The gut microbiome and its metabolomic potential in primary Sjögren syndrome (pSS) remain largely unexplored. Here, we perform whole-metagenome shotgun sequencing of fecal samples from 206 pSS patients and 355 non-pSS controls, integrating compositional and functional profiling with serum and fecal metabolomes. pSS is associated with extensive multi-kingdom alterations, including 49 bacterial (e.g., Streptococcus parasanguinis, Ligilactobacillus salivarius, and Veillonella parvula), 19 fungal (notably Candida albicans), and 1,323 viral species. These signatures form robust inter-kingdom correlations and achieve high diagnostic accuracy in an independent validation cohort. Functional and metabolomic analyses reveal enrichment of toxin-related and aromatic pathways and depletion of protective metabolites in patients. pSS-enriched bacteria harbor abundant immunogenic epitopes, virulence factors, and antimicrobial resistance genes, and induce proinflammatory responses ex vivo. Together, these findings outline a multi-faceted microbial framework for pSS and suggest mechanistic links between gut dysbiosis and immune dysregulation.

Osteoarthritis (OA), a prevalent degenerative joint disorder characterized by progressive cartilage loss and secondary low-grade inflammation, is recognized to be associated with cardiovascular diseases (CVD). Building upon the cardiovascular assessment framework of Life’s Essential 8 (LE8), emerging guidelines propose the integration of psychological health metrics (Patient Health Questionnaire-9, PHQ-9) into the expanded Life’s Crucial 9 (LC9) model. While LC9 demonstrates cardiovascular predictive capacity, its role in OA pathogenesis remains inadequately substantiated. This study analyzed data from 21,196 National Health and Nutrition Examination Survey (NHANES) participants (2005–2018). Survey-weighted logistic regression, weighted quantile sum (WQS) regression, and restricted cubic splines (RCS) assessed the LC9–OA association with prespecified confounders. Subgroup analyses were also conducted. Mediation analysis was performed to assess the potential mediating effects of central adiposity, specifically the Body Roundness Index (BRI) and Waist-to-Height Ratio (WHtR). Each 10-point higher LC9 was associated with lower odds of OA (OR = 0.79; 95

Background Runzaoling prescription (RZL) has been used clinically for many years, and has shown potential therapeutic effects in previous studies for the treatment of Sjögren's Syndrome (SS). Even so, the specific active components and underlying mechanisms by which RZL exerts its anti-SS effects remain unclear. Materials and methods Ultra-high performance liquid chromatography coupled with Q-Exactive Orbitrap tandem mass spectrometry (UHPLC-Q-Exactive Orbitrap MS/MS) was employed to systematically identify the chemical constituents of RZL in vitro, as well as those components that enter the bloodstream in mice. The main active components, core genes and related signaling pathways of RZL for SS were screened by network pharmacology. Furthermore, the affinity between important components and their primary targets was predicted using molecular docking technology. Finally, the animal model of spontaneous SS (NOD mice) was established to evaluate the efficacy of RZL. Results and Conclusions 728 components were identified in RZL, and 49 prototype components as well as 7 metabolites were identified from the blood of mice. Network pharmacological analysis showed that RZL targeted key proteins like ICAM1, TNF, TLR4, and EGFR through active components such as isorhapontigenin, hypaphorine and cyanidin, modulating pathways like NF-κB, PI3K/AkT, MAPK, HIF-1 and TNF to exhibit the anti-inflammatory effects for treating SS. Molecular docking revealed that key active components of RZL effectively interact with proteins in the NF-κB pathway. Animal studies indicated that RZL alleviated pathological damage, enhanced saliva production and submandibular gland index in SS model mice. Additionally, it may regulate the TLR4/MyD88/NF-κB signaling pathway and effectively inhibit the inflammatory response.

