Article: The gut–brain axis underlying hepatic encephalopathy in liver cirrhosis
Nature Medicine: 8 January 2025

Xiaolong He, Mengyao Hu, Yi Xu, Fangbo Xia, Yang Tan, Yuqing Wang, Huiling Xiang, Hao Wu, Tengfei Ji, Qian Xu, Lei Wang, Zhenhe Huang, Meiling Sun, Yu Wan, Peng Cui, Shaocong Liang, Yuan Pan, Siyu Xiao, Yan He, Ruixin Song, Junqing Yan, Xin Quan, Yingge Wei, Changze Hong, Weizuo Liao, Fuli Li, Emad El-Omar, Jinjun Chen, Xiaolong Qi, Jie Gao, Hongwei Zhou
Up to 50–70% of patients with liver cirrhosis develop hepatic encephalopathy (HE), which is closely related to gut microbiota dysbiosis, with an unclear mechanism. Here, by constructing gut–brain modules to assess bacterial neurotoxins from metagenomic datasets, we found that phenylalanine decarboxylase (PDC) genes, mainly from Ruminococcus gnavus, increased approximately tenfold in patients with cirrhosis and higher in patients with HE. Cirrhotic, not healthy, mice colonized with R. gnavus showed brain phenylethylamine (PEA) accumulation, along with memory impairment, symmetrical tremors and cortex-specific neuron loss, typically found in patients with HE. This accumulation of PEA was primarily driven by decreased monoamine oxidase-B activity in both the liver and serum due to cirrhosis. Targeting PDC or PEA reversed the neurological symptoms induced by R. gnavus. Furthermore, fecal microbiota transplantation from patients with HE to germ-free cirrhotic mice replicated these symptoms and further corroborated the efficacy of targeting PDC or PEA. Clinically, high baseline PEA levels were linked to a sevenfold increased risk of HE after intrahepatic portosystemic shunt procedures. Our findings expand the understanding of the gut–liver–brain axis and identify a promising therapeutic and predictive target for HE.
Why is this work important?
Your content goes here. Edit or remove this text inline or in the module Content settings. You can also style every aspect of this content in the module Design settings and even apply custom CSS to this text in the module Advanced settings.
Quote from Emad

Prof. Emad El-Omar
Director MRC