Skip to main content

Advertisement

Log in

Alterations of the intestinal microbiome and metabolome in women with rheumatoid arthritis

  • Research
  • Published:
Clinical and Experimental Medicine Aims and scope Submit manuscript

Abstract

Rheumatoid arthritis (RA) is more common in women, and many reports of sex differences have been reported in various aspects of RA. However, there has been a lack of specific research on women’s gut flora. To assess the association between the gut flora and RA patients, this study combined the microbiome with metabolomics. Fecal samples from RA patients and healthy controls were collected for 16S rRNA sequencing. Nontargeted liquid chromatography–mass spectrometry was used to detect metabolites in fecal samples. We comprehensively used various analytical methods to reveal changes in intestinal flora and metabolites in female patients. The gut flora of RA patients was significantly different from that of healthy women. The abundance of Bacteroides, Megamonas and Oscillospira was higher in RA patients, while the abundance of Prevotella, Gemmiger and Roseburia was lower than that of healthy women. Gemmiger, Bilophila and Odoribacter represented large differences in microflora between RA and healthy women and could be used as potential microorganisms in the diagnosis. Fatty acid biosynthesis was significantly different between RA patients and healthy women in terms of metabolic pathways. There were different degrees of correlation between the gut flora and metabolites. Lys-Phe-Lys and heptadecasphin-4-enine can be used as potential markers for RA diagnosis. There was an extremely significant positive correlation between Megamonas, Dialister and rheumatoid factors, which was found for the first time. These findings indicated that alterations of these gut microbiome and metabolome may contribute to the diagnosis and treatment of RA patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

The data used to support the findings of this study are included within the article.

References

  1. Di Florio DN, Sin J, Coronado MJ, Atwal PS, Fairweather D. Sex differences in inflammation, redox biology, mitochondria and autoimmunity. Redox Biol. 2020;31:101482.

    PubMed  PubMed Central  Google Scholar 

  2. Moorman CD, Sohn SJ, Phee H. Emerging therapeutics for immune tolerance: tolerogenic vaccines, T cell Therapy, and IL-2 therapy. Front Immunol. 2021;12:657768.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Favalli EG, Biggioggero M, Crotti C, Becciolini A, Raimondo MG, Meroni PL. Sex and management of rheumatoid arthritis. Clin Rev Allergy Immunol. 2019;56(3):333–45.

    PubMed  Google Scholar 

  4. Sparks JA. Rheumatoid arthritis. Ann Intern Med. 2019;170(1):ITC1–16.

    PubMed  Google Scholar 

  5. Charles J, Britt H, Pan Y. Rheumatoid arthritis. Aust Fam Physician. 2013;42(11):765.

    PubMed  Google Scholar 

  6. Ortona E, Pierdominici M, Maselli A, Veroni C, Aloisi F, Shoenfeld Y. Sex-based differences in autoimmune diseases. Ann Ist Super Sanita. 2016;52(2):205–12.

    CAS  PubMed  Google Scholar 

  7. Yu C, Liu C, Jiang J, et al. Gender differences in rheumatoid arthritis: interleukin-4 plays an important role. J Immunol Res. 2020;2020:4121524.

    PubMed  PubMed Central  Google Scholar 

  8. Klein SL, Morgan R. The impact of sex and gender on immunotherapy outcomes. Biol Sex Differ. 2020;11(1):24.

    PubMed  PubMed Central  Google Scholar 

  9. Tański W, Dudek K, Tomasiewicz A, Świątoniowska-Lonc N. Sexual dysfunction and quality of life in patients with rheumatoid arthritis. Int J Environ Res Public Health. 2022;19(5):3088.

    PubMed  PubMed Central  Google Scholar 

  10. Nicholson JK, Holmes E, Kinross J, et al. Host–gut microbiota metabolic interactions. Science. 2012;336(6086):1262–7.

    CAS  PubMed  Google Scholar 

  11. Ochoa-Repáraz J, Kirby TO, Kasper LH. The Gut microbiome and multiple sclerosis. Cold Spring Harb Perspect Med. 2018;8(6):a029017.

