The effect of Farnesoid X Receptor agonism on the gut microbiome and mortality during cholestatic liver disease Open Access

Abstract

Chronic liver diseases such as cholestatic liver diseases and non-alcoholic fatty liver disease are prevalent issues in today’s world. The last decade has witnessed an explosion of insights into the role of gut microbiota in cholestatic liver disease; however, much remains unknown. The liver begins the production of bile acids which break down fats in the diet. Cholestatic liver diseases tremendously alter the bile profile of the patient, but little is known about how this would affect the gut microbiota. Using a mouse model of cholestatic liver disease, multidrug resistance gene 2 knockout (Mdr2^-/-) mice, we studied how a high-fat diet (HFD) alters gut microbiota and disease outcomes during cholestatic liver disease progression. Mdr2^-/- mice were used because cholestatic liver disease is known to disrupt bile synthesis and transport in this mouse model. Bile acid synthesis can be activated by the Farnesoid X receptor (FXR) signaling pathway in mice. GW4064 is an agonist of the FXR pathway which influences the production of bile acids in mice. Our aim is to examine how the administration of GW4064 to Mdr2^-/- mice will influence their bile profile and their gut microbiota. Gut commensal bacteria Lactobacillus colonization of the intestine indicates a healthy microbiome. Our data suggest that the addition of the GW4064 agonist had an adverse effect on mouse mortality and Lactobacillus colonization levels within the gut. This could be due to a negative impact of the FXR agonist on commensal bacteria counts which allowed for pathogenic proliferation; however, I am unable to make that claim as there were no visible changes in mRNA expression due to the GW4064 agonist.

Table of Contents

1.    INTRODUCTION & AIMS

1.    Primary Sclerosing Cholangitis

2.    Gut Dysbiosis

3.    Bile Acid Synthesis

Figure 1: Bile Acid Synthesis Pathways

4.    Farnesoid X Receptor Regulation

Figure 2: Farnesoid X Receptor Signaling

5.    Our Aims and Objectives

2.    METHODS

Table 1: Experiment Layout

1.    Animal Experiments

2.    Standard Bacteriological Culture of Liver, Ileum, and Feces

3.    Quantitative Polymerase Chain Reaction

4.    Statistical Analysis

3.    RESULTS

1.    Mouse Mortality

Figure 3: Mortality of MDR2^-/- Mice

2.    Bacterial Colony Counts

Figure 4: Lactobacillus

Figure 5: Enteroccoccus

Figure 6: Unidentified Bacteria

3.    mRNA Expression

Figure 7: FGF15 mRNA Expression

Figure 8: FXR and CYP7A1 mRNA Expression

4.    DISCUSSION & FUTURE DIRECTIONS

5.    REFERENCES

6.    SUPPLEMENTAL TABLE

About this Honors Thesis

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School	Emory College
Department	Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Microbiology Health Sciences, Nutrition
Keyword	Gut Microbiome
Committee Chair / Thesis Advisor	Arash Grakoui, Emory University
Committee Members	David Weiss, Emory University Jacobus de Roode, Emory University

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