Role of bile acids in alcoholic liver disease mediated by gut microbiota

Post by Master, Doctor Mai Vien Phuong - Gastrointestinal Endoscopy - Department of Medical Examination & Internal Medicine - Vinmec Central Park International General Hospital.

Alcoholic liver disease is initially characterized by fatty liver, which can then develop into alcoholic hepatitis, cirrhosis and cirrhosis. Alcohol can cause damage to many target organs, especially the brain, intestines, and liver. It should be noted that drinking alcohol can alter the structure of the gut microbiota before liver disease occurs.

As an essential mediator of the gut-liver junction, bile acids regulate host-specific metabolic pathways, modulating inflammatory responses through farnesoid-activated receptors and binding bile acid receptors with G protein 1. Several clinical trials have demonstrated the signaling effect of bile acids in the setting of liver disease. The authors hypothesize the existence of the gut microbiota-bile acids-hepatic triangle and explore potential therapeutic strategies for liver diseases targeting this triangle. Bile acids are involved in immune and inflammatory responses in the liver via receptor 1 on the G cell membrane, the G protein-coupled bile acid receptor and the intracellular farnesoid-X receptor. The interaction between the gut microbiota and bile acids can control host immune homeostasis as well as inhibit liver inflammation.

Many studies in recent decades have shown that the function of bile acids goes beyond that of "digestive surfactants". At the host level, there is a clear relationship between bile acid signaling and innate immunity in the liver and gut. In other words, bile acids are the cornerstone of the immune axis between the liver and the gut microbiota. As a mediator in the gut-hepatic axis, bile acids can modulate inflammatory responses, host metabolism, and innate immunity, which are effective therapeutic targets in the context of various liver diseases. This is shown in the following table:

Abbreviation: PWD: Natural T cell; BA: Bile acids; LCA: lithocholic acid; TGR5: G-protein associated with bile acid receptor 1; Treg: Adjust T; PKA: Protein kinase A; RORγ: RAR-associated monoreading receptor gamma;
However, most contemporary studies on bile acids are based on transgenic mouse models, while the immune system, bile acid metabolism and gut microbiota of mice are very different from those of humans.

Alcoholic liver disease is initially characterized by fatty liver, which can then develop into alcoholic hepatitis, cirrhosis, and cirrhosis. Alcohol can cause damage to many target organs, especially the brain, intestines, and liver. It should be noted that drinking alcohol can alter the structure of the gut microbiota before liver disease occurs. Continued alcohol intake in patients with alcoholic cirrhosis may exacerbate intestinal microbiota disturbances, reduce the detection of intestinal bacteria in stool, and worsen the function of the duodenal and duodenal mucosa. Colon .
Chronic alcohol exposure is associated with gut microbiota disturbances in preclinical and human intestinal models as well as the pathogenesis of ALD. Previous studies have shown that the gut microbiota is altered in patients with alcoholic cirrhosis, characterized by an increase in endotoxin-producing bacteria and a decrease in gut bacteria. Changes in the composition of the gut microbiome can alter brain function, and alcohol abuse can also affect the gut-brain axis. This can aggravate alcoholism and cause emotional disturbances that, ultimately, accelerate the development of hepatic encephalopathy.
Compared with non-disease and non-drinkers, patients with alcoholic cirrhosis had higher endotoxin levels and worse gut microbiota disturbances even after alcohol cessation. This indicates that alcohol-induced damage to the gut microbiota continues even after stopping drinking, and that damage also extends to the gut-brain axis, leading to cognitive impairment.

4. The role of factor FXR in inhibiting inflammation and protecting the intestinal mucosal barrier FXR upregulates factor CYP7A1 which is a rate-limiting enzyme of bile acid synthesis via FGF15. In rats given long-term alcohol intake, ethanol has been shown to neutralize the negative regulation of bile acids by conjugated CDCA via the FXR pathway and increase the expression of CYP7A1 protein in cells. liver cells. This eventually leads to an increase in serum and liver bile acid concentrations.
FXR can induce the expression of antimicrobial molecules in intestinal epithelial cells to prevent alcohol-induced damage to intestinal tight junctions and avoid loss of intestinal barrier integrity. Gastric administration of FXR agonist fexaramine caused a decrease in serum alanine aminotransferase, hepatic IL-1B, and tumor necrosis factor protein levels. This is because FXR can increase small heterodimer partner proteins to inhibit intestinal inflammation and protect the integrity of the intestinal mucosal barrier. The above findings indicate that FXR agonists can negatively regulate bile acid synthesis and reduce serum bile acid concentrations, which may reduce alcoholic steatosis and hepatitis. Antibiotic use in chronic alcoholics has been found to reduce alcoholic liver disease. This is because antibiotics can kill gut bacteria, reduce bile acid levels, and inhibit the hydrolysis of bile acids. However, it can only reduce the toxicity of deoxycholic acid to hepatocytes and stabilize intestinal barrier function.
In summary, alcohol-related changes in the gut microbiota may ultimately alter bile acid composition. Interventions targeting the bile acid-FXR-FGF15 signaling pathway to regulate CYP7A1 synthesis and lipid metabolism can reduce the occurrence of ALD in mice. As a signaling molecule, bile acids can modulate the complex interactions between alcoholic liver disease that the gut microbiota mediates through the gut-liver-brain axis. Therefore, FGF19 and fexaramine are good approaches for the treatment of ALD.

References:
Shao JW, Ge TT, Chen SZ, Wang G, Yang Q, Huang CH, Xu LC, Chen Z. Role of bile acids in liver diseases mediated by the gut microbiome. World J Gastroenterol 2021; 27(22): 3010-3021 [DOI: 10.3748/wjg.v27.i22.3010]