    PubMed  PubMed Central  Google Scholar 

  12. Xiang K, Wang P, Xu Z, et al. Causal effects of gut microbiome on systemic lupus erythematosus: a two-sample mendelian randomization study. Front Immunol. 2021;12:667097.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Bolyen E, Rideout JR, Dillon MR, et al. Reproducible, interactive, scalable and extensible microbiome data science using QIIME 2. Nat Biotechnol. 2019;37(8):852–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Callahan BJ, McMurdie PJ, Rosen MJ, Han AW, Johnson AJ, Holmes SP. Dada2: high-resolution sample inference from illumina amplicon data. Nat Methods. 2016;13(7):581–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Katoh K, Misawa K, Kuma K, Miyata T. MAFFT: a novel method for rapid multiple sequence alignment based on fast fourier transform. Nucleic Acids Res. 2002;30(14):3059–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Price MN, Dehal PS, Arkin AP. FastTree: computing large minimum evolution trees with profiles instead of a distance matrix. Mol Biol Evol. 2009;26(7):1641–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Asnicar F, Weingart G, Tickle TL, Huttenhower C, Segata N. Compact graphical representation of phylogenetic data and metadata with GraPhlAn. PeerJ. 2015;3:e1029.

    PubMed  PubMed Central  Google Scholar 

  18. van Riel PL, Renskers L. The disease activity score (DAS) and the disease activity score using 28 joint counts (DAS28) in the management of rheumatoid arthritis. Clin Exp Rheumatol. 2016;34(5 Suppl 101):S40–4.

    PubMed  Google Scholar 

  19. Best JH, Kuang Y, Jiang Y, et al. Comparative efficacy (DAS28 remission) of targeted immune modulators for rheumatoid arthritis: a network meta-analysis. Rheumatol Ther. 2021;8(2):693–710.

    PubMed  PubMed Central  Google Scholar 

  20. Avuthu N, Guda C. Meta-analysis of altered gut microbiota reveals microbial and metabolic biomarkers for colorectal cancer. Microbiol Spectr. 2022;10(4):e0001322.

    PubMed  Google Scholar 

  21. Zhang S, Kong C, Yang Y, et al. Human oral microbiome dysbiosis as a novel non-invasive biomarker in detection of colorectal cancer. Theranostics. 2020;10(25):11595–606.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Yang HT, Liu JK, Xiu WJ, et al. Gut microbiome-based diagnostic model to predict diabetes mellitus. Bioengineered. 2021;12(2):12521–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Afridi R, Khan AU, Khalid S, et al. Anti-hyperalgesic properties of a flavanone derivative poncirin in acute and chronic inflammatory pain models in mice. BMC Pharmacol Toxicol. 2019;20(1):57.

    PubMed  PubMed Central  Google Scholar 

  24. Gandhi GR, Vasconcelos ABS, Wu DT, et al. Citrus flavonoids as promising phytochemicals targeting diabetes and related complications: a systematic review of in vitro and in vivo studies. Nutrients. 2020;12(10):2907.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Patel DK. Therapeutic potential of poncirin against numerous human health complications: medicinal uses and therapeutic benefit of an active principle of citrus species. Endocr Metab Immune Disord Drug Targets. 2021;21(11):1974–81.

    CAS  PubMed  Google Scholar 

  26. Sun H, Guo Y, Wang H, et al. Gut commensal Parabacteroides distasonis alleviates inflammatory arthritis. Gut. 2023;72:1664–77. https://doi.org/10.1136/gutjnl-2022-327756.

    Article  CAS  PubMed  Google Scholar 

  27. Cui Y, Zhang L, Wang X, et al. Roles of intestinal Parabacteroides in human health and diseases. FEMS Microbiol Lett. 2022;369(1):fnac072.

    PubMed  Google Scholar 

  28. Chen Y, Ma C, Liu L, et al. Analysis of gut microbiota and metabolites in patients with rheumatoid arthritis and identification of potential biomarkers. Aging (Albany NY). 2021;13(20):23689–701.

    CAS  PubMed  Google Scholar 

  29. Chu XJ, Cao NW, Zhou HY, et al. The oral and gut microbiome in rheumatoid arthritis patients: a systematic review. Rheumatology (Oxford). 2021;60(3):1054–66.

    PubMed  Google Scholar 

  30. Yang J, Li Y, Wen Z, Liu W, Meng L, Huang H. Oscillospira—a candidate for the next-generation probiotics. Gut Microbes. 2021;13(1):1987783.

    PubMed  PubMed Central  Google Scholar 

  31. Gophna U, Konikoff T, Nielsen HB. Oscillospira and related bacteria—from metagenomic species to metabolic features. Environ Microbiol. 2017;19(3):835–41.

    CAS  PubMed  Google Scholar 

  32. Kim JW, Kwok SK, Choe JY, Park SH. Recent advances in our understanding of the link between the intestinal microbiota and systemic lupus erythematosus. Int J Mol Sci. 2019;20(19):4871.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Henke MT, Kenny DJ, Cassilly CD, Vlamakis H, Xavier RJ, Clardy J. Ruminococcus gnavus, a member of the human gut microbiome associated with Crohn’s disease, produces an inflammatory polysaccharide. Proc Natl Acad Sci U S A. 2019;116(26):12672–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 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.

