Microbiome therapeutics for hepatic encephalopathy

Abstract

Hepatic encephalopathy (HE) is a complication of cirrhosis characterised by neuropsychiatric and motor dysfunction. Microbiota-host interactions play an important role in HE pathogenesis. Therapies targeting microbial community composition and function have been explored for the treatment of HE. Prebiotics, probiotics and faecal microbiota transplant (FMT) have been used with the aim of increasing the abundance of potentially beneficial taxa, while antibiotics have been used to decrease the abundance of potentially harmful taxa. Other microbiome therapeutics, including postbiotics and absorbents, have been used to target microbial products. Microbiome-targeted therapies for HE have had some success, notably lactulose and rifaximin, with probiotics and FMT also showing promise. However, there remain several challenges to the effective application of microbiome therapeutics in HE, including the resilience of the microbiome to sustainable change and unpredictable clinical outcomes from microbiota alterations. Future work in this space should focus on rigorous trial design, microbiome therapy selection, and a personalised approach to HE.

Keywords: ammonia; cirrhosis; fecal transplant; lactulose; probiotic; rifaximin.

Fig. 1. The pathogenic mechanisms of hepatic encephalopathy.

Changes to SCFAs, secondary bile acid, tight junction protein, and mucus production contribute to increased intestinal permeability. Intestinal bacterial products, including ammonia and LPS, are able to traverse the epithelial membrane and bypass the liver due to hepatic dysfunction and portosystemic shunting. They enter systemic circulation and reach the brain, where ammonia enters astrocytes and leads to neurotoxicity. LPS, lipopolysaccharide; SCFAs, short-chain fatty acids.

Fig. 2. Faecal microbiota transplant for hepatic encephalopathy: From bench to bedside.

Faecal microbiota transplant has multiple potential therapeutic mechanisms in HE, including several which improve intestinal barrier function: increasing SCFA, secondary bile acid, tight junction protein, and antimicrobial peptide production. By changing microbial community structure, ammonia and endotoxin production and translocation decreases. At the bedside, several small trials have suggested improved cognition and fewer overt HE episodes with faecal microbiota transplant. HE, hepatic encephalopathy; SCFA, short-chain fatty acid.

Fig. 3. The strengths, challenges, weaknesses, and future directions of faecal microbiota transplant for hepatic encephalopathy.

FMT, faecal microbiota transplant; HE, hepatic encephalopathy.