The gut-brain axis underlying hepatic encephalopathy in liver cirrhosis

Up to 50-70% of liver cirrhosis patients develop hepatic encephalopathy (HE), which is closely related to gut microbiota dysbiosis, with unclear mechanism. Here, through constructing gut-brain modules to assess bacterial neurotoxins from metagenomic datasets, we found phenylalanine decarboxylase (PDC) genes, mainly from Ruminococcus gnavus (R. gnavus), increased ~10-folds in cirrhosis and higher in HE patients. 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 HE patients. This accumulation of PEA was primarily driven by decreased monoamine oxidase-B (MAO-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 HE patients 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 7-folds increased risk of HE post-intrahepatic portosystemic shunt procedures. Our findings expand the understanding of gut-liver-brain axis and identify a promising therapeutic and predictive target for HE.