Author Identifier
Tharani Nandula Senavirathna: https://orcid.org/0000-0002-0973-3644
Date of Award
2025
Document Type
Thesis
Publisher
Edith Cowan University
Degree Name
Doctor of Philosophy
School
School of Medical and Health Sciences
First Supervisor
Lois Balmer
Second Supervisor
Ricky Lareu
Third Supervisor
Armaghan Shafaei Darestani
Abstract
Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis, hepatocellular ballooning, inflammation, and fibrosis and can progress to cirrhosis, liver failure or hepatocellular carcinoma. With the global rise in obesity and metabolic syndrome, NASH has become one of the leading causes of chronic liver disease worldwide. Yet, there remains a lack of safe, accessible and effective treatment options, highlighting the urgent need for alternative therapeutic approaches. Given the multifactorial nature of NASH, nutraceuticals; bioactive compounds derived from food are gaining attention for their potential to modulate metabolic, inflammatory and gut microbiota-related pathways. One such compound, ellagic acid (EA), a polyphenol abundant in fruits and nuts, has demonstrated antioxidant, anti-inflammatory and microbiota-modulating properties, making it a promising candidate for NASH intervention.
This thesis investigates the therapeutic efficacy of EA and its augmentation with inulin, a well-known prebiotic recognised for its ability to modulate gut microbiota. A preclinical mouse model was used to evaluate the impact of EA with and without inulin on key physiological, histological, biochemical, and metabolic outcomes in NASH.
NASH was successfully induced in C57BL/6J male mice using a Western-style diet over a 16-week period, followed by a 12-week intervention with EA, inulin, or their combination. EA treatment improved liver-to-body weight ratios reduced hepatic steatosis, inflammation and hepatocyte ballooning and enhanced biochemical markers of liver health. In contrast, inulin alone unexpectedly worsened several metabolic and liver function parameters. However, the combination of EA and inulin significantly improved both histological and metabolic outcomes, indicating a protective interaction during NASH progression. In EA-treated groups, metabolite profiling revealed elevated urinary levels of 3'-methylellagic acid, a primary EA metabolite. Notably, the combination treatment significantly increased the production of gut-derived postbiotic metabolites, urolithins A, C and D suggesting a synergistic effect enhancing EA metabolism and microbial transformation. Plasma bile acid profiling revealed that EA alleviated bile acid dysregulation in NASH by reducing harmful species such as cholic acid and tauro-ω-muricholic acid (T-ωMCA). In contrast, inulin alone worsened bile acid imbalance by further increasing taurochenodeoxycholic acid and T-ωMCA levels. However, when combined with EA, inulin exerted synergistic effects, particularly by reducing taurocholic acid, suggesting coordinated modulation of hepatic and gut derived pathways.
Together, these findings highlight the therapeutic promise of EA and its interaction with dietary prebiotics like inulin in modulating NASH progression. This work contributes to the growing field of personalised, microbiota-informed nutraceutical strategies for chronic liver disease management.
Access Note
Access to this thesis is embargoed until 18th December 2028
DOI
10.25958/vmpg-sc37
Recommended Citation
Senavirathna, T. N. (2025). Efficacy of ellagic acid and its microbial metabolites in a diet-induced mouse model of non-alcoholic steatohepatitis (NASH). Edith Cowan University. https://doi.org/10.25958/vmpg-sc37