New insights into short-chain fatty acids for rheumatoid arthritis relief

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease characterized by bone damage and synovial hyperplasia. The global prevalence of rheumatoid arthritis ranges from 0.2% to 1%, and the prevalence of rheumatoid arthritis in China ranges from 0.28% to 0.41%, affecting nearly 5 million people. It is currently believed that the pathogenesis of RA is mainly related to genetic and environmental factors.

Joint damage and chronic inflammation in patients with rheumatoid arthritis are immunomodulated. Among numerous environmental factors, the microflora of the gastrointestinal, oral, respiratory and reproductive tracts has attracted the attention of researchers in recent years. In particular, the gut microflora is considered to be an important environmental factor in the development of rheumatoid arthritis.

Short-chain fatty acids (SCFAs) are metabolites of gut microbes and are involved in host inflammatory responses and immunity. The purpose of this study was to investigate the role of rheumatoid factor in rheumatoid arthritis and its possible mechanism.

Recently, researchers from Zhejiang University published an article entitled "Short-chain fatty acids regulate B cell differentiation via FFAR2 to alleviate rheumatoid arthritis" in the British Journal of Pharmacology, which confirmed that single-chain fatty acids regulate B cells through FFAR2. differentiation, thereby relieving rheumatoid arthritis. This will provide new insights into the treatment of RA from an immunological and microbiological perspective.

In this study, the researchers analyzed the diversity of mouse gut microbiota using 16S rDNA sequencing and single-chain fatty acid content using gas chromatography-mass spectrometry. T cells and B cells were analyzed by flow cytometry. Bone injury was analyzed by micro-CT and X-ray films. Histopathological status was analyzed by hematoxylin-eosin staining.

The researchers also analyzed proteins in the tissue using immunohistochemistry and polymerase chain reaction. To explore the molecular mechanism of FFAR2 gene deletion in CD19+ B cell FFAR2-specific deficient mice.

The researchers found that RA patients had reduced levels of acetate, propionate, butyrate, and valerate, and the first three levels were positively correlated with the frequency of Bregs in peripheral blood, but not Tregs. Administration of three supercritical fatty acids prior to onset of collagen arthritis in mice ameliorated arthritis symptoms, increased Bregs frequency, and decreased transitional and follicular B cell frequencies.

However, this phenomenon could not be observed in mice lacking FFAR2 in CD19+ B cells. The effects of the three single-chain fatty acids on RA were FFAR2-dependent and independent of the other five B-cell receptors (FFAR3, Gpr109a, PPARγ, OLFR-78, and AhR).

Taken together, this study revealed the important role of SCFAs in rheumatoid arthritis. First, the levels of SCFAs derived from gut microbes were decreased in RA patients, and the levels of acetate, propionate, and butyrate were positively correlated with the frequency of CD19+CD21+CD24+ B cells.

Importantly, supplementation with three supercritical fatty acids improved arthritis symptoms in CIA mice, and the therapeutic effects of the three were synergistic. Mechanistically, the efficacy of the three SCFAs in the treatment of CIA was dependent on the expression of FFAR2 in CD19+ B cells. Briefly, SCFAs regulate B cell differentiation through FFAR2, thereby alleviating rheumatoid arthritis.