Role of the Gut⁻Liver Axis in Driving Parenteral Nutrition-Associated Injury

Abstract

For decades, parenteral nutrition (PN) has been a successful method for intravenous delivery of nutrition and remains an essential therapy for individuals with intolerance of enteral feedings or impaired gut function. Although the benefits of PN are evident, its use does not come without a significant risk of complications. For instance, parenteral nutrition-associated liver disease (PNALD)-a well-described cholestatic liver injury-and atrophic changes in the gut have both been described in patients receiving PN. Although several mechanisms for these changes have been postulated, data have revealed that the introduction of enteral nutrition may mitigate this injury. This observation has led to the hypothesis that gut-derived signals, originating in response to the presence of luminal contents, may contribute to a decrease in damage to the liver and gut. This review seeks to present the current knowledge regarding the modulation of what is known as the "gut⁻liver axis" and the gut-derived signals which play a role in PN-associated injury.

Keywords: chenodeoxycholic acid; cholesterol 7 alpha-hydroxylase 1; farnesoid x receptor; fibroblast growth factor 19; glucagon like peptide; parenteral nutrition; total parenteral nutrition.

Figure 1

Gut–Liver Axis. 1. Bile acids are secreted into the small intestine and travel through the gut. 2. FXR, with its highest concentration in the terminal ileum, is activated by bile acids. This results in FGF19 secretion into portal circulation. 3. FGF19 binds with its receptor, FGFR4 in hepatocytes. 4. FGF19 regulates CYP7A1, the rate-limiting step of bile acid synthesis, resulting in a decrease in bile acid synthesis, thus, hepatic bile acids are modulated by gut signaling. 5. TGR5 is activated by bile acids, leading to an increase in GLP-2, which promotes gut growth. CYP7A1: Cholesterol 7 alpha-hydroxylase; GLP-2: Glucagon-like peptide 2; FGF19: Fibroblast growth factor 19; FGFR4: Fibroblast growth factor receptor 4; FXR: Farnesoid X receptor; TGR5: Takeda G-protein-coupled receptor 5.