This project investigates the impact of food composition on the balance of gut bacterial populations and the metabolism of atherogenic metabolite TMAO as well as their roles in the pathogenesis of cardiovascular disease. Research outcomes from this project will provide novel insight into the pathophysiological conditions of myocarditis and atherosclerosis. It will further provide evidence to develop therapeutic strategy for cardiovascular disease by manipulating food consumption and gut microbiome populations.
Rationale: Emerging evidence suggests that food composition modulates the population of gut microbiome and dysbiosis of gut bacteria and plays an important role in the onset of cardiovascular disease. In humans, increased circulating gut bacterial metabolite Trimethylamine N-oxide (TMAO) is closely associated with high risk of cardiovascular disease. Trimethylamine (TMA), a precursor of TMAO, is exclusively produced by gut microbiome using dietary components, i.e. choline and carnitine in meat and dairy products, as substrates. The gut-derived TMA is then transferred to the liver where it is oxidized to TMAO by the flavin-containing monooxygenases. Recent study from Dr Su's group demonstrated that A. muciniphila regulates plasma metabolomic profile by inhibiting TMA and TMAO production which may suggest the cardio-protective benefit of A. muciniphila. In contrast, another gut bacteria strain, Prevotella, was reported to be involved in inflammatory response that can lead to the activation of T-helper-cell-17 immune response and contribute to the onset of a lethal inflammatory heart disease. However, whether alteration of food composition (e.g. high-fat diet and high choline diet) can change the population of A. muciniphila and Prevotella in the gut and how this contributes to the development of cardiovascular disease has not been studied yet.
Therefore, the overarching goal of this project is to investigate the impact of high-fat/high-choline diets on the communication between A. muciniphila and Prevotella and the association with the onset of myocarditis. Changes of the atherogenic metabolites TMA and TMAO in the development of atherosclerosis will further be investigated. Hypothesis and Aims: We hypothesize that high-fat/high choline diets can induce Prevotella-associated cardiovascular inflammation. Increased colonization of A. muciniphila in the gut will mitigate cardiovascular inflammation and atherosclerosis by inhibiting immune response, TMA and TMAO metabolism. The proposed work pursues two specific aims. Aim 1: Define the anti-inflammatory role of A. muciniphila against high-fat/high-choline diet induced myocarditis and atherosclerosis in a low-density-lipoprotein (LDL)-receptor-knockout (LDLR-KO) mouse model by suppressing the population of Prevotella and inhibiting activation of Toll-like receptor inflammatory signaling in the heart and arterial cells. Aim 2: Determine the mechanistic links among Prevotella, metabolites TMA/TMAO and key genes in cardiomyocytes and vascular endothelial cells in the development of cardiovascular disease. Significance: Successful delivery of this project will provide novel insight into the pathogenesis of myocarditis and atherosclerosis. It will further provide evidence to develop therapeutic strategy for cardiovascular disease via manipulation of food composition and gut bacterial populations.
Start Date: 1 October 2022
Duration: 3 years
How to apply: Applications must be submitted via: https://dap.qub.ac.uk/portal/user/u_login.php
Skills/experience required: Experience on small laboratory animals (e.g. mouse and rat) and/or general molecular biological techniques (e.g. Immunoblotting analysis and Q-PCR) would be an asset for this position.
Note: This project is in competition for DfE funding with a number of other projects. A selection process will determine the strongest candidates across the range of projects, who may then be offered funding for their chosen project.
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