The pathogenesis of gut microbiota in hepatic encephalopathy by the gut-liver-brain axis

Abstract

Hepatic encephalopathy (HE) is a neurological disease occurring in patients with hepatic insufficiency and/or portal-systemic blood shunting based on cirrhosis. The pathogenesis is not completely clear till now, but it is believed that hyperammonemia is the core of HE. Hyperammonemia caused by increased sources of ammonia and decreased metabolism further causes mental problems through the gut-liver-brain axis. The vagal pathway also plays a bidirectional role in the axis. Intestinal microorganisms play an important role in the pathogenesis of HE through the gut-liver-brain axis. With the progression of cirrhosis to HE, intestinal microbial composition changes gradually. It shows the decrease of potential beneficial taxa and the overgrowth of potential pathogenic taxa. Changes in gut microbiota may lead to a variety of effects, such as reduced production of short-chain fatty acids (SCFAs), reduced production of bile acids, increased intestinal barrier permeability, and bacterial translocation. The treatment aim of HE is to decrease intestinal ammonia production and intestinal absorption of ammonia. Prebiotics, probiotics, antibiotics, and fecal microbiota transplantation (FMT) can be used to manipulate the gut microbiome to improve hyperammonemia and endotoxemia. Especially the application of FMT, it has become a new treated approach to target microbial composition and function. Therefore, restoring intestinal microbial homeostasis can improve the cognitive impairment of HE, which is a potential treatment method.

Keywords: Fecal microbiota transplantation; Gut microbiota; Gut-brain-liver axis; Hyperammonemia.

Figure 1. Ammonia and vagus nerve affect the body through the gut–liver–brain axis

Ammonia and other products from the gut are delivered to the liver by the portal vein. When the liver is in a damaged state or portal-systemic shunting based on cirrhosis, unmetabolized ammonia and other toxic products can enter the brain through the blood–brain barrier (BBB). Under the synergy of inflammation of the brain, ammonia can cause neurocognitive impairment by making astrocyte swelling, brain cells lack of energy, and other mechanisms. These products also become afferent signals that transmit the signals to the nucleus tractus solitarius via the left nodose ganglion (NG). Vagal efferent fibers regulate peripheral regulatory T (pTreg) cells by acting on antigen-presenting cells (APC).

Figure 2. FMT and other methods treat HE

FMT is the processing of feces from healthy donors into capsules that are transferred to patients by oral or endoscopic means. Select a single donor who is rich in beneficial flora for treatment. Beneficial bacteria that enter the gut can improve the recipient’s intestinal environment in a variety of ways. In addition, there are probiotics, prebiotics, antibiotics, and other programs. These methods can reduce bacterial urease activity and pH, improve the intestinal barrier, increase SCFAs production, enhance host immunity, and reduce ammonia production.