Investigating gut-microbiota mediated polymerisation of deoxycholic acid in humans
File(s)
Author(s)
Bello, Adesola
Type
Thesis
Abstract
Cardiovascular diseases (CVD) continue to be the leading cause of death worldwide. Hypercholesterolemia (HC) is a modifiable risk factor in the development of CVD. Diet-based therapies, such as dietary fibres (DF) are first-line treatment options to be used solely or in conjunction with pharmacological options for cholesterol management. DF have been shown to reduce HC, but underlying mechanisms are unknown. Existing literature suggest that the hypocholesterolemic effect may be as a result of an interplay of diet, host metabolism, and gut microbiota (GM) which leads to the increased faecal excretion of bile acids (BA). Faecal BA excretion (FBAE) leads to a reduction of circulating cholesterol via a cascade of reactions, therefore increasing FBAE may be a cardioprotective mechanism.
A novel mechanism was thus hypothesised. DF may modulate GM to promote the polymerisation of secondary BA deoxycholic acid (DCA) to polydeoxycholic acid (PDC). PDC cannot be reabsorbed; it is subsequently excreted, triggering compensatory reactions that lead to reduced plasma cholesterol and its associated CVD risk.
This PhD project explored the mechanisms involved in and the effects of diet on PDC production in humans using a combination of cutting edge metabolomic and metagenomic tools.
An ultra-performance liquid chromatography-based method was developed for high throughput and sensitive detection and quantification of PDC. PDC was reliably detected in human faeces (up to 90% of total faecal DCA) and was found to correlate with anti-inflammatory butyrate producing GM and established beneficial GM like Bifidobacteria, and also with a high fibre high protein diet. More investigations are warranted to further elucidate the role of PDC in host physiology. Current indications suggest a beneficial role for PDC.
Abbreviations: CVD cardiovascular diseases; HC Hypercholesterolemia; DF dietary fibres; BA bile acids; GM gut microbiota, FBAE faecal bile acid excretion, DCA deoxycholic acid; PDC polydeoxycholic acid.
A novel mechanism was thus hypothesised. DF may modulate GM to promote the polymerisation of secondary BA deoxycholic acid (DCA) to polydeoxycholic acid (PDC). PDC cannot be reabsorbed; it is subsequently excreted, triggering compensatory reactions that lead to reduced plasma cholesterol and its associated CVD risk.
This PhD project explored the mechanisms involved in and the effects of diet on PDC production in humans using a combination of cutting edge metabolomic and metagenomic tools.
An ultra-performance liquid chromatography-based method was developed for high throughput and sensitive detection and quantification of PDC. PDC was reliably detected in human faeces (up to 90% of total faecal DCA) and was found to correlate with anti-inflammatory butyrate producing GM and established beneficial GM like Bifidobacteria, and also with a high fibre high protein diet. More investigations are warranted to further elucidate the role of PDC in host physiology. Current indications suggest a beneficial role for PDC.
Abbreviations: CVD cardiovascular diseases; HC Hypercholesterolemia; DF dietary fibres; BA bile acids; GM gut microbiota, FBAE faecal bile acid excretion, DCA deoxycholic acid; PDC polydeoxycholic acid.
Version
Open Access
Date Issued
2020-07-10
Date Awarded
2020-08
Citation
2020
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Frost, Gary
Swann, Jonathan
Publisher Department
Department of Metabolism, Digestion and Reproduction
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)