Bile Acids, Gut Microbiome and the Road to Fatty Liver Disease

Abstract

This article describes the complex interactions occurring between diet, the gut microbiome, and bile acids in the etiology of fatty liver disease. Perhaps 25% of the world's population may have nonalcoholic fatty liver disease (NAFLD) and a significant percentage (∼20%) of these individuals will progress to nonalcoholic steatohepatitis (NASH). Currently, the only recommended treatment for NAFLD and NASH is a change in diet and exercise. A Western-type diet containing high fructose corn syrup, fats, and cholesterol creates gut dysbiosis, increases intestinal permeability and uptake of LPS causing low-grade chronic inflammation in the body. Fructose is a "lipogenic" sugar that induces long-chain fatty acid (LCFA) synthesis in the liver. Inflammation decreases the oxidation of LCFA, allowing fat accumulation in hepatocytes. Hepatic bile acid transporters are downregulated by inflammation slowing their enterohepatic circulation and allowing conjugated bile acids (CBA) to increase in the serum and liver of NASH patients. High levels of CBA in the liver are hypothesized to activate sphingosine-1-phosphate receptor 2 (S1PR2), activating pro-inflammatory and fibrosis pathways enhancing NASH progression. Because inflammation appears to be a major physiological driving force in NAFLD/NASH, new drugs and treatment protocols may require the use of anti-inflammatory compounds, such as berberine, in combination with bile acid receptor agonists or antagonists. Emerging new molecular technologies may provide guidance in unraveling the complex physiological pathways driving fatty liver disease and better approaches to prevention and treatment. © 2021 American Physiological Society. Compr Physiol 11:1-12, 2021.

Figure 1. Bile acid transporters in the liver hepatocyte, ileal enterocyte, and proximal convoluted tubule in the kidney.

Bile acids are actively transported from the hepatocytes by the bile salt export protein (BSEP) or multidrug resistance protein 2 (MPR2) into bile duct. After secretion into the intestine, they are efficiently recovered by leal enterocytes using the apical sodium-dependent bile acid transporter (ASBT) and into the portal vein via the heterodimeric organic solute transporter (OSTα/β) on the basolateral membrane. Bile acids may also undergo hepatic-renal cycling, especially during cholestasis. Bile acids secreted by the kidney are usually modified by the sulfation of hydroxyl groups. The multidrug resistance-associated proteins (MRP3 or ABCC3 and MRP4 or ABCC4) and OSTα-OSTβ on the basolateral membrane are involved in ATP-dependent bile acid export from hepatocytes to systemic circulation.

Figure 2. Synthesis of the primary bile acids cholic acid and chenodeoxycholic acid from cholesterol in liver hepatocytes and metabolism by gut bacteria.

The primary bile acids, cholic acid, and chenodeoxycholic acid are synthesized in the hepatocytes from cholesterol and conjugated with taurine or glycine. Taurocholate is biotransformed by gut bacteria expressing bile salt hydrolases (BSH) to cholic acid and taurine. Gut bacteria can oxidize hydroxyl groups at the 3α, 7α, and 12α position on the steroid ring by 3α-hydroxysteroid dehydrogenases (3α-HSDH), 7α-hydroxysteroid dehydrogenases (7α-HSDH), and 12α-hydroxysteroid dehydrogenases (12α-HSDH), respectively. Oxo-bile acids may be further metabolized at the 3β, 7β, or 12β position by 3β-hydroxysteroid dehydrogenase (3β-HSDH), 7β-hydroxysteroid dehydrogenase (7β-HSDH) and 12β-hydroxysteroid dehydrogenase (12β-HSDH), respectively, producing iso and epi bile acids. Primary bile acids can be biotransformed to secondary bile acids by removing the 7α-hydroxyl group via a multistep 7α-dehydroxylation (7α-DeOH) biochemical pathway found in some species of the genus Clostridium.

Figure 3. Activation of the ERK1/2 and AKT signaling pathways by conjugated bile acids (CBA) via S1PR2.

High levels of CBA activate S1PR2 in liver cells, enhancing the upregulation of genes encoding pro-inflammatory and fibrosis mediators. Phosphorylated ERK1/2 is translocated into the nucleus, where it activates sphingosine kinase 2 (SphK2) via phosphorylation. SphK2 produces sphingosine-1-phosphate (S1P) that is a potent inhibitor of histone deacetylase 1 and 2 (HDAC1/2), allowing the epigenetic upregulation of gene transcription.

Figure 4. Alteration of the enterohepatic circulation of bile acids by NASH.

Liver diseases interrupt the enterohepatic circulation of bile acids, enhancing gut dysbiosis. This has the downstream effect of increasing gut permeability and absorption of pro-inflammatory mediators such as LPS. In NASH, there is an increase in the serum CBA that may activate the S1PR2 in hepatic cells, enhancing inflammation and activating pro-fibrotic gene expression in stellate cells.

Figure 5. The possible role of diet, gut dysbiosis and bile acids in the development of steatosis and NASH.

The road to Steatosis and NASH begins by consuming a Western-type diet containing large amounts of HFCS and fats, resulting in constant low-grade systemic inflammation due to gut dysbiosis and absorption of pro-inflammatory bacterial molecules. Under these dietary conditions, there is an upregulation of long-chain fatty acid synthesis in the liver and decreased oxidation and secretion of fats. Inflammation also downregulates bile acid transporters in the liver, slowing their enterohepatic circulation and allowing an increase in CBA in the liver, which activates S1PR2 stimulating hepatic inflammation and fibrosis pathways and promoting the development of cirrhosis and hepatocellular carcinoma (HCC).