A metabonomics study of the modulation of lipid and bile acid metabolism by the gut microbiota and consequences on obesity and fatty liver disease
File(s)
Author(s)
Sarafian, Magali
Type
Thesis
Abstract
Obesity and fatty liver disease are characterised by an imbalance between energy intake and energy expenditure. Genetic and environmental factors strongly contribute to impaired energy homoeostasis and can trigger metabolic disorders such as hypertension, hyperglycaemia and hypercholesterolemia which are associated with type 2 diabetes, cardiovascular diseases and metabolic syndrome. The mechanisms underpinning obesity and its co-morbidity are poorly understood but dysregulation of lipid metabolism is likely to contribute and can be studied by metabolic profiling using UPLC-MS. Moreover, the host-gut axis has a strong influence on obesity and fatty liver disease development by modulation of metabolic pathways. The analytical quality of the metabolic profiling methods is critical to understand the aetiopathogenesis of obesity.
Hence the aim of this PhD project is to investigate lipid metabolism in obesity and fatty liver disease. I developed and optimised a strategy for characterising the global lipid profile of plasma based on isopropanol precipitation and supplemented this with the development of a targeted assay for obtaining in depth profile of bile acids (BAs) (n=145) since BAs are known to play a specific role in obesity and fatty liver disease. Furthermore, BAs can provide insight into the role of the gut microbiota in obesity as they are metabolised by the gut microbiota.
The analytical pipeline for lipid and BA analysis are subsequently applied for two human clinical studies. i) The metabolic signatures associated with subcutaneous and visceral obesity were investigated. A significant increase of LPC (16:0), unconjugated BAs and sulphated BAs with a decrease of PC (16:0/20:3), taurine conjugates was observed in visceral obesity compared to subcutaneous obesity. ii) Subtle disease progression in fatty liver disease, NAFLD and NASH was evaluated. A significant increase of triacylglycerols, hyocholic acid and tauro-conjugated BAs with a decrease of phosphocholines were observed in NASH compared to NAFLD.
This phD project illustrated that metabonomic instrumentations (UPLC-MS and UPLC-MS/MS) are non-invasive and powerful analytical techniques to diagnose obesity and fatty liver disease. In addition, metabonomic analysis of urine and blood samples may offer the possibility to optimise individual diagnosis and management of patients with obesity and fatty liver disease.
Hence the aim of this PhD project is to investigate lipid metabolism in obesity and fatty liver disease. I developed and optimised a strategy for characterising the global lipid profile of plasma based on isopropanol precipitation and supplemented this with the development of a targeted assay for obtaining in depth profile of bile acids (BAs) (n=145) since BAs are known to play a specific role in obesity and fatty liver disease. Furthermore, BAs can provide insight into the role of the gut microbiota in obesity as they are metabolised by the gut microbiota.
The analytical pipeline for lipid and BA analysis are subsequently applied for two human clinical studies. i) The metabolic signatures associated with subcutaneous and visceral obesity were investigated. A significant increase of LPC (16:0), unconjugated BAs and sulphated BAs with a decrease of PC (16:0/20:3), taurine conjugates was observed in visceral obesity compared to subcutaneous obesity. ii) Subtle disease progression in fatty liver disease, NAFLD and NASH was evaluated. A significant increase of triacylglycerols, hyocholic acid and tauro-conjugated BAs with a decrease of phosphocholines were observed in NASH compared to NAFLD.
This phD project illustrated that metabonomic instrumentations (UPLC-MS and UPLC-MS/MS) are non-invasive and powerful analytical techniques to diagnose obesity and fatty liver disease. In addition, metabonomic analysis of urine and blood samples may offer the possibility to optimise individual diagnosis and management of patients with obesity and fatty liver disease.
Version
Open Access
Date Issued
2016-01
Date Awarded
2016-09
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Dr Dumas, Marc Emmanuel
Sponsor
Nestle PTC
Grant Number
RDLS015375
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)