Rheumatoid arthritis (RA) is a complex autoimmune disease characterized by joint destruction, systemic involvement, and increased autoantibodies, such as anti-citrullinated peptide antibodies (ACPAs). The gut microbiota plays a crucial role in maintaining the immune homeostasis of their human hosts. While gut microbiota dysbiosis in RA has been reported, the mechanism by which gut microbes contribute to the pathogenesis of RA has not yet been clarified. One of the obstacles in identifying disease-associated microbial features is the vast inter-individual diversity in the microbiome that often overwhelms disease-associated alterations and conceals the ‘culprit’ microbes.

In a study published in Science Advances, the researchers from the Beijing Institute of Genomics of the Chinese Academy of Sciences/China National Center for Bioinformation and Department of Rheumatology and Immunology, Peking University People’s Hospital, reported that butyrate-metabolizing species in the gut of RA patients participated in RA disease activity, autoantibody production, and joint deformation by affecting the net butyrate yield in the gut. This study highlights the critical role of butyrate-metabolizing bacteria in the pathogenesis of RA and elucidates the molecular mechanism of butyric acid in regulating the immune response of RA patients, which suggests the clinical therapeutic potential of butyric acid for RA.

Inspired by the twin studies in identifying disease-associated genetic variants, the researchers developed a novel method for the analysis of metagenome, i.e., quasi-paired cohort. This method paired samples of similar species profile, but opposite phenotypes, mimicking the twins in genetic studies. In this way, the diversity among individuals was well controlled, and the sensitivity and robustness of identifying disease-associated microbial signatures were greatly improved.

By using the ‘quasi-paired cohort’ method, the researchers found that a variety of butyrate-producing species and butyrate-consuming species showed significantly opposite distribution in gut flora between RA patients and healthy controls. The abundance of these butyrate-metabolizing species showed strong correlations to various clinical features, such as ACPA and rheumatoid factor. The diagnostic model established based on the abundance of these butyrate-metabolizing species was able to accurately distinguish RA patients from healthy people and predicted joint deformation in a validation cohort with an accuracy of 98.6%.

To further consolidate the role of butyrate metabolism in the pathogenesis and inflammatory response of RA, the researchers conducted measurements of fecal and serum metabolome, functions of immune cells of RA patients, and mouse models of collagen-induced arthritis. These experiments confirmed the decreased blood and fecal butyrate concentrations in RA patients and that butyrate was able to down-regulate the expression of various pro-inflammatory factors, induce Treg cell differentiation, and inhibit Th 17, Tfh cell, and osteoclast activity. Butyrate supplementation to diet can significantly inhibit the occurrence of arthritis in the CIA model mice by promoting the balance of Tfh and Treg, and reducing the production of autoantibodies.

This study demonstrated the critical role of intestinal butyrate metabolism in the pathogenesis and development of RA, suggesting novel diet or microbe-based therapeutics for improving RA in the future.