Enterohepatic bacterial infections dysregulate the FGF15-FGFR4 endocrine axis

Guillaume Romain,Alfredo Menendez,Ellen T Arena,L Caetano M Antunes,Michael T Chow,Sarah Tremblay,Scott Covey,B Brett Finlay

doi:10.1186/1471-2180-13-238

Abstract

BackgroundEnterohepatic bacterial infections have the potential to affect multiple physiological processes of the body. Fibroblast growth factor 15/19 (FGF15 in mice, FGF19 in humans) is a hormone that functions as a central regulator of glucose, lipid and bile acid metabolism. FGF15/19 is produced in the intestine and exert its actions on the liver by signaling through the FGFR4-βKlotho receptor complex. Here, we examined the in vivo effects of enterohepatic bacterial infection over the FGF15 endocrine axis.ResultsInfection triggered significant reductions in the intestinal expression of Fgf15 and its hepatic receptor components (Fgfr4 and Klb (βKlotho)). Infection also resulted in alterations of the expression pattern of genes involved in hepatobiliary function, marked reduction in gallbladder bile volumes and accumulation of hepatic cholesterol and triglycerides. The decrease in ileal Fgf15 expression was associated with liver bacterial colonization and hepatobiliary pathophysiology rather than with direct intestinal bacterial pathogenesis.ConclusionsBacterial pathogens of the enterohepatic system can disturb the homeostasis of the FGF15/19-FGFR4 endocrine axis. These results open up a possible link between FGF15/19-FGFR4 disruptions and the metabolic and nutritional disorders observed in infectious diseases.

Highlights

Enterohepatic bacterial infections have the potential to affect multiple physiological processes of the body
We examined the disruption of the enterohepatic fibroblast growth factor 15/19 (FGF15/19)fibroblast growth factor receptor 4 (FGFR4) endocrine axis during bacterial infections of the enterohepatic system
Enterohepatic infections downregulate the expression of intestinal Fgf15 The terminal ileum is the main site of production of FGF15, it is a major port of entry for Salmonella and an important site for its pathogenesis

Summary

Introduction

Enterohepatic bacterial infections have the potential to affect multiple physiological processes of the body. Fibroblast growth factor 15/19 (FGF15 in mice, FGF19 in humans) is a hormone that functions as a central regulator of glucose, lipid and bile acid metabolism. FGF15/19 has a crucial role in the control of whole body glucose and lipid metabolism and energy expenditure [7,8] It is a key regulator of de novo synthesis of bile acids via the repression of cholesterol 7 alpha hydroxylase (CYP7A1) expression in hepatocytes [9]. FGF15 represses the apical Na+-dependent bile acid transporter (ASBT) expression in hepatic cholangiocytes [10] and facilitates gallbladder filling by promoting gallbladder muscle distension [11]. Signaling to hepatic target cells occurs through the interaction of FGF15/19 with the tyrosine kinase receptor fibroblast growth factor receptor

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