Silke Cresswell
Relevant Thesis-Based Degree Programs
Affiliations to Research Centres, Institutes & Clusters
Graduate Student Supervision
Doctoral Student Supervision
Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world. Gastrointestinal comorbidities, especially constipation and slow colonic transit time, affect most patients and can manifest decades before motor symptom onset, leading to speculation that the gut microbiota may be involved in disease etiology and pathophysiology.Leveraging clinical cohorts and in vitro models, I investigated the microbiota’s role in PD. Bacterial (16S) and fungal (ITS2) amplicon sequencing elucidated the composition of the microbiota in PD patients and controls, and paired serum metabolomics helped infer microbial function. I showed that the PD microbiota had a reduced abundance of several co-abundant short-chain fatty acid producing bacteria, including well-known butyrate producing genera such as Faecalibacterium and Roseburia. The butyrate production capacity of the PD microbiota was inversely associated with colonic transit time as estimated by Bristol Stool Scale score. Conversely, the PD microbiota had a higher abundance of several co-abundant bacteria with diverse metabolic capacities, including the mucin-degrading Akkermansia muciniphila. PD-enriched microbes were strongly associated with increased colonic transit time and serum concentrations of the proteolytic microbial metabolites p-cresol and phenylacetylglutamine. These findings generated mechanistic hypotheses that were carried into in vitro experiments. Regarding PD-relevant microbial metabolites, I showed that butyrate dampened cytokine production and immune cell attachment in a blood brain barrier endothelial cell line, while p-cresol caused inflammation and downregulated genes involved in gut peptide and serotonin biosynthesis in an enteroendocrine cell line. A final clinically-informed mechanistic insight came from the observation that the abundance of the PD-enriched genus Bifidobacterium was correlated with levodopa (L-DOPA) dose in patients. L-DOPA is the primary treatment for PD. It is taken orally, absorbed in the intestines, and must reach the brain intact to exert its clinical effect. Peripheral breakdown of L-DOPA is an ongoing clinical concern, including metabolism by gut microbes. Through in vitro assays, a pathway was discovered whereby certain Bifidobacterium species can metabolize L-DOPA into its equivalent lactic acid using existing tyrosine metabolism genes. In conclusion, in this thesis I demonstrate compositional and functional alterations in the PD microbiota with important downstream consequences on gut function and therapeutic management.
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Master's Student Supervision
Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.
Parkinson’s disease (PD) is a complex neurodegenerative disorder with a multifaceted etiology involving the nervous, gastrointestinal, and immune systems. Although motor dysfunctions are the most notable clinical feature of PD, the disease is also associated with various non-motor symptoms, many of which occur before the onset of motor signs. Prodromal gastrointestinal symptoms, alterations in the gut microbiome, and trans-vagal propagation of α-synuclein aggregates from the gut to the brainstem suggest a possible intestinal origin for PD. Another pathophysiological feature of PD is the inefficient utilization of glucose by neuronal cells, which leads to bioenergetic deficits in the brain. Current PD therapies only provide symptomatic relief without addressing the underlying causes. Therefore, dietary interventions have emerged as a promising therapeutic approach that can target multiple disease mechanisms. For example, the Mediterranean diet (MeDi) and the ketogenic diet (KD) have shown promise in alleviating gastrointestinal and bioenergetic deficits in PD, respectively, while providing symptomatic relief.The KD provides an alternative source of energy to the brain, while the MeDi replenishes the population of short-chain fatty acid (SCFA)-producing bacteria. However, classical KDs may unfavorably alter the gut microbiome and decrease SCFA levels. Therefore, combining the principles of the MeDi and KD may allow us to harness the potential benefits of both dietary interventions while maintaining gut health. This thesis will analyze the literature on PD pathophysiology, particularly with respect to the microbiome-gut-brain axis, as well as the biological mechanisms of dietary interventions to propose a mechanistic framework for the application of Mediterranean-ketogenic diets in PD. Additionally, to investigate the safety and feasibility of Mediterranean-ketogenic diets (MeDi-KD) and MeDi diets supplemented with medium-chain triglycerides (MeDi-MCT) in PD patients, an open-label, randomized, cross-over clinical trial was designed, the protocol for which will also be presented.
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