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A high-fiber diet synergizes with Prevotella copri and exacerbates rheumatoid arthritis


Both preclinical and established rheumatoid arthritis (RA) patients display alterations in the gut microbiome. Prevotella spp. are preferentially enriched in a subset of RA patients. Here, we isolated a Prevotella strain, P. copri RA, from the feces of RA patients and showed that colonization of P. copri RA exacerbated arthritis in a collagen-induced arthritis (CIA) model. With the presence of P. copri RA colonization, a high-fiber diet exacerbated arthritis via microbial alterations and intestinal inflammation. Colonization of P. copri together with a high-fiber diet enabled the digestion of complex fiber, which led to the overproduction of organic acids, including fumarate, succinate and short-chain fatty acids. Succinate promoted proinflammatory responses in macrophages, and supplementation with succinate exacerbated arthritis in the CIA model. Our findings highlight the importance of dysbiosis when evaluating the effects of dietary interventions on RA pathogenesis and provide new insight into dietary interventions or microbiome modifications to improve RA management.

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Data availability

The genome sequences and RNA sequence data produced in this study are available at the Sequence Read Archive of the National Center for Biotechnology Information (the accession numbers for the sequences reported in this paper are NCBI SRA: SRR14576269).


  1. Raychaudhuri S, Sandor C, Stahl EA, Freudenberg J, Lee HS, Jia X, et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet. 2012;44:291–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Scher JU, Abramson SB. The microbiome and rheumatoid arthritis. Nat Rev Rheumatol. 2011;7:569–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bang SY, Lee KH, Cho SK, Lee HS, Lee KW, Bae SC. Smoking increases rheumatoid arthritis susceptibility in individuals carrying the HLA-DRB1 shared epitope, regardless of rheumatoid factor or anti-cyclic citrullinated peptide antibody status. Arthritis Rheum. 2010;62:369–77.

    Article  CAS  PubMed  Google Scholar 

  4. Guerreiro CS, Calado A, Sousa J, Fonseca JE. Diet, microbiota, and gut permeability-the unknown triad in rheumatoid arthritis. Front Med (Lausanne). 2018;5:349.

    Article  PubMed  Google Scholar 

  5. Zhang X, Zhang D, Jia H, Feng Q, Wang D, Liang D, et al. The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment. Nat Med. 2015;21:895–905.

    Article  CAS  PubMed  Google Scholar 

  6. Scher JU, Sczesnak A, Longman RS, Segata N, Ubeda C, Bielski C, et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife. 2013;2:e01202.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Alpizar-Rodriguez D, Lesker TR, Gronow A, Gilbert B, Raemy E, Lamacchia C, et al. Prevotella copri in individuals at risk for rheumatoid arthritis. Ann Rheum Dis. 2019;78:590–3.

    Article  CAS  PubMed  Google Scholar 

  8. Jubair WK, Hendrickson JD, Severs EL, Schulz HM, Adhikari S, Ir D, et al. Modulation of inflammatory arthritis in mice by gut microbiota through mucosal inflammation and autoantibody generation. Arthritis Rheumatol. 2018;70:1220–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tett A, Pasolli E, Masetti G, Ercolini D, Segata N. Prevotella diversity, niches and interactions with the human host. Nat Rev Microbiol. 2021.

  10. Kovatcheva-Datchary P, Nilsson A, Akrami R, Lee YS, De Vadder F, Arora T, et al. Dietary fiber-induced improvement in glucose metabolism is associated with increased abundance of prevotella. Cell Metab. 2015;22:971–82.

    Article  CAS  PubMed  Google Scholar 

  11. Marietta EV, Murray JA, Luckey DH, Jeraldo PR, Lamba A, Patel R, et al. Suppression of inflammatory arthritis by human gut-derived prevotella histicola in humanized mice. Arthritis Rheumatol. 2016;68:2878–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Maeda Y, Kurakawa T, Umemoto E, Motooka D, Ito Y, Gotoh K, et al. Dysbiosis contributes to arthritis development via activation of autoreactive T cells in the intestine. Arthritis Rheumatol. 2016;68:2646–61.

