Serum metabolites and gut microbiota mediate the causal link between anxiety and nonalcoholic fatty liver disease: a Mendelian randomization analysis

Background Nonalcoholic fatty liver disease (NAFLD) is defined by liver fat accumulation exceeding 5% in individuals who do not consume significant amounts of alcohol. This condition can advance to more severe outcomes, including fibrosis, cirrhosis, and liver cancer. Although numerous factors contribute to the progression of NAFLD, the influence of psychological elements, especially anxiety, remains inadequately explored. Methods This study applied Mendelian randomization (MR) using genome-wide association data from 4761 NAFLD cases and 373 227 controls to investigate the causal relationship between psychological factors and NAFLD. We conducted both multivariable and mediation MR analyses to determine how anxiety influences NAFLD through pathways involving gut microbiota and metabolites. Furthermore, we examined datasets related to anxiety and NAFLD from the Gene Expression Omnibus, identified differentially expressed genes, and conducted enrichment analyses on the genes shared between these two conditions. Results The MR analysis established a direct causal relationship between genetically predicted anxiety and the development of NAFLD (β=0.229, 95% confidence interval = 1.11–1.41, P = 0.0002). This association was confirmed by multivariable MR, independent of BMI and type 2 diabetes. Mediation MR revealed that specific metabolites and fatty acid-related gut microbiota mediate the relationship between anxiety and NAFLD. Additionally, enrichment analysis confirmed the involvement of fatty acids in genes common to both anxiety and NAFLD. Conclusion This study suggests that genetically predicted anxiety contributes to the development of NAFLD by influencing specific gut microbiota and metabolites, underscoring the vital role of mental health in mitigating NAFLD risk.