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Revisiting the gut–joint axis: links between gut inflammation and spondyloarthritis

Nature Reviews Rheumatology volume 16, pages 415–433 (2020)Cite this article

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A Publisher Correction to this article was published on 30 July 2020

This article has been updated

Abstract

Gut inflammation is strongly associated with spondyloarthritis (SpA), as exemplified by the high prevalence of inflammatory bowel disease (IBD) and the even higher occurrence of subclinical gut inflammation in patients with SpA. The gut–joint axis of inflammation in SpA is further reinforced by similarities in immunopathogenesis at both anatomical sites and by the clinical success of therapies blocking TNF and IL-23 in IBD and in some forms of SpA. Many genetic risk factors are shared between SpA and IBD, and changes in the composition of gut microbiota are seen in both diseases. Current dogma is that inflammation in SpA initiates in the gut and leads to joint inflammation; however, although conceptually attractive, some research does not support this causal relationship. For example, therapies targeting IL-17A are efficacious in the joint but not the gut, and interfering with gut trafficking by targeting molecules such as α4β7 in IBD can lead to onset or flares of SpA. Several important knowledge gaps remain that must be addressed in future studies. Determining the true nature of the gut–joint axis has real-world implications for the treatment of patients with co-incident IBD and SpA and for the repurposing of therapeutics from one disease to the other.

Key points

  • The majority of European patients with spondyloarthritis (SpA) have subclinical gut inflammation, and a minority have coexisting inflammatory bowel disease.

  • Many genetic risk factors for ankylosing spondylitis (AS) are shared with inflammatory bowel disease, and some of these AS risk factors cluster in pathways that are important in gut immunity.

  • Type 3 immune cytokines (for example, IL-17) are important in the gut and joint; however, their effects might be tissue specific.

  • Intestinal microbial dysbiosis occurs in SpA, but whether it is a cause, or effect, of underlying immunological alterations is unknown.

  • The failure rate of current therapies for SpA is unacceptably high; whether this failure is related to underlying gut inflammation is unknown.

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Fig. 1: Clinical manifestations of the gut–joint axis of inflammation in SpA.
Fig. 2: Shared and disease-specific GWAS-identified risk genes for AS and Crohn’s disease.
Fig. 3: Immunological changes in the gut–joint axis of inflammation in SpA.
Fig. 4: The relationship between gut and joint inflammation in SpA.

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Acknowledgements

The authors thank A. Hoorens (UZ Gent) for providing the histology pictures in Fig. 1.

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Authors and Affiliations

  1. VIB Center for Inflammation Research, Ghent, Belgium

    Eric Gracey, Lars Vereecke, Mareike Fröhling, Filip Van den Bosch & Dirk Elewaut

  2. Department of Internal Medicine and Pediatrics, UZ Gent, Ghent University, Ghent, Belgium

    Eric Gracey, Lars Vereecke, Mareike Fröhling, Filip Van den Bosch & Dirk Elewaut

  3. Ghent Gut Inflammation Group, Ghent University, Ghent, Belgium

    Lars Vereecke, Martine De Vos & Dirk Elewaut

  4. F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Dermot McGovern

  5. Friedrich-Alexander University Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Germany

    Georg Schett

  6. IBD Center, Department of Gastroenterology, Humanitas Clinical and Research Center – IRCCS –, Rozzano, Milan, Italy

    Silvio Danese

  7. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy

    Silvio Danese

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Contributions

E.G. researched data for the article; E.G., L.V., D.M., G.S., F.V.d.B. and D.E. made substantial contributions to discussions of the content; E.G., M.F., F.V.d.B. and D.E. wrote the article and E.G., M.F., G.S., S.D., M.D.V., F.V.d.B. and D.E. reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Eric Gracey or Dirk Elewaut.

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Competing interests

F.V.d.B. declares that he has received speaker’s and/or consultancy fees from Abbvie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Galapagos, Merck, Pfizer, Novartis, Sanofi and UCB. D.E. declares that his work is supported by grants from the Fund for Scientific Research Flanders, the Research Council of Ghent University and an Excellence of Science (EOS) grant from the Fund for Scientific Research Flanders. The other authors declare no competing interests.

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Nature Reviews Rheumatology thanks F. Ciccia, H. Xu and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Gracey, E., Vereecke, L., McGovern, D. et al. Revisiting the gut–joint axis: links between gut inflammation and spondyloarthritis. Nat Rev Rheumatol 16, 415–433 (2020). https://doi.org/10.1038/s41584-020-0454-9

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