Clinical science workshop: targeting the gut-liver-brain axis

Area of Science:

• Clinical Science
• Gastroenterology
• Neurology

Background:

• The gut-liver-brain axis plays a central role in hepatic encephalopathy (HE) pathogenesis.
• Inter-organ ammonia metabolism is integral to HE development, involving the intestines, liver, brain, kidneys, and muscles.
• Gut microbiome alterations, including dysbiosis and bacterial translocation, contribute to HE pathophysiology.

Purpose of the Study:

• To review the role of the gut-liver-brain axis in hepatic encephalopathy (HE).
• To discuss therapeutic targets for HE based on ammonia metabolism and inflammation.

Main Methods:

• Review of current literature on ammonia metabolism and the gut-liver-brain axis in HE.
• Discussion of the roles of various organs in ammonia and glutamine metabolism.
• Analysis of the impact of gut microbiome, inflammation, and comorbidities on HE.

Main Results:

• Patients with advanced cirrhosis exhibit enteric dysbiosis, bacterial overgrowth, and increased gut permeability.
• Bacterial products trigger inflammatory responses in the liver, leading to cytokine release and systemic inflammation (endotoxemia).
• Comorbidities like diabetes and insulin resistance can exacerbate HE by affecting gut transit and ammonia metabolism.

Conclusions:

• Therapies should target ammonia production, utilization, or excretion at an organ level.
• Reducing systemic inflammation and endotoxemia is essential for managing HE.
• Combined therapeutic strategies addressing both hyperammonemia and inflammation offer the most promising approach for HE treatment.