肝性脑病 z-bio 2025-02-05 878

　　The serum PEA level in patients with liver cirrhosis is correlated with the abundance of fecal PDC coding genes, and patients with high serum PEA levels before TIPS surgery have a higher risk of developing HE after TIPS surgery

　　Under the support of National Natural Science Foundation of China projects (approval numbers: 81925026, 82272387, 31900101, 82130068, 82372305), the teams of Professor Zhou Hongwei and Professor Chen Jinjun from Southern Medical University, together with Professor Gao Jie from Guangzhou Medical University and Professor Qi Xiaolong from Southeast University, have made progress in the study of the mechanism of hepatic encephalopathy (HE) driven by intestinal microbiota imbalance. The related research results, titled "The gut brain axis underlying hepatic encephalopathy in liver cirrhosis", were published online on January 8, 2025 in the journal Nature Medicine. The link to the paper is: https://www.nature.com/articles/s41591-024-03405-9 .

　　Hepatic encephalopathy is a common and serious complication in patients with cirrhosis, with a complex pathogenesis. According to traditional theory, the pathogenesis of HE is mainly attributed to "ammonia poisoning", which refers to the inability of the liver to effectively remove ammonia from the blood, resulting in the accumulation of ammonia in the brain and causing nerve damage. However, blood ammonia levels are not fully correlated with the occurrence and severity of HE, indicating the existence of other unexplained causes of hepatic encephalopathy in cirrhosis.

　　The research team first constructed a gene set that can evaluate the neural activity metabolites derived from gut microbiota, known as the "gut brain module". By analyzing the gut brain module in the gut microbiota metagenomic data of patients with cirrhosis, it was found that the monoamine synthesis module was significantly enriched. Further enzyme activity screening experiments confirmed that phenylalanine decarboxylase (PDC) from Ruminococcus gnavus is a key rate limiting enzyme in the microbial monoamine synthesis module. Animal experiments have confirmed that the colonization of Vibrio rumenalis in cirrhotic mice can lead to the accumulation of phenylethylamine (PEA) in their brains, and exhibit typical hepatic encephalopathy symptoms such as memory impairment and flapping tremors. Using fecal microbiota transplantation experiments, the research team found that liver cirrhosis mice colonized with fecal microbiota from HE patients exhibited significant memory impairment, and the use of PDC inhibitors or PEA neutralizing antibodies could effectively block the neurotoxic effects of fecal microbiota from HE patients. Finally, the team found that the abundance of active rumen bacteria and PDC genes in the feces of HE patients was significantly higher than that of non HE cirrhosis patients, and positively correlated with serum PEA levels; In the cohort of liver cirrhosis patients undergoing intrahepatic portal vein shunting, patients with high preoperative PEA levels had a 7-fold higher risk of developing HE compared to patients with low PEA levels (Figure).

　　This study reveals a new mechanism by which gut active rumen bacteria drive hepatic encephalopathy through PDC and its product PEA, providing a potential new target for the precise diagnosis and treatment of HE.