    Article  CAS  PubMed  Google Scholar 

  13. De Filippis F, Pasolli E, Tett A, Tarallo S, Naccarati A, De Angelis M, et al. Distinct genetic and functional traits of human intestinal prevotella copri strains are associated with different habitual diets. Cell Host Microbe. 2019;25:444–53 e443.

    Article  PubMed  Google Scholar 

  14. Gálvez EJC, Iljazovic A, Amend L, Lesker TR, Renault T, Thiemann S, et al. Distinct polysaccharide utilization determines interspecies competition between intestinal prevotella spp. Cell Host Microbe. 2020;28:838–52 e836.

    Article  PubMed  Google Scholar 

  15. Tett A, Huang KD, Asnicar F, Fehlner-Peach H, Pasolli E, Karcher N, et al. The Prevotella copri complex comprises four distinct clades underrepresented in Westernized populations. Cell Host Microbe. 2019;26:666–79 e667.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wright DP, Rosendale DI, Robertson AM. Prevotella enzymes involved in mucin oligosaccharide degradation and evidence for a small operon of genes expressed during growth on mucin. FEMS Microbiol Lett. 2000;190:73–9.

    Article  CAS  PubMed  Google Scholar 

  17. Fehlner-Peach H, Magnabosco C, Raghavan V, Scher JU, Tett A, Cox LM, et al. Distinct polysaccharide utilization profiles of human intestinal prevotella copri Isolates. Cell Host Microbe. 2019;26:680–90.e685.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. De Vadder F, Kovatcheva-Datchary P, Zitoun C, Duchampt A, Bäckhed F, Mithieux G. Microbiota-produced succinate improves glucose homeostasis via intestinal gluconeogenesis. Cell Metab. 2016;24:151–7.

    Article  PubMed  Google Scholar 

  19. Singh V, Yeoh BS, Chassaing B, Xiao X, Saha P, Aguilera Olvera R, et al. Dysregulated microbial fermentation of soluble fiber induces cholestatic liver cancer. Cell. 2018;175:679–94 e622.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Singh V, Yeoh BS, Walker RE, Xiao X, Saha P, Golonka RM, et al. Microbiota fermentation-NLRP3 axis shapes the impact of dietary fibres on intestinal inflammation. Gut. 2019;68:1801–1812.

    Article  CAS  PubMed  Google Scholar 

  21. Ferreyra JA, Wu KJ, Hryckowian AJ, Bouley DM, Weimer BC, Sonnenburg JL. Gut microbiota-produced succinate promotes C. difficile infection after antibiotic treatment or motility disturbance. Cell Host Microbe. 2014;16:770–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Connors J, Dawe N & Van Limbergen J. The role of succinate in the regulation of intestinal inflammation. Nutrients. 2018;11.

  23. Battino M, Forbes-Hernández TY, Gasparrini M, Afrin S, Cianciosi D, Zhang J, et al. Relevance of functional foods in the Mediterranean diet: the role of olive oil, berries and honey in the prevention of cancer and cardiovascular diseases. Crit Rev Food Sci Nutr. 2019;59:893–920.

    Article  CAS  PubMed  Google Scholar 

  24. Petersson S, Philippou E, Rodomar C, Nikiphorou E. The Mediterranean diet, fish oil supplements and Rheumatoid arthritis outcomes: evidence from clinical trials. Autoimmun Rev. 2018;17:1105–14.

    Article  CAS  PubMed  Google Scholar 

  25. Hu Y, Costenbader KH, Gao X, Hu FB, Karlson EW, Lu B. Mediterranean diet and incidence of rheumatoid arthritis in women. Arthritis Care Res (Hoboken). 2015;67:597–606.