Aims: Kaempferol has demonstrated promising therapeutic potential in the treatment of rheumatoid arthritis (RA), yet its underlying mechanisms remain to be fully elucidated. This study aimed to investigate the role of kaempferol in modulating ferroptosis resistance in tumour necrosis factor-alpha (TNF-α)-induced fibroblast-like synoviocytes (RA-FLS), and to explore its molecular targets and signalling pathways involved in RA progression. Methods: Proteomic and transcriptomic analyses were employed to identify the key pathways regulated by kaempferol in TNF-α-induced RA-FLS. The effects of kaempferol on oxidative stress, ferroptosis, and cellular proliferation in RA-FLS were evaluated using flow cytometry, measurements of malondialdehyde (MDA) and superoxide dismutase (SOD) activity, FerroOrange staining, transmission electron microscopy (TEM), cell counting kit (CCK-8) assay, and 5-ethynyl-2-deoxyuridine (EdU) assay. Protein and messenger RNA (mRNA) expression levels were validated using Western blotting and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Additionally, a TNF-α-induced collagen-induced arthritis (CIA) rat model was established to examine the anti-inflammatory and antiproliferative effects of kaempferol in vivo. The functional role of the glutamate-cysteine ligase modifier (GCLM) subunit was further investigated using GCLM-overexpressing RA-FLS models. Results: Kaempferol significantly modulated oxidative phosphorylation and glutathione metabolism pathways, reducing reactive oxygen species (ROS) and lipid peroxidation levels in RA-FLS. It suppressed TNF-α-induced RA-FLS proliferation by promoting ROS accumulation and inducing ferroptosis. In the CIA model, kaempferol effectively alleviated joint swelling and reduced inflammatory cytokine levels. Mechanistically, kaempferol downregulated GCLM expression in RA-FLS, resulting in decreased p65 nuclear translocation and inhibition of nuclear factor kappa B (NF-κB) activation. This regulatory effect restored intracellular ROS, thereby overcoming ferroptosis resistance and inhibiting synoviocyte hyperproliferation. Conclusion: Kaempferol exerts anti-inflammatory and antiproliferative effects in RA by targeting the GCLM/NF-κB signalling axis. By restoring ROS and iron homeostasis and overcoming ferroptosis resistance, kaempferol inhibits RA-FLS proliferation and mitigates synovial inflammation, suggesting its potential as a novel therapeutic agent for RA treatment. Cite this article: Bone Joint Res 2026;15(5):482–496.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease marked by persistent synovial inflammation, autoantibody production, cartilage damage, and bone erosion. Biologic disease-modifying antirheumatic drugs (DMARDs) and targeted small-molecule therapies have improved disease control, but durable remission remains difficult for many patients. Low-grade synovitis and structural damage may continue despite treatment. Extracellular vesicles (EVs) may contribute to this residual activity by carrying signals that are not captured by soluble cytokine measurements alone. In the inflamed joint, EVs are released by fibroblast-like synoviocytes, macrophages, neutrophils, endothelial cells, chondrocytes, and osteoclast precursors. Their cargo includes citrullinated proteins, inflammatory mediators, miRNAs, lipids, and matrix-degrading enzymes and often reflects the state of the parent cell. This mini-review examines EV biogenesis, movement across the synovial barrier, and uptake by recipient cells in RA. It evaluates evidence linking EV cargo to NF-κB, MAPK, JAK-STAT, and cGAS-STING signaling; innate and adaptive immune activation; fibroblast-like synoviocyte invasion; and osteoclast differentiation. We also assess the current evidence for EVs as biomarkers and therapeutic vehicles, with particular attention to methodological and translational limitations.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. The underlying molecular mechanisms remain incompletely defined. Transcriptomic data of RA and normal synovial samples (GSE89408) were analyzed to identify the differentially expressed genes (DEGs). WGCNA, GO/KEGG enrichment, and PPI analysis were performed on the DEGs to screen for hub genes involved in RA progression. The proliferation, apoptosis, migration, and invasion of the MH7A fibroblast-like synoviocytes were evaluated through routine functional assays. QRT-PCR and Western blotting were conducted for molecular validation. Bioinformatics analyses identified FOXC1 as a hub transcription factor in RA and confirmed its co-expression with ATP7A. FOXC1 was markedly upregulated in RA tissues and fibroblasts, where it enhanced ATP7A expression. Overexpression of FOXC1 or ATP7A promoted the proliferation, invasion, and migration of RA fibroblasts while inhibiting apoptosis. Knockdown of ATP7A abrogated the effects of FOXC1. Mechanistically, the FOXC1-ATP7A axis activated PI3K/AKT/mTOR signaling and reduced markers of cuproptosis in the MH7A cells, suggesting an essential role in maintaining fibroblast pathogenicity. FOXC1 is a novel upstream regulator of ATP7A in synovial fibroblasts, and the FOXC1/ATP7A/PI3K/AKT pathway mediates RA pathogenesis by activating the synovial fibroblasts and suppressing cuproptosis. Targeting this axis may provide new therapeutic opportunities for RA.

