CoEN: Gut microbes, Neuroinflammation and Alzheimer's disease: determining the immunoregulatory role of gut microbiota on brain and behaviour

Alzheimer's disease (AD) is the leading cause of age-related dementia worldwide yet there are no successful treatments available to stop or reverse the progression of AD. Chronic low-grade inflammation (referred to as inflammaging) is central to the reduction in brain plasticity and cognitive failure of AD. However, a major gap in knowledge exists in the mechanisms underlying the inflammation processes in AD, how they relate to cognitive demise, and how to prevent it. Ground-breaking studies have now implicated an altered gut microbiota in the inflammation associated with AD. We propose that the low grade, chronic inflammatory state in AD is precipitated by an altered gut microbiota. In our research programme, we will (1) stratify an inflammatory signature in faecal samples from AD and mild cognitive impairment (MCI) patients, (2) investigate how gut microbiota influence brain and behaviour using fecal microbiota transplantation from AD/MCI patients to animal models of inflammation, (3) assess brain plasticity using neural stem cells in response to patients' serum. Our results will inform how an altered (inflammatory) gut microbiota coupled with an inflammatory serum signature in AD/MCI patients may be used as a biomarker to classify disease stage and prognosis, which may offer future individualised therapeutic intervention.

Chronic low-grade inflammation (inflammaging) is a key feature in Alzheimer's disease (AD). Recent reports suggest that an altered gut microbiota can promote a brain inflammatory response. Partner 3 has shown an association between pro-inflammatory gut microbiota and A pathology in AD patients. However, the mechanisms by which changes in gut microbiota composition mediate the neuroinflammation, neuroplasticity changes and cognitive dysfunctions in AD remain unknown. We propose that the inflammaging in AD is precipitated by an altered gut microbiota. In our research programme, we will (1) stratify an inflammatory signature in faecal samples from AD and mild cognitive impairment (MCI) patients, (2) investigate how gut microbiota influence neuroplasticity, neurogenic processes and cognitive behaviour using fecal microbiota transplantation from AD/MCI patients to a novel animal model of chronic low-grade hippocampal inflammation, (3) identify a gut microbiota/inflammation signature modulating neural stem cell health/hippocampal neurogenic process using a novel in vitro parabiosis assay employing human neural stem cells growing in presence of patients' serum. Our results will inform how a gut microbiota and inflammatory pattern signature in AD/MCI patients may be used as a biomarker to classify disease stage and prognosis, which may offer future individualised therapeutic intervention for AD.

Expected outcomes and deliverables, including their health and socioeconomic impacts:
The expected outcome of our innovative approach will determine whether a gut microbiota signature and an associated inflammatory pattern can be used as predictive, diagnostic or preventative for AD. The project will further provide key readouts in behavioural and neuroplasticity measures as well as identify microglial phenotypes responsive to changes in gut microbiota. The outcome is designed to deliver creative solutions and significant new data for improved understanding of mechanisms of AD pathogenesis and discovery of original therapeutic targets for AD. Specifically, we will establish (1) a specific gut microbiota signature in AD/MCI patients, (2) the connection between gut microbiota, inflammation and neuroplasticity, (3) the impact of AD/MCI gut microbiota on cognitive function, and neuroplasticity through inflammatory mechanisms. Combining a multidiscipline approach, with already established collaboration with industry, the research outcome presents an exciting opportunity to develop transformative disease-modifying therapeutic/diagnostic platforms with innovative targeting of gut microbiota in AD.


The health and socioeconomic benefits of developing novel therapeutic approaches to treat AD are immense, as dementia, affects 48 million people worldwide, and 10.5 million in Europe. A doubling of these figures will occur every 20 years without better preventative strategies and evidence-based treatments. The health and socioeconomic costs associated with this are unsustainable, and current annual societal and economics cost for dementia is approx $818 bn (World Alzheimer Report, 2015). Multi-billion Euro pharmaceutical investments have been directed at specifically reducing Abeta, to treat AD and have been unsuccessful. Thus, new original solutions and novel target discovery as delivered by outcomes of this proposal are urgently needed. The application of our findings has the potential to improve the quality of life of people with AD, their families and carers, with associated improved healthcare, and inherent benefits to the economy. A thorough dissemination and exploitation programme will be established to maximise effective knowledge transfer of our research outcomes to key groups (patient groups, research scientists, healthcare professionals, technologists, industry, policy makers and educators). This will maximise future progress of the project outcomes, including following project completion, integrated with funding applications to national, EU and international agencies, and industrial engagement.