Exploring the Impact of the Liver-Intestine-Brain Axis on Brain Function in Non-Alcoholic Fatty Liver Disease

Abstract

This study investigates the molecular complexities of Non-alcoholic Fatty Liver Disease (NAFLD)-induced brain dysfunction, with a focus on the liver-intestine-brain axis and potential therapeutic interventions. The main objectives include understanding critical microbiota shifts in NAFLD, exploring altered metabolites, and identifying key regulatory molecules influencing brain function. The methods employed encompassed 16S rRNA sequencing to scrutinize stool microbiota in NAFLD patients and healthy individuals, non-targeted metabolomics using LC-MS to uncover elevated levels of deoxycholic acid (DCA) in NAFLD mice, and single-cell RNA sequencing to pinpoint the pivotal gene Hpgd in microglial cells and its downstream janus kinase 2/signal transducer and activator of transcription 3 (Jak2/Stat3) signaling pathway. Behavioral changes and brain function were assessed in NAFLD mice with and without Fecal Microbiota Transplantation (FMT) treatment, utilizing various assays and analyses. The results revealed significant differences in microbiota composition, with increased levels of Bacteroides in NAFLD patients. Additionally, elevated DCA levels were observed in NAFLD mice, and FMT treatment demonstrated efficacy in ameliorating liver function and brain dysfunction. Hpgd inhibition by DCA activated the Jak2/Stat3 pathway in microglial cells, leading to inflammatory activation, inhibition of mitochondrial autophagy, induction of neuronal apoptosis, and reduction in neuronal action potentials. This study elucidates the intricate molecular mechanisms underlying the liver-gut-brain axis in NAFLD, and the identification of increased DCA and the impact of Jak2/Stat3 signaling on microglial cells highlight potential therapeutic targets for addressing NAFLD-induced brain dysfunction.