ABSTRACT
INTRODUCTION: Observational studies and clinical trials have supported the association between gut microbiota and psoriatic arthritis. However, the causal link between gut microbiota and psoriatic arthritis is still unclear. METHODS: A two-sample bi-directional Mendelian randomization analysis was performed using the summary statistics of gut microbiota from the largest available genome-wide association study meta-analysis (n = 13,266) conducted by the MiBioGen consortium. The summary statistics of psoriatic arthritis were extracted directly from the FinnGen consortium, which consists of 3186 psoriatic arthritis patients and 24,086 controls. Sensitivity analyses were conducted to assess the validity of our findings. Enrichment analyses were used to investigate the biofunction and pathways. RESULTS: Inverse variance weighted (IVW) estimates suggested that family Rikenellaceae (P = 0.032) and genus Ruminococcaceae UCG011 (P = 0.014) had a detrimental effect on psoriatic arthritis. We also noticed the negative association between the class Methanobacteria (P = 0.032), order Methanobacteriales (P = 0.032), family Methanobacteriaceae (P = 0.032), genus Eubacterium fissicatena group (P = 0.010), genus Methanobrevibacter (P = 0.031), and genus Butyricicoccus (P = 0.041) with psoriatic arthritis. Sensitivity analyses showed that genus Butyricicoccus had pleiotropy and heterogeneity. According to the results of reverse MR analysis, the causal effect of psoriatic arthritis was found on six taxa, respectivelyc family Clostridiaceae1, family Defluviitaleaceae, genus Butyrivibrio, genus Defluviitaleaceae UCG011, genus Clostridium sensu stricto1, and genus Ruminococcaceae UCG011. CONCLUSION: This two-sample bidirectional Mendelian randomization analysis suggested that the gut microbiota had a causal effect on psoriatic arthritis and implied the potential role of probiotics in the management and prevention of psoriatic arthritis.
ABSTRACT
Background: Deposition of immune complexes drives podocyte injury acting in the initial phase of lupus nephritis (LN), a process mediated by B cell involvement. Accordingly, targeting B cell subsets represents a potential therapeutic approach for LN. Ginsenoside compound K (CK), a bioavailable component of ginseng, possesses nephritis benefits in lupus-prone mice; however, the underlying mechanisms involving B cell subpopulations remain elusive. Methods: Female MRL/lpr mice were administered CK (40 mg/kg) intragastrically for 10 weeks, followed by measurements of anti-dsDNA antibodies, inflammatory chemokines, and metabolite profiles on renal samples. Podocyte function and ultrastructure were detected. Publicly available single-cell RNA sequencing data and flow cytometry analysis were employed to investigate B cell subpopulations. Metabolomics analysis was adopted. SIRT1 and AMPK expression were analyzed by immunoblotting and immunofluorescence assays. Results: CK reduced proteinuria and protected podocyte ultrastructure in MRL/lpr mice by suppressing circulating anti-dsDNA antibodies and mitigating systemic inflammation. It activated B cell-specific SIRT1 and AMPK with Rhamnose accumulation, hindering the conversion of renal B cells into plasma cells. This cascade facilitated the resolution of local renal inflammation. CK facilitated the clearance of deposited immune complexes, thus reinstating podocyte morphology and mobility by normalizing the expression of nephrin and SYNPO. Conclusions: Our study reveals the synergistic interplay between SIRT1 and AMPK, orchestrating the restoration of renal B cell subsets. This process effectively mitigates immune complex deposition and preserves podocyte function. Accordingly, CK emerges as a promising therapeutic agent, potentially alleviating the hyperactivity of renal B cell subsets during LN.
