BRC funded PhD
Aim: To understand the potential association between the gut virome and the pathogenesis and/or the progression of heart failure (HF). To evaluate the potential of the phage cell-free DNA blood screening to identify dysbiotic microbiota signatures.
Background: The gut microbiome is known to play a critical role in modulating the immune system, inflammation, metabolism, weight and many other aspects of health [1, 2]. Gut dysbiosis is associated with cardiovascular, gastrointestinal, lung diseases, as well as metabolic diseases [3]. We and others have observed that patients with HF reveal a significant reduction in intestinal microbial diversity compared to healthy individuals [4, 5]. Of note, many of the frequent comorbidities of HF such as hypertension, obesity, diabetes mellitus, and renal dysfunction are linked to gut dysbiosis themselves and further promote disease progression. However, though gut microbiota consists of microorganisms including bacteria, archaea, fungi, and viruses, most association studies between gut microbiota and cardiac diseases focus mainly on bacteria [4-6]. Notwithstanding, the role of viruses, particularly bacteriophages (90% of total gut virome) that play a critical role in shaping the eco-evolutionary adaptation of bacterial populations in specific niches has not yet been studied. Furthermore, recent findings indicate that phage signatures in cell-free DNA (cfDNA) hold a strong noninvasive diagnostic value [7-9]. Thus, characterising the gut and circulatory cfDNA virome could potentially provide novel but early diagnostic and intervention targets in heart failure.
Research Plan: To characterise the gut phageome in HF using samples obtained from patients and experimental animal models. To establish an experimental platform to identify phage genome signatures in the blood cellfree DNA and computationally predict their bacterial prey. Validate results using the stool samples and appropriate screening assays for targeted bacterial species.
Expected outcomes and impact: To understand the interplay between the gut virome and microbial dysbiosis in heart failure and determine the specific roles of key bacteriophages within this dynamic. To develop a phageome cell-free DNA screening platform and infer tissue-specific microbial signatures. This project is expected to have a significant impact in the areas of cardiovascular disease and phage-based diagnostics. HF is a leading cause of hospitalization and deaths in UK and worldwide, and the microbiome/virome component of the disease is limited while its therapeutic potential is underexplored. We will utilize the findings from this project to develop phage-based diagnostic and/or therapeutic tool(s) to ameliorate cardiac disease phenotype and identify biomarkers (EU, NIHR, UKRI).
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