    Article  PubMed  Google Scholar 

  26. Ingegnoli F, Schioppo T, Scotti I, Ubiali T, De Lucia O, Murgo A, et al. Adherence to Mediterranean diet and patient perception of rheumatoid arthritis. Complement Ther Med. 2020;52:102519.

    Article  PubMed  Google Scholar 

  27. Wastyk HC, Fragiadakis GK, Perelman D, Dahan D, Merrill BD, Yu FB, et al. Gut-microbiota-targeted diets modulate human immune status. Cell. 2021;184:4137–53 e4114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Brand DD, Latham KA, Rosloniec EF. Collagen-induced arthritis. Nat Protoc. 2007;2:1269–75.

    Article  CAS  PubMed  Google Scholar 

  29. Qiu Z, Sheridan BS. Isolating lymphocytes from the mouse small intestinal immune system. J Vis Exp. 2018.

  30. Wang Y, Li N, Yang JJ, Zhao DM, Chen B, Zhang GQ, et al. Probiotics and fructo-oligosaccharide intervention modulate the microbiota-gut brain axis to improve autism spectrum reducing also the hyper-serotonergic state and the dopamine metabolism disorder. Pharm Res. 2020;157:104784.

    Article  CAS  Google Scholar 

  31. Zheng X, Qiu Y, Zhong W, Baxter S, Su M, Li Q, et al. A targeted metabolomic protocol for short-chain fatty acids and branched-chain amino acids. Metabolomics. 2013;9:818–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhang H, Yohe T, Huang L, Entwistle S, Wu P, Yang Z, et al. dbCAN2: a meta server for automated carbohydrate-active enzyme annotation. Nucleic Acids Res. 2018;46:W95–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gatto D, Paus D, Basten A, Mackay CR, Brink R. Guidance of B cells by the orphan G protein-coupled receptor EBI2 shapes humoral immune responses. Immunity. 2009;31:259–69.

    Article  CAS  PubMed  Google Scholar 

  34. Ikeda Y, Ikata T, Mishiro T, Nakano S, Ikebe M, Yasuoka S. Cathepsins B and L in synovial fluids from patients with rheumatoid arthritis and the effect of cathepsin B on the activation of pro-urokinase. J Med Invest. 2000;47:61–75.

    CAS  PubMed  Google Scholar 

  35. Chiang H-I, Li J-R, Liu C-C, Liu P-Y, Chen H-H, Chen Y-M, et al. An association of gut microbiota with different phenotypes in chinese patients with rheumatoid arthritis. J Clin Med. 2019;8.

  36. Khan S, Waliullah S, Godfrey V, Khan MAW, Ramachandran RA, Cantarel BL, et al. Dietary simple sugars alter microbial ecology in the gut and promote colitis in mice. Sci Transl Med. 2020;12.

  37. Ndeh D, Rogowski A, Cartmell A, Luis AS, Baslé A, Gray J, et al. Complex pectin metabolism by gut bacteria reveals novel catalytic functions. Nature. 2017;544:65–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, et al. Succinate is an inflammatory signal that induces IL-1 beta through HIF-1 alpha. Nature. 2013;496:238-+.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Pianta A, Arvikar S, Strle K, Drouin EE, Wang Q, Costello CE, et al. Evidence of the immune relevance of prevotella copri, a gut microbe, in patients with rheumatoid arthritis. Arthritis Rheumatol. 2017;69:964–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhou C, Zhao H, Xiao XY, Chen BD, Guo RJ, Wang Q, et al. Metagenomic profiling of the pro-inflammatory gut microbiota in ankylosing spondylitis. J Autoimmun. 2020;107:102360.

    Article  CAS  PubMed  Google Scholar 

  41. Anderson JW, Baird P, Davis RH Jr, Ferreri S, Knudtson M, Koraym A, et al. Health benefits of dietary fiber. Nutr Rev. 2009;67:188–205.