ObjectiveUsing liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology, we investigated differences in serum metabolites among rheumatoid arthritis (RA) patients in different seasons.MethodsSerum samples were collected from 60 patients meeting the diagnostic criteria for RA and divided into four groups based on different seasons. Metabolites in the serum samples were analyzed using a liquid chromatography-mass spectrometry (LC-MS) system comprising the Waters ACQUITY UPLC I-Class plus/Thermo QE plus ultra-high-performance liquid chromatography and high-resolution mass spectrometry instruments. Principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal partial least squares discriminant analysis (OPLS-DA) to identify seasonally differential metabolites and investigate their metabolic pathways and enrichment patterns.ResultsA total of 3,787 metabolites were detected in serum, with the majority of differentially expressed metabolites classified as “Lipids and Lipid-Like Molecules.” Metabolites in the serum of RA patients across the four seasons exhibited varying degrees of differences. The significantly different metabolites identified between groups were 223 (C1_vs_C2), 977 (C1_vs _C3), and 778 (C1_vs_C4), with 62 common different metabolites among them. These differential metabolites were primarily found in the “Lipids and Lipid-Like Molecules” and “Organic acids and derivatives” categories. We also identified key differentially expressed metabolites. C1_vs_C2 includes Behenic acid (d3), Stizolamine, and Cyanidin 7-arabinoside; C1_vs_C3 includes Phosphatidylinositol-3,4,5-trisphosphate, N-Docosahexaenoyl Threonine, and Alginic acid; C1_vs_C4 includes 9,10-DiHOME, Perfluorotridecanoic acid, and 3,4-Dehydro-gamma,chi-carotene. KEGG metabolic pathway enrichment analysis showed that the differential metabolites were enriched in metabolic pathways such as Carbohydrate metabolism and Lipid metabolism.ConclusionThis study elucidates the regulatory role of seasonal factors in serum metabolic profiles of RA patients. The identified seasonally variable metabolites may provide potential reference points for seasonal monitoring of RA and optimization of personalized treatment regimens, opening new metabolomics perspectives for disease diagnosis and management.

