The role of microbiota in hepatic encephalopathy

Abstract

Hepatic encephalopathy (HE), which consists of minimal (MHE) and overt (OHE) stages, is a model for impaired gut-liver-brain axis in cirrhosis. Microbiota changes in both stages have been associated with impaired cognition, endotoxemia, and inflammation. There is dysbiosis (reduced autochthonous taxa [Lachnospiraceae, Ruminococcaceae, and Clostridiales XIV] and increased Enterobacteriaceae and Streptococcaceae) with disease progression. In MHE, there is an increased abundance of Streptococcus salivarius linked to cognition and ammonia. In OHE, stool Alcaligenaceae and Porphyromonadaceae are associated with poor cognition. Colonic mucosal microbiome in cirrhosis is significantly different compared with stool and independently related to cognition. HE treatment can affect microbial composition and function; cognitive improvement in MHE after rifaximin, a non-absorbable antibiotic, occurred without significant stool microbiota composition change but improved metabolic linkages. Similarly, there are only modest lactulose and rifaximin-associated changes on microbiota composition in OHE. HE represents an important model to study microbiome-brain interactions.

Keywords: cirrhosis; correlation network; covert hepatic encephalopathy; dysbiosis; endotoxin; lactulose; minimal hepatic encephalopathy; probiotic; rifaximin; systemic inflammation.

Figure 1. Schema of brain dysfunction due to altered microbiota in cirrhosis. Dysbiosis due to altered gut microbiota function and composition in cirrhosis is potentially related to the decreased hepatic bile acid synthesis and subsequent release into the intestine, systemic inflammation due to the underlying liver disease and due to continued exposure of certain etiological conditions such as alcohol directly on the gut. This dysbiosis results in an increase in gut-derived products such as ammonia, endotoxin, inflammatory cytokines, and bacterial DNA into the systemic circulation via the poorly functioning liver, through porto-systemic shunting or directly through the thoracic duct. In the setting of this systemic inflammatory milieu, synthetic dysfunction due to liver disease, poor ammonia clearance due to sacropenia, and continued exposure to neurotoxins such as alcohol and hepatitis C, the brain of a patient with cirrhosis can manifest with overt or minimal hepatic encephalopathy.