Behcet's Disease (BD) is a multisystem vasculitis characterized by disease alternated with recurrent episodes and remissions, involving genital, oral, ocular uvea, cutaneous, and articular manifestations. The nuclear factor (NF)-κB signaling pathway paly an important role in the BD progression. It encompasses diverse gene, protein, and cellular regulatory mechanisms operating across various levels, alongside microbiological and experimental studies involving animals and cells. At the protein research findings, activation of the NF-κB pathway in BD patients is marked by elevated plasma levels of soluble CD40 ligand, which stimulates neutrophils to release reactive oxygen species and extracellular traps, thereby promoting inflammation. At the cellular research findings, macrophages in BD patients polarize towards classically activated macrophages phenotype through the NF-κB pathway, exacerbating the inflammatory response. The activation of NF-κB is associated with increased expression of anti-apoptotic proteins in T cells, leading to prolonged inflammation. Microbiological investigations reveal that the decreased gut microbiota diversity in BD patients compromises intestinal barrier integrity. NF-κB pathway involvement in regulating neutrophil and type 1 helper T cell (Th) 1/Th17 cell function worsens inflammation. Genetically, BD patients exhibit polymorphisms in immune regulatory genes, which contribute to inflammation through the NF-κB pathway. Mutations in NF-κB-associated genes elevate the risk of BD, while mutations in the endogenous inhibitor A20 lead to abnormal NF-κB activity, sustaining inflammation. Animal experiments and in vitro experiments corroborate the efficacy of NF-κB inhibitors in attenuating inflammation. Targeting upstream inflammatory factors within the NF-κB pathway yields positive outcomes in BD patients. In summary, the NF-κB signaling pathway plays a pivotal role in the development of BD. Developing NF-κB inhibitors may open new avenues for treating BD. Further research is necessary to comprehensively elucidate the precise mechanisms by which NF-κB operates in the pathogenesis of BD, as well as its potential clinical applications in therapy.
Objective To explore causal relationships between the gut microbiome and chronic respiratory diseases (asthma and chronic obstructive pulmonary disease (COPD)) and to dissect the underlying biological mechanisms. Methods Cross-sectional observational study: using data from 3 662 participants in the U.S. National Health and Nutrition Examination Survey (NHANES 2007–2012), dietary information was collected as a proxy for gut-microbiome features and linked to lung-function parameters and respiratory symptoms. Two-sample Mendelian randomization (MR): leveraging summary statistics from the Dutch Microbiome Project and Canada serum-metabolite genome-wide association studies (GWAS), we tested the causal effects of 412 gut-microbiome traits (207 taxa and 205 functional pathways) on asthma, COPD, and lung-function indices (FEV1, FVC, FEV1/FVC). Mediation MR was further performed to quantify the mediating roles of 1 091 serum metabolites. Functional validation: single-nucleotide polymorphism (SNP)-based gene mapping was used to prioritize candidate genes, which were then interrogated in COPD and asthma transcriptomic datasets (GSE38974 and GSE69683). Results Observational findings: higher probiotic intake was associated with increased asthma risk (OR=1.76, 95%CI 1.01 to 3.05, P=0.036) but reduced emphysema risk (OR=6.144×10?7, 95%CI 3.059×10?7 to 6.144×10?7, P<0.001). Dietary fiber intake correlated with lower cough prevalence (OR=0.97, 95%CI 0.96 to 0.99, P=0.006) and improved lung function. MR results: 23 microbial taxa and 21 metabolic pathways showed significant causal effects on asthma or COPD. For instance, adolescentis-group Bifidobacterium and Oxalobacter exacerbated asthma, whereas the phospholipid biosynthesis I pathway conferred protection. Lachnospiraceae bacterium 7_1_58FAA and Parasutterella excrementihominis increased COPD risk, while the reductive incomplete TCA cycle and aspartate pathway were protective. Among serum metabolites, 87 and 97 metabolites-including taurochenodeoxycholate-3-sulfate (protective against asthma) and sphingomyelin (protective against COPD)-significantly mediated the causal influences of the gut microbiome. Bioinformatic analyses: gut-microbiome-linked genes (e.g., FXYD1, SCN3B) were differentially expressed in COPD and asthma and were enriched in ion-channel transport, muscle contraction, and blood-circulation processes. Conclusion By integrating observational data, MR, and transcriptomics, this study provides the first multi-omics evidence that specific gut microbes and their metabolic pathways exert causal effects on asthma and COPD through serum metabolite mediation. These effects likely operate via modulation of ion homeostasis, muscle contraction, and blood circulation, offering novel avenues for early diagnosis and targeted intervention in chronic respiratory diseases.