RESUMEN
AIMS: The gut microbiota has been found to be altered in different inflammatory disorders, but its involvement in the regulation of inflammatory cytokines remains unclear. Therefore, this study aimed to investigate the impacts of gut microbiota on circulating inflammatory cytokines and their potential roles in host diseases. MAIN METHODS: Two-sample Mendelian randomization (MR) analyses were conducted using summary-level data from genome-wide association studies (GWAS) to identify significant causal associations between 196 gut microbiota and 41 inflammatory cytokines. Meta-analysis was applied to test the robustness of the results. Enrichment analyses of identified cytokines were further utilized to infer the effects of gut microbiota on the host. KEY FINDINGS: The MR analyses and meta-analyses identified the following significant causal associations: phylum Euryarchaeota on interleukin-2 (IL-2) (ßIVW = 0.085, P = 1.5 × 10-2) and interleukin-8 (IL-8) (ßIVW = 0.065, P = 4.1 × 10-2), phylum Tenericutes and class Mollicutes on macrophage inflammatory protein 1a (MIP1a) (ßIVW = -0.142, P = 7.0 × 10-3), class Bacilli on hepatocyte growth factor (HGF) (ßIVW = -0.106, P = 2.5 × 10-2), order Enterobacteriales on monocyte chemoattractant protein-1 (MCP1) (ßIVW = 0.182, P = 1.8 × 10-2), and genus Lachnospiraceae NC2004 group on TNF-related apoptosis-inducing ligand (TRAIL) (ßIVW = -0.207, P = 6.0 × 10-4). Enrichment analyses suggested that phylum Euryarchaeota and order Enterobacteriales might be risk factors for certain autoimmune diseases and neoplasms, while the phylum Tenericutes may have a protective effect. SIGNIFICANCE: This study represents the first evidence confirming the causal effect of specific gut microbial taxa on circulating inflammatory cytokines and sheds light on their potential roles in the development and progression of various host diseases.
RESUMEN
GSK-126 is recognized as an inhibitor of enhancer of zeste homolog-2 (EZH2) activity. Because of its inhibition of EZH2 activation, GSK-126 is considered a potential anti-tumor drug. EZH2 is a histone methyltransferase that catalyzes histone 3 tri-methylation at lysine 27 (H3K27me3), resulting in gene silencing. A previous report showed that decreased H3K27me3 levels in the hippocampus may promote seizure susceptibility, possibly restricting the clinical application of GSK-126. The role of GSK-126 in seizure susceptibility was investigated in this study. We first determined a critical concentration of pentamethazol (PTZ) under which mice exhibit no seizures. We then found that mice pretreated with GSK-126 and injected with the same concentration of PTZ experienced marked convulsions. Peripheral injections of GSK-126 decreased H3K27me3 levels in the hippocampus of mice, while some seizure-related genes (Oasl1, Sox7, armcx5, Ncx3, etc.) were found to be differentially expressed in the hippocampus of those mice . These differences in the expression levels might reflect the crucial role of these genes and related pathways in the promotion of seizure susceptibility. Our results suggest that GSK-126 promotes seizure susceptibility due to its role as an EZH2 inhibitor. These findings may provide evidence to support the development of GSK-126 as a clinical drug.
