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Zooming the link between diet and brain health: how phenolic metabolites modulate brain inflammation

Periodic Reporting for period 1 - LIMBo (Zooming the link between diet and brain health: how phenolic metabolites modulate brain inflammation)

Reporting period: 2019-04-01 to 2020-09-30

Currently a big concern of our aging society is to efficiently delay the onset of neurodegenerative diseases, which are progressively rising in incidence. The paradigm that a diet rich in the phenolics, prevalent e.g. in fruits, is beneficial to brain health has reached the public. However, their mechanistic actions in brain functions remain to be seen, particularly since the nature of those acting in the brain remains overlooked.
LIMBO’s project addresses this gap by identifying candidate compounds that can support development of effective strategies to delay neurodegeneration. In particular we have been analyzing the potential of dietary phenolics in both prevention and treatment (i.e delay) of neuroinflammation – key process shared in neurodegenerative diseases. We are focused on the low molecular weight (LMW) (poly)phenol metabolites derived from dietary phenolics and investigate their brain permeability and their effects in both established and unknown response pathways of microglia cells - the innate immune cells of the central nervous system, either alone or when communicating with other brain cells. Ultimately, to attain an integrated view of their effects I will establish nutrition trials in mice. LIMBo considers both pro- and anti- inflammatory processes to preliminary validate the action of any promising metabolite in prevention and/or therapeutics.
The project can be divided into 3 major objectives as listed below:
1. Identify low molecular weight (poly)phenol metabolites in brain and screen their capability to attenuate microglia-mediated neuroinflammation
2. Elucidate the molecular mechanisms mediating the effects of LMW (poly)phenol metabolites in brain cells undergoing inflammation
3. Attain an integrated perception of dietary phenolics effects in a mice model of neuroinflammation and a mice model of Parkinson’s disease.

The evaluation of all these datasets is essential to build an integrated vision of dietary phenolics effects in brain health, particularly how they influence brain dysfunction with inflammation and ultimately of their potential in prevention and/or therapeutics of neurodegenerative diseases.
We first listed all described LMW (poly)phenol metabolites and reviewed the molecular mechanisms underlying their effects in the brain and their specific role on neuroinflammation identifying the gaps. Moreover, we also gather the sparse data available for the brain bioavailability of these human LMW (poly)phenol metabolites including evidence of crossing blood brain barrier in silico, in vitro and in vivo. Based on this we decided to update our library with all described LMW (poly)phenol metabolites (around 130) either acquiring commercially or by synthesis of the remaining.
To get a comprehensive overview of LMW (poly)phenol metabolites neuroprotective preventive effects towards neuroinflammation we screen their anti-neuroinflammatory properties to protect microglia cells from a strong inflammatory insult by monitoring the release of pro-inflammatory cytokines and neurotoxic factors. Kinetics and the dose response of their protective effects using near-physiological conditions of both concentration and residence time for each metabolite was established.
The brain permeability of all LMW (poly)phenol metabolites was evaluated in silico and for the 3 top compounds, presenting higher activity, its brain permeability was confirmed in vivo. Compounds were injected intravenously at levels similar to that of their physiological post-absorption after an intake of berry fruits serving - hence nutritionally relevant. Brain extracts are been analysed for detection of the LMW (poly)phenol metabolites and their end-route metabolites by untargeted metabolomics.
Ultimately, we aim to use specific LMW (poly)phenol metabolites to gain insights on new routes of their metabolism inside the brain and push our knowledge on the neuroactive molecular mechanisms of the novel end-route metabolites. In the end, confirmation of the identity of the end-route metabolites will also require their chemical synthesis.
The comprehensive analysis of LMW (poly)phenol metabolites ability to reach the brain and capacity to attenuate microglia activation and therefore reducing neuroinflammation fills the current identified gaps in this area, therefore constituting progresses to the state of the art. We predict to uncover the molecular targets of the most active metabolites and validate the effects and targets in vivo. At the end LIMBo will provides valuable scientific insights for future implementation of healthy brain diets. LIMBo also creates far-reaching opportunities by generating knowledge that impacts our fundamental understanding on the diversity of phenolic metabolites and their specific influences in neuroinflammation and potential use as prodrugs.