The gut microbiome has been implicated in the development of autoimmune diseases, including gout. However, the role of the gut virome in gout pathogenesis remains underexplored. We employed a reference-dependent virome approach to analyze fecal metagenomic data from 102 gout patients (77 in the discovery cohort and 25 in the validation cohort) and 86 healthy controls (HCs) (63 and 23 in each cohort). A subset of gout patients in the discovery cohort provided longitudinal samples at Weeks 2, 4, and 24. Our analysis revealed significant alterations in the gut virome of gout patients, including reduced viral richness and shifts in viral family composition. Notably, Siphoviridae, Myoviridae, and Podoviridae were depleted, while Quimbyviridae, Retroviridae, and Schitoviridae were enriched in gout patients. We identified 359 viral operational taxonomic units (vOTUs) associated with gout. Enriched vOTUs in gout patients predominantly consisted of Fusobacteriaceae, Bacteroidaceae, and Selenomonadaceae phages, while control-enriched vOTUs included Ruminococcaceae, Oscillospiraceae, and Enterobacteriaceae phages. Longitudinal analysis revealed that a substantial proportion of these virome signatures remained stable over 6 months. Functional profiling highlighted the enrichment of viral auxiliary metabolic genes, suggesting potential metabolic interactions between viruses and host bacteria. Notably, gut virome signatures effectively discriminated gout patients from HCs, with high classification performance in the validation cohort. This study provides the first comprehensive characterization of the gut virome in gout, revealing its potential role in disease pathogenesis and highlighting virome-based signatures as promising biomarkers for gout diagnosis and future therapeutic strategies.

Euphorbia fischeriana has been traditionally used in Chinese medicine for tuberculosis (TB) treatment since ancient times. In this study, we first report the identification of an abietane-type diterpenoid, 17-hydroxy-jolkinolide B (HJKB), from E. fischeriana, which exhibits potent antimycobacterial activity against both Mycobacterium tuberculosis H37Ra strain and clinical isolates. The minimum inhibitory concentrations (MICs) of HJKB against diverse M. tuberculosis strains range from 1 to 12 μg/mL. Notably, HJKB demonstrates significant bactericidal activity against intracellular M. tuberculosis H37Ra in macrophage models, accompanied by anti-inflammatory effects at concentrations of 2-5 μg/mL. Using a combination of chemoproteomic analysis and pull-down assays, we explored the preliminary antimycobacterial mechanism of HJKB. Results indicate that HJKB interacts with the target proteins RpoB and RpoC in M. tuberculosis H37Ra, a finding further corroborated by molecular docking studies. RpoB and RpoC are essential subunits of the DNA-directed RNA polymerase holoenzyme, which is critical for bacterial ribosomal transcription regulation. In summary, HJKB represents a bioactive constituent of E. fischeriana with anti-TB efficacy, acting as a transcription inhibitor against M. tuberculosis. This study not only elucidates its antimycobacterial mechanism but also provides a preclinical foundation for the development of natural product-based TB therapeutics.

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder shaped by host genetics and environmental exposures, including the gut microbiota. While bacterial dysbiosis in SLE is well characterized, the role of the gut mycobiome and its cross-kingdom interactions remains largely unexplored. Using fecal metagenomic sequencing from 117 SLE patients and 115 healthy controls (HCs), we established a non-redundant fungal genome catalog and revealed significant alterations in fungal composition, function, and cross-kingdom ecology. Fungal diversity was increased in SLE, with enrichment of potentially pathogenic taxa such as Candida, Malassezia, and Trichophyton, and depletion of commensal genera such as Pichia. Functional analysis showed expanded biosynthetic and redox capacities in SLE-associated fungi, including enrichment of RiPP- and terpene-related biosynthetic gene clusters and oxidative stress–related Pfam domains. Several predicted metabolites—such as kynurenine, phenylacetic acid, secondary bile acids, and acylcarnitines—were linked to immune activation and inflammation, suggesting that fungal metabolism may contribute to immune dysregulation. Network analysis revealed sparser and less centralized fungal–bacterial interactions in SLE, indicating disrupted ecological stability and the emergence of fungal taxa as key structural drivers. Integrating fungal and bacterial profiles markedly improved diagnostic performance (AUC = 0.934), underscoring the complementary predictive value of the gut mycobiome. In contrast, post-treatment samples showed reduced fungal richness but no major compositional shifts. This study provides a comprehensive, multi-dimensional view of the gut mycobiome in SLE, demonstrating its taxonomic, functional, and ecological remodeling. Our findings highlight the potential contribution of fungal metabolic and redox activities to SLE pathogenesis and support the inclusion of fungi in multi-kingdom microbiome frameworks for disease diagnosis and therapeutic development.

