**Background:** Hepatic encephalopathy (HE) is a severe neuropsychiatric complication of acute and chronic liver disease, associated with over 20% of mortality in acute liver failure. It ranges from minimal HE (MHE) to overt HE (OHE) and coma, with about 70% of cirrhosis patients developing symptoms. The condition arises from portosystemic shunting, allowing intestinal-derived toxins to reach the brain. Key contributors include ammonia and bile acids (BAs), which are modulated by gut microbiota. Current treatments focus on reducing ammonia via lactulose, rifaximin, and probiotics, but BA dysregulation is increasingly recognized as a critical factor.
**Methods:** This narrative review synthesized literature from PubMed and Google Scholar using search terms including BA receptors, BAs, ammonia, farnesoid X receptor (FXR), TGR5, S1PR2, cirrhosis, and hepatic encephalopathy. The review covers human and animal studies, focusing on the roles of ammonia and BAs in HE pathogenesis.
**Key Results:** Ammonia, produced by urease-producing bacteria (e.g., Streptococcaceae, Enterobacteriaceae), crosses the blood-brain barrier (BBB) and is converted to glutamine in astrocytes, causing osmotic stress, mitochondrial dysfunction, and cerebral edema. Chronic hyperammonemia induces neuroinflammation via TNF-α, IL-6, and IL-1β, and microglia activation through CCL2. In cirrhosis patients, microglia activation marker CD14 is elevated. However, germ-free mice with hyperammonemia do not develop neuroinflammation, indicating ammonia alone is insufficient.
BILE ACIDS ARE ELEVATED IN HE
total BA pool increases in fulminant hepatic failure, and specific BAs (e.g., taurocholic acid [TCA] increased ~76-fold in cirrhosis) are found in cerebrospinal fluid of cirrhotic patients with HE. In animal models, injection of chenodeoxycholic acid (CDCA) or deoxycholic acid (DCA) increases BBB permeability, and feeding DCA or cholic acid (CA) worsens neurological decline in azoxymethane (AOM)-induced HE mice. Conversely, reducing BA pool size via cholestyramine or Cyp7A1 knockout attenuates neurological decline.
BA RECEPTORS PLAY DISTINCT ROLES
FXR activation in the brain reduces cholesterol clearance via CYP46A1, leading to cholesterol accumulation and neurological decline. Whole-body FXR knockout mice show impaired cognitive and motor function, but targeted brain FXR knockdown delays neurological decline. TGR5 activation with betulinic acid delays neurological decline and reduces Ccl2 mRNA in AOM mice, while TGR5 mRNA is reduced in cerebral cortex of HE patients. S1PR2, activated by conjugated BAs like TCA, increases CCL2 and microglia activation; its antagonist JTE-013 attenuates neuroinflammation and neurological impairment.
Treatments targeting gut microbiota include probiotics (e.g., VSL#3, Lactobacillus strains) which reduce hospitalization and HE progression in a meta-analysis of 14 randomized trials. Synbiotics (probiotics plus fermentable fiber) reduce blood ammonia and reverse MHE. Lactulose, a standard therapy, reduces ammonia and attenuates motor impairments in hyperammonemia rats. Rifaximin eliminates ammonia-producing bacteria and reduces inflammation. Cholestyramine, which lowers BA pool size, delays neurological decline and attenuates microglia activation in AOM mice.
**Clinical Implications:** HE management should address both ammonia and BA dysregulation. Probiotics, lactulose, and rifaximin are effective in reducing ammonia and improving outcomes, but BA-targeted therapies like cholestyramine show promise in animal models. The gut-liver-brain axis is critical, and dietary modulation (e.g., Western diet exacerbates inflammation) may influence HE risk. Future research should explore BA receptor modulators (e.g., FXR antagonists, TGR5 agonists) and their role in neurological diseases like Alzheimer's, given shared pathways in cholesterol metabolism.