The influence of gut microbiota on circulating inflammatory cytokines and host: A Mendelian randomization study with meta-analysis

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) (BIVW = 0.085, P = 1.5 x 10-2) and interleukin-8 (IL-8) (BIVW = 0.065, P = 4.1 x 10-2), phylum Tenericutes and class Mollicutes on macrophage inflammatory protein 1a (MIP1a) (BIVW =-0.142, P = 7.0 x 10-3), class Bacilli on hepatocyte growth factor (HGF) (BIVW = - 0.106, P = 2.5 x 10-2), order Enterobacteriales on monocyte chemoattractant protein-1 (MCP1) (BIVW = 0.182, P = 1.8 x 10-2), and genus Lachnospiraceae NC2004 group on TNF-related apoptosis-inducing ligand (TRAIL) (BIVW =-0.207, P = 6.0 x 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.