    Article  PubMed  Google Scholar 

  42. Slavin JL, Brauer PM, Marlett JA. Neutral detergent fiber, hemicellulose and cellulose digestibility in human subjects. J Nutr. 1981;111:287–97.

    Article  CAS  PubMed  Google Scholar 

  43. Flint HJ, Bayer EA, Rincon MT, Lamed R, White BA. Polysaccharide utilization by gut bacteria: potential for new insights from genomic analysis. Nat Rev Microbiol. 2008;6:121–31.

    Article  CAS  PubMed  Google Scholar 

  44. Nunns GR, Vigneshwar N, Kelher MR, Stettler GR, Gera L, Reisz JA, et al. Succinate activation of SUCNR1 predisposes severely injured patients to neutrophil-mediated ARDS. Ann Surg. 2020.

  45. Littlewood-Evans A, Sarret S, Apfel V, Loesle P, Dawson J, Zhang J, et al. GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis. J Exp Med. 2016;213:1655–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Chen Y, Ma C, Liu L, He J, Zhu C, Zheng F, et al. Analysis of gut microbiota and metabolites in patients with rheumatoid arthritis and identification of potential biomarkers. Aging (Albany NY). 2021;13.

  47. Lam KC, Araya RE, Huang A, Chen Q, Di Modica M, Rodrigues RR, et al. Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment. Cell. 2021;184:5338–56.e5321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Fan L, Xu C, Ge Q, Lin Y, Wong CC, Qi Y, et al. A. muciniphila suppresses colorectal tumorigenesis by inducing TLR2/NLRP3-mediated M1-Like TAMs. Cancer Immunol Res. 2021;9:1111–24.

    Article  CAS  PubMed  Google Scholar 

  49. Ansaldo E, Slayden LC, Ching KL, Koch MA, Wolf NK, Plichta DR, et al. Akkermansia muciniphila induces intestinal adaptive immune responses during homeostasis. Science. 2019;364:1179–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chen BD, Jia XM, Xu JY, Zhao LD, Ji JY, Wu BX, et al. An autoimmunogenic and proinflammatory profile defined by the gut microbiota of patients with untreated systemic lupus erythematosus. Arthritis Rheumatol. 2021;73:232–43.

    Article  CAS  PubMed  Google Scholar 

  51. Nguyen Y, Salliot C, Gelot A, Gambaretti J, Mariette X, Boutron-Ruault MC, et al. Mediterranean diet and risk of rheumatoid arthritis: findings from the French E3N-EPIC cohort study. Arthritis Rheumatol. 2021;73:69–77.

    Article  PubMed  Google Scholar 

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We thank all donors who participated in this study.


This work was supported by the National Natural Science Foundation of China (81788101, 82230060, 81630064, and 81701624), the CAMS Innovation Fund for Medical Sciences (CIFMS) (2021-I2M-1-017, 2021-I2M-1-047, 2021-I2M-1-040, and 2021-I2M-1-016), the Capital’s Funds for Health Improvement and Research (2020-2-4019) and the National Key Research and Development Program of China (Grant no. 2018YFE0207300).

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Authors and Affiliations



Conception and design of the study: LJJ, ZHL, and XZ; implementation of in vivo and in vitro experiments: LJJ, MMS and SNY; analysis of 16 S rRNA sequencing data and the transcriptome data analysis: LJJ; statistical analysis: MMS and HZ; critical comments: YDL, YZZ, MW, TTW, XZ and ZHL; drafting of manuscript: LJJ and SNY; final approval of the version of the article to be published: all authors.

Corresponding authors

Correspondence to Zhihua Liu or Xuan Zhang.

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The authors declare no competing interests.

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All studies reported here were approved by the Institutional Review Board and Animal Care and Use Committee of Peking Union Medical College Hospital (PUMCH).

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Jiang, L., Shang, M., Yu, S. et al. A high-fiber diet synergizes with Prevotella copri and exacerbates rheumatoid arthritis. Cell Mol Immunol 19, 1414–1424 (2022).

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