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease with increasing mortality worldwide. Traditional obesity indicators inadequately predict the mortality risk in this population. Thus, the research aimed to evaluate new obesity indicators to explore their close association with RA mortality. This study analyzed 101,316 National Health and Nutrition Examination Survey participants (1999–2018) to evaluate alternative adiposity indices for RA mortality prediction. Missing data were imputed using the random forest method. Key covariates were selected using the Boruta algorithm and weighted univariate Cox regression. Multivariable-adjusted models generated hazard ratios (95

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease treated with tocilizumab in patients unresponsive to methotrexate. This study aimed to identify gene expression profiles and predictive models for tocilizumab treatment response in RA patients.Methods: Using the GSE78068 dataset from 38 RA patients, we identified differentially expressed genes between remission and non-remission groups. Predictive models were created using CART, random forest, and SVM techniques, with model genes selected through LASSO regression. Gene set enrichment and immune cell landscape analyses were performed to understand biological pathways and immune cell composition.Results: Analysis revealed 40 differentially expressed genes, with LASSO regression identifying 8 model genes significantly associated with remission. The SVM-based model achieved the highest performance (AUC=1.0, Brier score=0.025).Conclusions: This study developed an effective 8-gene model for predicting tocilizumab treatment response, potentially supporting personalized therapy in RA patients.

This study investigated the mechanisms by which 6-gingerol affected miRNAs in mesenchymal stem cell exosomes and the regulation on NF-κB signaling pathways in synovial cells and GES-1 via miR-30c-2-3p. In addition, the study evaluated potential protective effects of 6-gingerol on synovial tissue and gastric mucosa based on a rat model. The role of 6-gingerol was evaluated using assays including Western Blotting, transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), qPCR, immunofluorescence, dual luciferase reporter gene assay, ELISA, CCK-8 cell viability assay, and protein expression analysis. Meanwhile, the effects of 6-gingerol on synovial tissue and gastric mucosa were evaluated using an animal model. 6-Gingerol exhibited anti-inflammatory effects by upregulating miR-30c-2-3p, targeting the TAB1 gene, and suppressing NF-κB signaling pathway activation. In both synovial cells and GES-1, 6-gingerol significantly reduced the concentration of inflammatory factors and increased cell viability. In addition, 6-gingerol regulated key molecules in the NF-κB signaling pathway through miR-30c-2-3p, thereby reducing inflammatory response. Based on the rat model, 6-gingerol showed protective effects on synovial tissue and gastric mucosa, while miR-30c-2-3p antagomir might attenuate the therapeutic effects. 6-Gingerol effectively suppressed the NF-κB signaling pathway activation via upregulating miR-30c-2-3p expression, which targeted TAB1. This led to significant anti-inflammatory and protective effects in synovial cells and GES-1.

IntroductionDiabetes mellitus (DM), a globally prevalent chronic metabolic disorder characterized by persistent hyperglycemia, has been increasingly linked to dysbiosis of the oral microbiome. However, the relationship between the virome, a crucial component of the oral microbiome, and DM remains poorly understood.MethodsTo explore the characteristics of the oral virome in DM patients, we analyze the oral viral communities of 45 DM patients and 40 healthy controls (HC) using a publicly available metagenomic dataset.ResultsOur analysis revealed no significant differences in a-diversity between DM patients and HC. However, Podovirus was enriched in DM patients, whereas Microviridae was more prevalent in HC. A total of 1,131 virus signal was identified, primarily belonging to the Siphovirus and Myovirus taxa. Notably, HC-enriched vOTUs exhibited broader host tropism, predominantly infecting Prevotella, Fusobacterium, and Gemella, whereas DM-enriched vOTUs showed narrower specificity for Pauljensenia and Veillonella. Cross-kingdom network analysis suggested that certain viruses (HMP_1157.k81_309051) may have potential links to the development of DM, and the bacteria genus F0040 might play a significant role in maintaining oral health. Additionally, the random forest model based on viral markers effectively distinguished between HC and DM patients (AUC =90.8%), significantly outperforming the bacterial model.DiscussionThis indicates that these unique viral markers could serve as potential targets for DM intervention. Taken together, our findings reveal distinct alterations in the oral virome of DM patients and highlight its promise as a novel diagnostic and therapeutic target in metabolic disease research.