    CAS  PubMed  Google Scholar 

  35. Zaiss MM, Joyce Wu HJ, Mauro D, Schett G, Ciccia F. The gut-joint axis in rheumatoid arthritis. Nat Rev Rheumatol. 2021;17(4):224–37.

    PubMed  Google Scholar 

  36. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Xu X, Gao Z, Yang F, et al. Antidiabetic effects of gegen qinlian decoction via the gut microbiota are attributable to its key ingredient berberine. Genomics Proteomics Bioinformatics. 2020;18(6):721–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Martin-Gallausiaux C, Marinelli L, Blottière HM, et al. SCFA: mechanisms and functional importance in the gut. Proc Nutr Soc. 2021;80(1):37–49.

    CAS  PubMed  Google Scholar 

  39. Cheng M, Zhao Y, Cui Y, et al. Stage-specific roles of microbial dysbiosis and metabolic disorders in rheumatoid arthritis. Ann Rheum Dis. 2022;81(12):1669–77.

    CAS  PubMed  Google Scholar 

  40. Guo R, Li S, Zhang Y, et al. Dysbiotic oral and gut viromes in untreated and treated rheumatoid arthritis patients. Microbiol Spectr. 2022;10(5):e0034822.

    PubMed  Google Scholar 

  41. Wang Q, Zhang SX, Chang MJ, et al. Characteristics of the gut microbiome and its relationship with peripheral CD4+ T cell subpopulations and cytokines in rheumatoid arthritis. Front Microbiol. 2022;13:799602.

    PubMed  PubMed Central  Google Scholar 

  42. Zhang L, Han R, Zhang X, et al. Fecal microbiota in patients with ankylosing spondylitis: correlation with dietary factors and disease activity. Clin Chim Acta. 2019;497:189–96.

    CAS  PubMed  Google Scholar 

  43. Li Y, Li Z, Sun W, Wang M, Li M. Characteristics of gut microbiota in patients with primary Sjögren’s syndrome in northern China. PLoS ONE. 2022;17(11):e0277270.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Luu M, Visekruna A. Short-chain fatty acids: bacterial messengers modulating the immunometabolism of T cells. Eur J Immunol. 2019;49(6):842–8.

    CAS  PubMed  Google Scholar 

  45. Yao Y, Cai X, Zheng Y, et al. Short-chain fatty acids regulate B cells differentiation via the FFA2 receptor to alleviate rheumatoid arthritis. Br J Pharmacol. 2022;179(17):4315–29.

    CAS  PubMed  Google Scholar 

  46. Martin-Gallausiaux C, Marinelli L, Blottière HM, Larraufie P, Lapaque N. SCFA: mechanisms and functional importance in the gut. Proc Nutr Soc. 2021;80(1):37–49.

    CAS  PubMed  Google Scholar 

  47. Chen MX, Wang SY, Kuo CH, Tsai IL. Metabolome analysis for investigating host-gut microbiota interactions. J Formos Med Assoc. 2019;118(Suppl 1):S10–22.

    PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank all investigators and supporters involved in this study. The manuscript had been polished by one or more of the highly qualified native English speaking editors at AJE, and this certificate was verified on the AJE website using the verification code 4OEA-BCC5-9OED-CD19-9754.

Funding

This work was supported by Natural Science Foundation Project of Nanjing University of Traditional Chinese Medicine (XZR2020039), and National Natural Science Foundation of China (81871709).

Author information

Authors and Affiliations

Authors

Contributions

RL and DWC contributed to conception and design. HFY contributed to methodology and interpretation. LXY and NL contributed to data collection. XXW and CJW contributed to statistical analysis. XXW and RL contributed to writing—original draft. GXZ, QHL, and DWC contributed to writing—review and editing. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Dawei Cui or Rui Liu.

Ethics declarations

Conflict of interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

Ethical approval

All patients and healthy volunteers signed informed consent forms, which were approved by the ethics committee of Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine (ethics approval number: 2021–266), and written informed consent was obtained from all participants. The study complied with the ethical standards of the Declaration of Helsinki (https://www.wma.net/what-we-do/medical-ethics/declaration-of-helsinki/).

Consent for publication

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 3574 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yun, H., Wang, X., Wei, C. et al. Alterations of the intestinal microbiome and metabolome in women with rheumatoid arthritis. Clin Exp Med 23, 4695–4706 (2023). https://doi.org/10.1007/s10238-023-01161-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10238-023-01161-7

Keywords

Navigation