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  • Review Article
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The gut microbiome in systemic lupus erythematosus: lessons from rheumatic fever

Nature Reviews Rheumatology volume 20, pages 143–157 (2024)Cite this article

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Abstract

For more than a century, certain bacterial infections that can breach the skin and mucosal barriers have been implicated as common triggers of autoimmune syndromes, especially post-infection autoimmune diseases that include rheumatic fever and post-streptococcal glomerulonephritis. However, only in the past few years has the importance of imbalances within our own commensal microbiota communities, and within the gut, in the absence of infection, in promoting autoimmune pathogenesis become fully appreciated. A diversity of species and mechanisms have been implicated, including disruption of the gut barrier. Emerging data suggest that expansions (or blooms) of pathobiont species are involved in autoimmune pathogenesis and stimulate clonal expansion of T cells and B cells that recognize microbial antigens. This Review discusses the relationship between the gut microbiome and the immune system, and the potential consequence of disrupting the community balance in terms of autoimmune development, focusing on systemic lupus erythematosus. Notably, inter-relationships between expansions of certain members within gut microbiota communities and concurrent autoimmune responses bear features reminiscent of classical post-infection autoimmune disease. From such insights, new therapeutic opportunities are being considered to restore the balance within microbiota communities or re-establishing the gut-barrier integrity to reinforce immune homeostasis in the host.

Key points

  • Systemic lupus erythematosus (SLE) development involves many genetic and environmental factors, and emerging data implicate various gut pathobionts as inciting and exacerbating factors.

  • Emerging data highlight parallels between autoimmune diseases such as SLE and post-streptococcal illnesses including rheumatic fever.

  • Increased permeability of the gut barrier allows microbes and microbial metabolites to interact with host immune cells, subsequently driving pathological progression.

  • Additional longitudinal studies will facilitate more in-depth elucidation of the inter-relationships between SLE and gut dysbiosis in individual patients.

  • The impact of dietary factors, antibiotics and other exposures on microbial resilience and dysbiosis, and subsequent development or flares of autoimmune disease, are also important topics for future research.

  • Modulating the gut microbiome of patients with SLE holds promise as a therapeutic intervention that could provide a more targeted and effective approach to treating the disease than broad immunosuppression.

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Fig. 1: Potential role of pathobionts and intestinal barrier dysfunction in systemic lupus erythematosus.
Fig. 2: Representation of Ruminococcus gnavus strain-specific glycans.
Fig. 3: Postulated steps in systemic lupus erythematosus aetiopathogenesis and gut microbiota involvement.

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Acknowledgements

The central themes presented in this Review were originally presented in a special session on “Molecular mimicry, autoimmunity and the streptococcal connection: a common cause of autoimmune conditions” at the 2022 ACR Convergence meeting. The authors would like to thank J. Weiser, M. Henke and D. Littman for their advice, as well as R. Xavier and H. Vlamakis, E. Pamer, and E. Allen-Vercoe for providing R. gnavus strains for their research studies. Finally, the authors would like to thank J. Colton and S. Colton for their generous support. The work of the authors is supported by funds from National Institutes of Health Grants R01-AR42455 (G.J.S.), National Institutes of Health Grants P50-AR070591 (G.J.S.), National Institutes of Health Contract NIAID HHSN272201400019C (G.J.S.), National Institutes of Health 5T32AR069515-07 (A.A.), Lupus Research Alliance (G.J.S.), Judith and Stewart Colton Autoimmunity Center (G.J.S.), and P. Robert Majumder Charitable Trust (G.J.S.).

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Authors and Affiliations

  1. Department of Medicine, NYU Grossman School of Medicine, New York, NY, USA

    Gregg J. Silverman, Doua F. Azzouz & Abhimanyu Amarnani

  2. Division of Bioanalytical Chemistry, Priority Area Infections, Research Center Borstel, Leibniz Lung Center, Borstel, Germany

    Nicolas Gisch

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All authors researched data for the article, contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission. G.J.S., A.A. and N.G. wrote the article.

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Correspondence to Gregg J. Silverman.

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Competing interests

G.J.S. declares that NYU has been awarded US patent 11241488B2, and additional patent applications (No. 63/533,004 and 63/354,159). N.G., D.F.A and A.A. declare no competing interests.

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Glossary

B cell superantigen

Molecules that directly bind to and stimulate B cells via their antigen receptor, often binding to sites outside the paratopic sites that bind conventional antigens.

Commensal microbes

Resident microorganisms that coexist with a host without causing harm or necessarily receiving any mutual benefit.

Microbiome

The collective microorganisms, such as bacteria, fungi, viruses and protozoa, that live within and on the human body.

Pathobiont

A commensal microorganism that can cause disease under certain conditions, such as following a change in the host’s immune status or following an imbalance in the gut microbiota, but does not drive overt infectious disease in the host.

Pathogen

A microorganism, such as a bacterium, virus, fungus or parasite, that causes disease in its host, often through tissue destruction.

Resilience

The capacity of the gut microbiome to recover and regain balance in composition and functionality after being exposed to various stressors.

Symbiont

An organism that lives in a mutually beneficial relationship with another organism.

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Silverman, G.J., Azzouz, D.F., Gisch, N. et al. The gut microbiome in systemic lupus erythematosus: lessons from rheumatic fever. Nat Rev Rheumatol 20, 143–157 (2024). https://doi.org/10.1038/s41584-023-01071-8

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