes: interacting lineages key for the bone anabolic and catabolic activities of parathyroid hormone. Ann N Y Acad Sci, 2016, 1364(1): 11-24.
30. Zhou L, Zhang M, Wang Y, et al. Faecalibacterium prausnitzii produces butyrate to maintain Th17/Treg balance and to ameliorate colorectal colitis by inhibiting histone deacetylase 1. Inflamm Bowel Dis, 2018, 24(9): 1926-1940.
31. Zhang M, Zhou L, Wang Y, et al. Faecalibacterium prausnitzii produces butyrate to decrease c-Myc-related metabolism and Th17 differentiation by inhibiting histone deacetylase 3. Int Immunol, 2019, 31(8): 499-514.
32. Matei DE, Menon M, Alber DG, et al. Intestinal barrier dysfunction plays an integral role in arthritis pathology and can be targeted to ameliorate disease. Med, 2021, 2(7): 864-883.e9.
33. Rashid T, Ebringer A. Autoimmunity in rheumatic diseases is induced by microbial infections via crossreactivity or molecular mimicry. Autoimmune Dis, 2012, 2012: 539282.
34. Garabatos N, Santamaria P. Gut microbial antigenic mimicry in autoimmunity. Front Immunol, 2022, 13: 873607.
35. Zhou C, Zhao H, Xiao XY, et al. Metagenomic profiling of the pro-inflammatory gut microbiota in ankylosing spondylitis. J Autoimmun, 2020, 107: 102360.
36. Pianta A, Arvikar SL, Strle K, et al. Two rheumatoid arthritis-specific autoantigens correlate microbial immunity with autoimmune responses in joints. J Clin Invest, 2017, 127(8): 2946-2956.
37. 方灵芝, 曹格溪, 关丽叶, 等. 某院门诊甲氨蝶呤片超说明书使用的循证医学分析与管理. 中国现代应用药学, 2020, 37(16): 1993-1997.
38. Schiff MH, Sadowski P. Oral to subcutaneous methotrexate dose-conversion strategy in the treatment of rheumatoid arthritis. Rheumatol Int, 2017, 37(2): 213-218.
39. Cronstein BN, Aune TM. Methotrexate and its mechanisms of action in inflammatory arthritis. Nat Rev Rheumatol, 2020, 16(3): 145-154.
40. Maksimovic V, Pavlovic-Popovic Z, Vukmirovic S, et al. Molecular mechanism of action and pharmacokinetic properties of methotrexate. Mol Biol Rep, 2020, 47(6): 4699-4708.
41. Zaragoza-García O, Castro-Alarcón N, Pérez-Rubio G, et al. DMARDs-gut microbiota feedback: implications in the response to therapy. Biomolecules, 2020, 10(11): 1479.
42. Nayak RR, Alexander M, Deshpande I, et al. Methotrexate impacts conserved pathways in diverse human gut bacteria leading to decreased host immune activation. Cell Host Microbe, 2021, 29(3): 362-377.e11.
43. Tang D, Zeng T, Wang Y, et al. Dietary restriction increases protective gut bacteria to rescue lethal methotrexate-induced intestinal toxicity. Gut Microbes, 2020, 12(1): 1714401.
44. Neumann VC, Shinebaum R, Cooke EM, et al. Effects of sulphasalazine on faecal flora in patients with rheumatoid arthritis: a comparison with penicillamine. Br J Rheumatol, 1987, 26(5): 334-337.
45. Rodrigues GSP, Cayres LCF, Gonçalves FP, et al. Detection of increased relative expression units of bacteroides and prevotella, and decreased Clostridium leptum in stool samples from brazilian rheumatoid arthritis patients: a pilot study. Microorganisms, 2019, 7(10): 413.
46. Gargaro AR, Soteriou A, Frenkiel TA, et al. The solution structure of the complex of Lactobacillus casei dihydrofolate reductase with methotrexate. J Mol Biol, 1998, 277(1): 119-134.
47. Huang X, Fang Q, Rao T, et al. Leucovorin ameliorated methotrexate induced intestinal toxicity via modulation of the gut microbiota. Toxicol Appl Pharmacol, 2020, 391: 114900.
48. Scher JU, Sczesnak A, Longman RS, et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. Elife, 2013, 2: e01202.
49. Artacho A, Isaac S, Nayak R, et al. The pretreatment gut microbiome is associated with lack of response to methotrexate in new-onset rheumatoid arthritis. Arthritis Rheumatol, 2021, 73(6): 931-942.
50. Han M, Zhang N, Mao Y, et al. The potential of gut microbiota metabolic capability to detect drug response in rheumatoid arthritis patients. Front Microbiol, 2022, 13: 839015.
51. Pannu AK. Methotrexate overdose in clinical practice. Curr Drug Metab, 2019, 20(9): 714-719.
52. Yan H, Su R, Xue H, et al. Pharmacomicrobiology of methotrexate in rheumatoid arthritis: gut microbiome as predictor of therapeutic response. Front Immunol, 2021, 12: 789334.
53. Touchefeu Y, Montassier E, Nieman K, et al. Systematic review: the role of the gut microbiota in chemotherapy- or radiation-induced gastrointestinal mucositis - current evidence and potential clinical applications. Aliment Pharmacol Ther, 2014, 40(5): 409-421.
54. Letertre MPM, Munjoma N, Wolfer K, et al. A two-way interaction between methotrexate and the gut microbiota of male Sprague-Dawley rats. J Proteome Res, 2020, 19(8): 3326-3339.
55. Higuchi T, Yoshimura M, Oka S, et al. Modulation of methotrexate-induced intestinal mucosal injury by dietary factors. Hum Exp Toxicol, 2020, 39(4): 500-513.
56. Scher JU, Nayak RR, Ubeda C, et al. Pharmacomicrobiomics in inflammatory arthritis: gut microbiome as modulator of therapeutic response. Nat Rev Rheumatol, 2020, 16(5): 282-292.
57. Maier L, Pruteanu M, Kuhn M, et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature, 2018, 555(7698): 623-628.

West China Medical Journal

Exploration of pathogenesis of rheumatoid arthritis and efficacy of methotrexate based on intestinal microbiota

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