The imbalance between pathogenic and beneficial species of the intestinal microbiome and metabolism in rheumatoid arthritis (RA) remains unclarified. Here, using shotgun-based metagenome sequencing for a treatment-naïve patient cohort and a “quasi-paired cohort” method, we observed a deficiency of butyrate-producing species and an overwhelming number of butyrate consumers in RA patients. These outcomes mainly occurred in patients with positive ACPA, with a mean AUC of 0.94. This panel was also validated in established RA with an AUC of 0.986 in those with joint deformity. In addition, we showed that butyrate promoted T _regs , while suppressing T _convs and osteoclasts, due to potentiation of the reduction in HDAC expression and down-regulation of proinflammatory cytokine genes. Dietary butyrate supplementation conferred anti-inflammatory benefits in a mouse model by rebalancing T _FH cells and T _regs , as well as reducing antibody production. These findings reveal the critical role of butyrate-metabolizing species and suggest the potential of butyrate-based therapies for RA patients.

Rheumatoid arthritis (RA) is widespread globally, with the emergence of metabolites derived from both the host and microbes playing a pivotal role in its pathogenesis. This study aims to elucidate the relationships between serum metabolites and the immunological and clinical features of RA. Serum samples were collected from 35 RA patients and 37 healthy controls (HC). Metabolite profiling was performed using gas chromatography-mass spectrometry (GC/MS). Principal component analysis revealed a significant distinction between the RA and HC cohorts. Employing univariate statistical analysis, we identified 36 differential metabolites. Among these, 9 metabolites, including galactose and glucose, were found to be enriched, while the remaining metabolites, such as citric acid, fumaric acid, and inosine, were depleted in RA. These diverse metabolites encompassed various metabolic processes, including the biosynthesis of fatty acids, amino acids, and glucose. The enrichment of glucose and galactose in RA exhibited a substantial correlation with elevated IgG levels, as determined through correlation analysis. Conversely, the depletion of citric acid was correlated with elevated levels of C3 and CRP. Methionine, which also declined in RA patients, displayed a negative correlation with ESR. Furthermore, galactose and glucose exhibited significant positive correlations with naïve B cells, while the decreased eicosanoic acid level in RA was significantly associated with an increase in natural killer cells. Our findings suggest that the altered serum metabolite profile in RA is closely linked to disease severity and the dysregulated immune responses observed in RA patients. Key Points • Identified nine metabolites with upregulated expression and twenty-seven metabolites with downregulated expression.• Established a correlation between alterations in serum metabolite levels and inflammatory markers in RA patients.• Discovered a significant association between changes in serum metabolites and immune cell profiles in RA patients.

Objectives Viruses have been considered as important participants in the development of rheumatoid arthritis (RA). However, the profile of enteric virome and its role in RA remains elusive. This study aimed to investigate the atlas and involvement of virome in RA pathogenesis. Methods Faecal samples from 30 pairs of RA and healthy siblings that minimise genetic interferences were collected for metagenomic sequencing. The α and β diversity of the virome and the virome–bacteriome interaction were analysed. The differential bacteriophages were identified, and their correlations with clinical and immunological features of RA were analysed. The potential involvement of these differential bacteriophages in RA pathogenesis was further investigated by auxiliary metabolic gene annotation and molecular mimicry study. The responses of CD4⁺ T cells and B cells to the mimotopes derived from the differential bacteriophages were systemically studied. Results The composition of the enteric bacteriophageome was distorted in RA. The differentially presented bacteriophages correlated with the immunological features of RA, including anti-CCP autoantibody and HLA-DR shared epitope. Intriguingly, the glycerolipid and purine metabolic genes were highly active in the bacteriophages from RA. Moreover, peptides of RA-enriched phages, in particular Prevotella phage and Oscillibacter phage could provoke the autoimmune responses in CD4⁺ T cells and plasma cells via molecular mimicry of the disease-associated autoantigen epitopes, especially those of Bip. Conclusions This study provides new insights into enteric bacteriophageome in RA development. In particular, the aberrant bacteriophages demonstrated autoimmunity-provoking potential that would promote the occurrence of the disease.

Palatine tonsils are the only air-contacted lymphoid organs that constantly engage in crosstalk with commensal microorganisms and serve as the first handling sites against microbial antigens. While tonsil inflammations have been implicated in various autoimmune diseases, including rheumatoid arthritis (RA), the precise role of tonsillar microbiota in autoimmune pathogenesis remains inadequately characterized. In this study, we profiled the tonsillar microbiota and identified a notable dysbiosis in patients with RA, particularly within the Streptococcus genus. Specifically, patients with RA exhibited an enrichment of pathogenic Streptococcus species, including S . pyogenes , S . dysgalactiae , and S . agalactiae . Colonization with these bacteria significantly exacerbated arthritis severity and increased autoimmune responses in collagen-induced arthritis (CIA). Furthermore, immunization with peptides derived from these pathogenic Streptococcus species directly induced experimental arthritis. Conversely, patients with RA demonstrated a marked deficiency in commensal Streptococcus members, notably S . salivarius . Treatment of CIA mice with S . salivarius attenuated the progression of arthritis and downregulated autoimmune responses. These findings highlight a pathogenic link of tonsillar microbiota with RA, shedding light on their contribution to autoimmunity.

We revealed that the profile of the urinary tract microbiota in RA featured with increased microbial richness and shifted taxa, associated with immunological and metabolic changes of the disease, underlining the interplay between urinary microbiota and host autoimmunity.

Behçet’s syndrome (BS), a chronic vasculitis, leads to recurrent oral ulcers, severely impacting quality of life. Here we report the results of a randomized, double-blind, placebo-controlled trial (NCT04065672) to evaluate the efficacy and safety of low-dose interleukin-2 (LD-IL-2) in BS patients. 60 participants with active oral ulcers are randomly assigned to receive LD-IL-2 or placebo. The primary endpoint is the oral ulcer count at week 12. The LD-IL-2 group has significantly fewer oral ulcers than the placebo group (0.69 ± 1.05 vs. 1.57 ± 0.90, P = 0.001) with greater improvements in ulcer pain, disease activity, and quality of life. No infections or severe adverse events are observed in either group. LD-IL-2 expands regulatory T (Treg) cells and decreased the ratio of effector T cell to Treg cells. Thus, LD-IL-2 therapy might be an effective and safe treatment in BS patients and is associated with the modulation of CD4 + T cell populations.