Gut microbiota, lipids, immunity, and liver disease: Insights from Mendelian Randomization and murine models

Abstract Liver diseases, including NAFLD and cirrhosis, are significant health issues. This study used Mendelian Randomization (MR) to identify causal links between gut microbiota, lipidomes, immunophenotypes, inflammatory factors, and liver diseases, while also evaluating the therapeutic potential of Lactobacillus salivarius in NAFLD murine models. Summary statistics from GWAS for gut microbiota traits, lipidome components, immune cell counts, inflammatory cytokines, and liver disease traits were analyzed. MR analysis identified causal relationships, with sensitivity analyses confirming the results. Notable findings included 53 gut microbiota taxa, 28 lipidome components, 92 immune cell types, and 8 cytokines linked to liver diseases. Key taxa like Megamonas funiformis increased liver disease risk, while phosphatidylcholines (PCs) were protective. Immune markers such as CD33 on CD33dim HLA-DR- correlated with higher risk, while CD3 on CD39 + resting Tregs and LIF/LIF-R were protective. In vivo, Lactobacillus salivarius treatment significantly improved metabolic and hepatic parameters. The study emphasizes the causal role of gut microbiota and related factors in liver diseases and highlights Lactobacillus salivarius as a promising therapeutic option for NAFLD.