The impact of antibiotic-induced gut dysbiosis on cholestatic liver disease: The role of age and the effect of bacterial reconstitution

Hales, Jack Cameron (2024) The impact of antibiotic-induced gut dysbiosis on cholestatic liver disease: The role of age and the effect of bacterial reconstitution. Doctoral thesis, University of East Anglia.

Preview

PDF Download (11MB) | Preview

Abstract

The gut and liver have a well-defined, reciprocal metabolic and signalling relationship, the gut-liver axis, which is dependent upon functional cooperation. Dysfunction in either the gut or liver can result in concurrent issues in both organs. Antibiotics can constitute a significant disruption to the gut microbiota and whilst the immediate effects of antibiotics upon the gut-liver axis are under increasing scrutiny, lingering changes to microbial population and metabolomics remain poorly defined. The effects on the gut-liver axis are also mostly unidentified.

Our study investigates long-term, antibiotic induced, perturbation to the gut-liver axis and how this may subsequently affect liver metabolism, immunity and cholestatic disease progression. To do this, we use a longitudinal murine model of antibiotic depletion, microbial recovery and surgically induced cholestatic injury. Liver, intestinal, faecal and serum samples were collected, and various analyses were conducted. Liver tissue was analysed by flow cytometry, qPCR, histochemistry and immunohistochemistry. Serum was assessed for liver damage markers by biochemical analysis, the intestinal microbiota by shotgun metagenomics and liver and intestinal metabolite content by LC-MS. Additionally, macrophages were differentiated from bone marrow haematopoietic stem cells to investigate their behaviour.

Our results suggest that, following antibiotic depletion, the recovered gut bacteriome has a modified population composition which produces an altered faecal pool of both bile acids and short chain fatty acids. These changes appear to prime the liver and general innate immune response of young mice for pro-fibrotic responses to cholestatic injury. These effects were seen to be alleviated by reconstitution of the antibiotic depleted bacterial species Bacteroides thetaiotaomicron. Aged mice show no antibiotic induced changes to cholestatic disease severity.

These results have significant implications, not only for the administration of antibiotics in cases of chronic disease, but also, in highlighting the role of dysbiosis and disrupted microbial metabolism in cholestatic disease more generally.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User:	Jennifer Whitaker
Date Deposited:	25 Apr 2025 14:57
Last Modified:	25 Apr 2025 15:07
URI:	https://ueaeprints.uea.ac.uk/id/eprint/99093
DOI:

Downloads

Actions (login required)

View Item