Background: Despite establishing an association between gut microbiota and spondyloarthritis (SpA) subtypes, the causal relationship between them remains unclear.Methods: Gut microbiota data were obtained from the MiBioGen collaboration, and SpA genome-wide association study (GWAS) summary data were obtained from the FinnGen collaboration. We conducted a two-sample Mendelian randomization (MR) analysis using the inverse-variance-weighted method supplemented with four additional MR methods (MR-Egger, weighted median, simple mode, and weighted mode). Pleiotropy and heterogeneity were also assessed. Reverse MR analysis was used to detect reverse causal relationships.Results: We identified 23 causal links between specific gut microbiota taxa and SpA levels. Of these, 22 displayed nominal causal associations, and only one demonstrated a robust causal connection. Actinobacteria id.419 increased the risk of ankylosing spondylitis (AS) (odds ratio (OR) = 1.86 (95% confidence interval (CI): 1.29–2.69); p = 8.63E−04). The family Rikenellaceae id.967 was associated with a reduced risk of both AS (OR = 0.66 (95% CI: 0.47–0.93); p = 1.81E−02) and psoriatic arthritis (OR = 0.70 (95% CI: 0.50–0.97); p = 3.00E−02). Bacillales id.1674 increased the risk of AS (OR = 1.23 (95% CI: 1.00–1.51); p = 4.94E−02) and decreased the risk of enteropathic arthritis (OR = 0.56 (95% CI: 0.35–0.88); p = 1.14E−02). Directional pleiotropy, or heterogeneity, was not observed. No reverse causal associations were observed between the diseases and the gut microbiota.Conclusion: Our MR analysis suggested a genetic-level causal relationship between specific gut microbiota and SpA, providing insights into the underlying mechanisms behind SpA development mediated by gut microbiota.

Inflammatory response following central nervous system (CNS) injury is a significant, multifaceted process that requires further studies. Microglia and macrophages play key roles in CNS inflammation. However, it is still undefined what activity PD-1 plays in M1 polarization and what mechanisms PD-1 regulates the polarization of microglia and macrophages. This study was design to determine whether PD-1 influences M1 polarization of microglia and macrophages and explore PD-1 regulatory mechanisms in M1 polarization using the model mouse and proteomics analysis. It applied six newborn and sixty 6-8 week-old C57BL/6 mice, sixty PD-1 knockout (KO) mice, sixty PD-L1 KO mice, and fifteen PD-1 over-expressed mice. Our studies have shown that programmed death-1 (PD-1) is upregulated in microglia and macrophages in spinal cord injury (SCI), and polarized stimulation induces the expression of PD-1 in cultured microglia and macrophages. We have also observed that following SCI in a PD-1 KO model mouse, there is an increase in M1 polarization of macrophages. PD-1 and PD-L1 were upregulated with M1 polarization in peritoneal macrophages, Raw 264.7 and cerebral cortex-derived microglia, and M1 polarization was inhibited by PD-1 and PD-L1 through STAT1/NF-κB and Akt/mTOR signaling pathways in bone marrow-derived macrophages of PD-1 KO and PD-L1 KO mice. This study supported that PD-1/PD-L1 inhibits M1 polarization of microglia and macrophages through STAT1/NF-κB and Akt/mTOR signaling pathways. PD-1 regulated M1 polarization could be a key clinical target of novel immune-focused therapeutic strategies for CNS injury and inflammatory response.

Purpose: Hydroxychloroquine is an effective treatment for rheumatic diseases; however, retinal damage is a possible side effect. We aimed to identify the retinal area and related risk factors associated with cone density reduction caused by hydroxychloroquine. Methods: We recorded the retinal images of patients with rheumatic diseases taking hydroxychloroquine (n = 44) and compared them with images of healthy controls (n = 107). Cone density was obtained in vertical and horizontal axes. Regions of decreased cone density and associations between age, rheumatic disease type, dosage for ideal body weight, and cone density were evaluated. Results: Cone densities were significantly lower in hydroxychloroquine-treated patients than in sex- and age-matched controls in the vertical axis (P < 0.001), with no significant difference in the horizontal axis (P = 0.120); in healthy elderly than in healthy young people in the horizontal axis (P < 0.001), with no significant difference in the vertical axis (P = 0.100); in hydroxychloroquine-treated elderly than in hydroxychloroquine-treated young patients in both axes (both P < 0.05); among patients with different rheumatic disease types, with no significant difference in the vertical axis (P = 0.294). The daily dose was negatively correlated with cone density in the vertical axis and inferior quadrant. Conclusions: Hydroxychloroquine reduces retinal cone cell density in the vertical axis. Cone density loss in the horizontal axis increases with age; further, hydroxychloroquine dosage is negatively correlated with cone density in the vertical axis and inferior quadrant. Early screening of hydroxychloroquine-related retinal injury should consider changes in cone density in the vertical axis.

Chronic periodontitis (CP) is a multifactorial inflammatory disease. Growing evidence links dysregulated serum metabolites to CP pathogenesis, yet their causal roles in disease progression remain poorly defined. We performed bidirectional Mendelian randomization (MR) analysis to evaluate causal relationships between 486 serum metabolites and CP. Inverse-variance weighted, MR-Egger, and weighted median methods were employed to mitigate research bias. Sensitivity was evaluated via the Cochran Q test, MR-Egger, and leave-one-out analysis. Metabolic pathway analysis (based on metabolomics data) was carried out via the MetaboAnalyst 6.0. We analyzed RNA-seq data to identify genes and mechanisms involved in serum metabolite regulation of CP development. Bidirectional MR identified 22 metabolites associated with CP risk, with 6 metabolites exhibiting protective effects and 16 linked to risk-increasing associations. Sensitivity analyses confirmed robustness across multiple MR methods, and reverse MR excluded reverse causality. Caffeine metabolism and lysine degradation emerged as the core pathways. Nineteen overlapping genes were identified via transcriptomic integration as key mediators. Enrichment analysis highlighted FoxO signaling and p53-mediated signaling. This study deepens the understanding of metabolic crosstalk and its role in CP pathogenesis, revealing novel biomarkers and therapeutic targets that inform diagnostic precision and therapeutic innovation. However, limitations such as sample size constraints should be noted. Future research could validate these findings in larger populations and explore the underlying biological mechanisms linking these metabolites to CP.