Sex-specific Effects of High-fat Diet on Intestinal Microbiota in Cholestatic Liver Disease Open Access
Koduri, Nitya (Spring 2024)
Abstract
The interaction between the gut microbiome and the immune cells has not been fully understood. Moreover, it is not known whether the alteration of gut microbiota is sex-specific. Through investigating the differences in the gut microbiome of males and females, this project aims to identify specific biomarkers that directly influence immune cells and provide background for future therapeutic interventions against cholestatic liver disease. Recent studies suggest a correlation between gut dysbiosis and neurologic diseases. This study also aims to understand the potential sex-specific impact of gut bacteria and its translocation to the brain. In this study, a mouse model of cholestatic liver disease (i.e., multidrug resistance gene 2 knockout (Mdr2-/-) and WT (FVB/N) control mice were used. 12-weeks-old male and female mice were treated with a high-fat diet (HFD) containing 0.5% sodium cholate to investigate how the addition of cholic acid would modulate disease pathogenesis. Moreover, the study also included anti-inflammatory therapy such as anti-interleukin-6 treatment on disease progression. Interestingly, both male and female Mdr2-/- mice succumbed to HFD diet within 2-3 weeks of HFD feeding, but females had significantly prolonged survival. The anti-inflammatory treatment, anti-IL6 prolonged the survival of male mice in comparison to the HFD-only group. We reveal increased enrichment of the gut bacteria, Enterococcus faecalis, in males in comparison to females when fed HFD.. Interestingly, Staphylococcus sp. was present in both the ileum and brain of the mice exposed to HFD, suggesting translocation of the bacteria in the gut to the brain. Based on the results of this project, we propose that estrogen is involved in the cholestasis-driven inflammatory pathway thus explaining the differences observed between males and females. Future studies aim to evaluate if inflammation or IL-6 plays a role in gut permeability and further gut dysbiosis. The next steps for this study would involve experimentally testing this mechanism by ablating estrogen in females or injecting estrogen in males to observe differences in the disease progression, cholestasis, and gut microbiome composition. We also aim to evaluate the mechanism behind the translocation of gut bacteria in the brain.
Table of Contents
Introduction and Aims.........................................................................................................1 Cholestatic Liver Disease........................................................................................1 Gut Dysbiosis and Inflammatory Markers................................................................2 Neurologic Impact....................................................................................................3 Aims and Objectives................................................................................................3 Methods..............................................................................................................................4 Mouse Strains..........................................................................................................4 Organ Culture..........................................................................................................5 Intestinal Permeability Assay...................................................................................6 Results...............................................................................................................................6 Mouse mortality.......................................................................................................6 Figure 3........................................................................................................7 Figure 4........................................................................................................8 Gut Microbiome Difference.....................................................................................8 Figure 5........................................................................................................9 Figure 6.......................................................................................................10 Figure 7.......................................................................................................11 Figure 8.......................................................................................................12 Figure 9.......................................................................................................13 Gut Permeability.....................................................................................................14 Figure 10......................................................................................................14 Translocation of Gut Bacteria to Brain....................................................................15 Figure 11......................................................................................................15 Discussion and Future Directions......................................................................................16 Figure 12.................................................................................................................18 References.........................................................................................................................20
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Sex-specific Effects of High-fat Diet on Intestinal Microbiota in Cholestatic Liver Disease () | 2024-04-11 11:11:43 -0400 |
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