The Role of Metabolites in CSF on NAFLD Development: A Mendelian Randomisation Analysis.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition linked to metabolic syndrome. Recent studies suggest that metabolites in cerebrospinal fluid (CSF) may play a role in NAFLD development; however, the specific causal relationship between the two remains unclear. METHODS: This bidirectional two-sample Mendelian randomisation (MR) study analysed the causal relationships between 337 CSF metabolites and NAFLD. We used genome-wide association study (GWAS) datasets from the OpenGWAS and FinnGen databases. MR analysis was mainly conducted through the inverse-variance weighted method from the 'TwoSampleMR' R package, and sensitivity analyses were conducted to validate findings. RESULTS: A total of 24 CSF metabolites were found to have significant causal relationships with NAFLD, with 13 identified in the discovery group and 13 in the validation group. These metabolites predominantly include amino acids, amino acid derivatives, esters, lipids, lipid derivatives, nucleotides, organic acids, carbohydrates and vitamins. Notably, metabolites of lipid derivatives such as 7-alpha-hydroxy-3-oxo-4-cholestenoate (7-HOCA) exhibited a consistent positive causal effect on NAFLD, and nucleotide metabolites uracil showed a consistent inverse causal effect on NAFLD both in the discovery and validation groups. Sensitivity analyses showed robust results without significant pleiotropy or heterogeneity. CONCLUSION: This study reveals significant causal associations between specific CSF metabolites and NAFLD, emphasising the importance of the brain-liver axis in NAFLD pathogenesis. These findings provide a scientific basis for developing early diagnostic biomarkers and personalised therapeutic strategies targeting CSF metabolites, potentially improving NAFLD management and patient outcomes.