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 proinflammatory 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.

Bile acids and sphingolipids in non-alcoholic fatty liver disease

“…Sevelamer is a non-absorbable polymer that not only binds bile acids in the intestine to form non-absorbable complexes and reduces bile acid uptake by intestinal epithelial cells but also modulates the gut microbiome and bile acid metabolism [60] . The role of bile acids and gut microbiome in NAFLD has also been reviewed recently [22] …”

“…In the past 2 decades, numerous studies have shown that bile acid-mediated activation of the nuclear receptor, farnesoid X receptor (FXR), and G protein-coupled receptors (GPCRs), Takeda G-protein- coupled receptor 5 (TGR5) and sphingosine-1 phosphate receptor 2 (S1PR2), play important roles in the progression of NAFLD and other metabolic diseases via modulating hepatic lipid metabolism, immune responses, and the gut microbiome. [22,23,33] Sphingolipid metabolism and signaling pathways Sphingolipids are essential structural components of all eukaryotic membranes. The synthetic pathways of sphingolipids have been well characterized.…”

“…In the past decade, numerous studies have shown that sphingolipid metabolism dysregulation is closely associated with multiple metabolic disorders, including NAFLD [17–20] . Furthermore, the role of bile acid-mediated signaling pathways in NAFLD has recently been extensively discussed [22,23] . In this review, we will highlight the recent advances in the sphingolipid field and discuss connections between bile acids and sphingolipid signaling with a focus on NAFLD.…”

“…[17][18][19][20] Furthermore, the role of bile acid-mediated signaling pathways in NAFLD has recently been extensively discussed. [22,23] In this review, we will highlight the recent advances in the sphingolipid field and discuss connections between bile acids and sphingolipid signaling with a focus on NAFLD.…”

Ring Trial on Quantitative Assessment of Bile Acids Reveals a Method- and Analyte-Specific Accuracy and Reproducibility

“…Changes in the systemic bile acid profile and quantities are linked to many different health outcomes like the early microbiome development [ 13 ], NAFLD [ 14 ], liver cancer [ 15 ], and the change of the intestinal topology after bariatric surgery [ 16 ].…”