The gut viral community has been increasingly recognized for its role in human physiology and health; however, our understanding of its genetic makeup, functional potential, and disease associations remains incomplete. In this study, we collected 11,286 bulk or viral metagenomes from fecal samples across large-scale Chinese populations to establish a Chinese Gut Virus Catalogue (cnGVC) using a de novo virus identification approach. We then examined the diversity and compositional patterns of the gut virome in relation to common diseases by analyzing 6311 bulk metagenomes representing 28 disease or unhealthy states. The cnGVC contains 93,462 nonredundant viral genomes, with over 70

Dysbiosis of the human gut virome is associated with a variety of factors, yet the underlying mechanisms remain poorly understood. This study aims to map the current research trajectory of the human gut virome and propose a strategic framework for future scientific research. A bibliometric analysis was performed on articles retrieved from the Web of Science (WoS) Core Collection database covering the period 2000 to 2024, utilizing VOSviewer, CiteSpace, and the R software environment. Over the past 20 years, the number of published papers and citations in the field of enterovirus research has shown a significant growth trend. This trend is attributed to the breakthrough progress of high-throughput sequencing technology and the iterative upgrade of viral genome databases such as CheckV, which has made the classification resolution of the enterovirus group more accurate and discovered a large number of unknown bacteriophages. Technological innovation has led to a fundamental transformation in the research model, evolving from the traditional single-virus species identification to the multi-omics integrated analysis of virus-host interaction networks. It is worth noting that the existing research shows a distinct feature of "imbalance between dry and wet experiments". Most of the achievements are based on bioinformatics analysis, while the translational medicine research involving virus isolation, culture and functional verification is still in its infancy (accounting for only 25

The traditional Chinese medicine Euphorbia fischeriana Steud (E. fischeriana) has been used for treating lymph node tuberculosis (TB) for a long time. This study demonstrates that Jolkinolide B, a component of E. fischeriana, exhibits antimycobacterial activity with a minimum inhibitory concentration (MIC) of 3 μg/mL against M. tuberculosis H37Ra. Additionally, it shows bactericidal effect on RAW264.7 macrophages infected with M. tuberculosis at a concentration of 2 × MIC. Mechanistic study via transcriptome revealed that Jolkinolide B significantly reduced the transcription of 17 ribosomal proteins, thereby inhibiting protein synthesis in M. tuberculosis. RT-qPCR confirmed that Jolkinolide B decreased the expression of mycobacterial ribosomal proteins in a concentration-dependent manner. Finally, morphological observations indicated that Jolkinolide B caused the tubercle bacilli to become shorter and deformed. This study highlights a natural compound from E. fischeriana and clarifies its mechanism of action against TB, supporting the rational use of traditional Chinese medicine (TCM) and antibiotics in TB treatment.

The contribution of gut microbiota to human high-altitude adaptation remains inadequately understood. Here a comparative analysis of gut microbiota was conducted between healthy individuals living at sea level and high altitude using deep whole-metagenome shotgun sequencing, to investigate the adaptive mechanisms of gut microbiota in plateau inhabitants. The results showed the gut bacteriomes in high-altitude individuals exhibited greater within-sample diversity and significant alterations in both bacterial compositional and functional profiles when compared to those of sea-level individuals, indicating the potential selection of unique bacteria associated with high-altitude environments. The strain-level investigation revealed enrichment of Collinsella aerofaciens and Akkermansia muciniphila in high-altitude populations. The characteristics of gut virome and gut mycobiome were also investigated. Compared to sea-level subjects, high-altitude subjects exhibited a greater diversity in their gut virome, with an increased number of viral operational taxonomic units (vOTUs) and unique annotated genes. Finally, correlation analyses revealed 819 significant correlations between 42 bacterial species and 375 vOTUs, while no significant correlations were observed between bacteria and fungi or between fungi and viruses. The findings have significantly contributed to an enhanced comprehension of the mechanisms underlying the high-altitude geographic adaptation of the human gut microbiota.

