Host: The Japanese Society of Toxicology
The gut microbiota influences liver function through intestinal absorption and the subsequent transfer of their metabolites to the liver. This relationship, called “gut-liver axis”, is therefore important in liver diseases. Hepatic encephalopathy (HE) is an end-stage clinical feature of liver cirrhosis (LC) caused by hyperammonaemia and the resulting neuropsychiatric disorders. Ammonia, a neurotoxic substance that can cross the blood-brain barrier, is produced abundantly by gut microbiota. Excess ammonia is normally converted into urea in hepatocytes. However, liver malfunction and the portosystemic shunts in LC patients cause a direct influx of ammonia into the systemic circulation, resulting in hyperammonaemia and neuropsychiatric disorders. However, species causing hyperammonaemia in HE patients remain unknown. In this study, we aimed to identify specific gut microbial species responsible for hyperammonaemia in HE patients, focusing on the responses to a non-absorbable antibiotic, rifaximin (RFX). We compared the faecal gut microbial profiles of healthy control and HE patients by 16S rRNA gene amplicon sequencing. We used linear discriminant analysis effect size (LEfSe) to identify species, and verified their function in vivo in mouse LC model. We found that urease-positive gut bacterial species, which is known to originally reside in oral cavity, is responsible for hyperammonaemia in RFX-responders, suggesting that these bacterial species transfer to the intestine through breaking stomach acid barrier due to the medication of proton pump inhibitors.
