Understanding the role of the gut microbiome in the pathogenesis and prevention of dementia

Evidence is increasing that the gut microbiome plays a key role in dementia through circulating immune and metabolic signals. These signals may impact brain structure and function at neuroimaging and may be relevant for various diseases underlying dementia including Alzheimer (AD) and Parkinson disease (PD), Fronto-temporal Dementia (FTD) and vascular cognitive impairment (VCI). The mechanism through which the gut microbiome modulates the risk of dementia is an area of research that has remained virtually unexplored in human studies. There is a large body of literature showing the microbiome is involved in endocrine (obesity and diabetes) and vascular pathology (stroke and cardiovascular disease). An important question to answer is how the gut microbiome leads to neurodegeneration as seen in AD and PD. Gut bacteria may alter the function of the brain directly through the nervus vagus. However, there is increasing interest in the changes in immune and metabolic signals in the circulation that are induced by the microbiome. At present we do not know which metabolic and immune signals of the microbiome are relevant to the pathogenesis of dementia. Knowledge is also lacking on whether and how the genome interacts with the microbiome in the pathogenesis of dementia. The gut microbiome composition and diversity is determined by exposures over the life course such as life style (e.g., diet and physical activity) and medication including antibiotics (exposome). This makes it an attractive target for preventive interventions. Understanding the molecular pathways linking the gut to brain pathology is an important step towards preventive and therapeutic interventions targeting the gut microbiome. The general objective of this project is to understand how the interplay between the gut microbiome, human genome and exposome impacts the risk of dementia and common underlying diseases combining beyond state of the art genomics, metabolomics and organ-on-chip technology with epidemiological, clinical, radiologic and pathological research. The specific aims of the study are to examine: 1.Immune and metabolic signals of the gut microbiome in plasma in the general population and dementia patients; 2. The impact of these signals on vascular pathology, brain structure, cognitive function and dementia risk; 3. Interaction of the human host genome and exposome with gut microbiome signaling in the circulation; 4. Which immune and metabolic signals cross the neurovascular unit into the brain; 5. Impact of epidemiological and therapeutics interventions on dementia prevention. The study will be based in the Rotterdam Study of the ErasmusMC, which allows us to address a wide range of outcomes ranging from early pathology (cognitive function and changes at Magnetic Resonance Imaging (MRI)) to late stages of dementia. Recent developments in Next Generation Sequencing Technology enable in-depth studies of our microbiome in large epidemiological cohorts and we have sequenced the gut microbiome for 1450 non-demented subjects. The study will also use 1500 samples from population cohort Lifelines-DEEP (LLD), for which extensive phenotyping, metagenomics sequencing, and multi-omics analysis have been performed. Information on diet, medication, diseases and environmental factors in both Rotterdam and LLD cohort would allow creation of the nationwide reference panel, and identification of the genetic and environmental factors that influence microbiome in healthy individuals. For LLD, the longitudinal sampling and measurements of phenotypes after 5 years of stool sample collection will be available. In combination with metabolomics studies this allows us to determine the predictive value of microbiome related metabolomics changes in relation to dementia in the Rotterdam Study and patients series of the Memory Clinics of the ErasmusMC and VUMC. To measure immune and metabolic signals, we will use the high-throughput metabolomics facilities and miniaturized technology of the Leiden Academic Centre for Drug Research (LACDR), Leiden University, and the Netherlands. We will study the interplay between the microbiome, human genome and exposome using the vast experience in big-data analyses in the research team. To enable evidence-based therapeutic preventive interventions, we further will study how the microbiome alters immune and metabolic signaling across the neurovascular unit. This question will be answered within the setting of LACDR and Mimetas, where we can combine the high-throughput miniaturized-metabolomics with organ-on-chip technology that has been developed by MIMETAS as part of two ongoing H2020 projects. The findings in the model will be validated using the blood and brain tissue of the VUMC 100+ study.