BACKGROUND/PURPOSE(S):The gut microbiota and its metabolites play crucial roles in pathogenesis of arthritis, highlighting gut microbiota as a promising avenue for modulating autoimmunity. However, the characterization of the gut virome in arthritis patients, including osteoarthritis (OA) and gouty arthritis (GA), requires further investigation. METHODS:We employed virus-like particle (VLP)-based metagenomic sequencing to analyze gut viral community in 20 OA patients, 26 GA patients, and 31 healthy controls, encompassing a total of 77 fecal samples. RESULTS:Our analysis generated 6819 vOTUs, with a considerable proportion of viral genomes differing from existing catalogs. The gut virome in OA and GA patients differed significantly from healthy controls, showing variations in diversity and viral family abundances. We identified 157 OA-associated and 94 GA-associated vOTUs, achieving high accuracy in patient-control discrimination with random forest models. OA-associated viruses were predicted to infect pro-inflammatory bacteria or bacteria associated with immunoglobulin A production, while GA-associated viruses were linked to Bacteroidaceae or Lachnospiraceae phages. Furthermore, several viral functional orthologs displayed significant differences in frequency between OA-enriched and GA-enriched vOTUs, suggesting potential functional roles of these viruses. Additionally, we trained classification models based on gut viral signatures to effectively discriminate OA or GA patients from healthy controls, yielding AUC values up to 0.97, indicating the clinical utility of the gut virome in diagnosing OA or GA. CONCLUSION:Our study highlights distinctive alterations in viral diversity and taxonomy within gut virome of OA and GA patients, offering insights into arthritis etiology and potential treatment and prevention strategies.

ObjectiveSystemic sclerosis(SSc) remains unclear, studies suggest that inflammation may be linked to its pathogenesis. Hence, we conducted a bidirectional Mendelian randomization (MR) analysis to evaluate the association between cytokine and growth factor cycling levels and the risk of SSc onset.MethodsIn our study, the instrumental variables(IVs) for circulating cytokines were sourced from the genome-wide association study (GWAS) dataset of 8293 Finnish individuals. The SSc data comprised 302 cases and 213145 controls, and was included in the GWAS dataset. We employed four methods for the MR analysis: MR Egger, Inverse variance weighted (IVW), Weighted medium, and Weighted Mode, with IVW being the primary analytical method. Sensitivity analyses were performed using heterogeneity testing, horizontal pleiotropy testing, and the Leave One Out (LOO) method. We also conducted a reverse MR analysis to determine any reverse causal relationship between SSc and circulating cytokines.ResultsAfter Bonferroni correction, MR analysis revealed that the Interleukin-5 (IL-5) cycle level was associated with a reduced risk of SSc [odds ratio (OR)=0.48,95% confidence interval (CI): 0.27-0.84, P=0.01]. It also indicated that the Stem cell growth factor beta (SCGF-β) cycling level might elevate the risk of SSc (OR = 1.36, 95% CI: 1.01-1.83, P = 0.04). However, the reverse MR analysis did not establish a causal relationship between SSc and circulating cytokine levels. Additionally, sensitivity analysis outcomes affirm the reliability of our results.ConclusionOur MR study suggests potential causal relationships between IL-5, SCGF-β, and the risk of SSc. Further research is essential to determine how IL-5 and SCGF-β influence the development of SSc.