Work Package 3: Gut-brain mechanisms

Although beneficial effects of multi-domain lifestyle interventions on cognition in older adults have been shown, the underlying mechanisms still remain to be resolved. This understanding is important, as it can: 1) explain why and how the intervention works, 2) provide biomarkers to measure intervention efficacy, 3) reveal why some participants do not respond to the intervention, and 4) provide further leads to continue improving the intervention.

In the cognitive decline process occurring during ageing, distinct – but potentially interrelated – mechanisms play a role such as: structural and functional alterations of the brain, peripheral and central inflammation, as well as metabolic and vascular alterations. The link between peripheral and central processes, as captured in the gut-brain axis, might be key in regulating the beneficial effects of a multi-domain lifestyle intervention.

The main objectives of WP3 are to assess:

  1. how multi-domain lifestyle interventions affect central and peripheral processes and how they interact, e.g. brain structure and function as well as immune-metabolic processes;
  2. whether we can intervene at the peripheral level to beneficially affect brain function and cognition and what determines intervention success. In this context, a particular focus will be on gut health, and the gut-brain axis;
  3. how non-invasive markers of intervention success relate to intervention effects on peripheral and central mechanisms of cognitive decline and their interaction.
Profielfoto Wilma Steegenga

Wilma Steegenga
Academic leader
Wageningen University and Research

Ateequr Rehman
Impact leader
DSM Nutritional Products

Design / methods

We will employ two human intervention designs:

  1. HELI: a 6-month low- versus high-intensity multi-domain lifestyle intervention (for aim 1 and 3)
  2. COMBI: a 6-week placebo-controlled gut-health intervention (for aim 2 and 3)

We will assess brain structure and function using Magnetic Resonance Imaging (MRI) and collect stool and blood samples at the start and end of each intervention. With regard to gut health, we will perform a qualitative and quantitative analysis of the microbiota, we will carry out targeted and untargeted metabolomics and we will analyse a wide panel of biomarkers. The blood samples will be used to examine the effects of the interventions on inflammation, metabolic, cardiovascular and nutrition-related markers. Additionally, we will perform metabolomics analyses to verify the levels of microbiota-derived metabolites in the systemic circulation.

Moreover, through in vitro studies employing sophisticated cell models of the gut, blood-brain barrier and neuronal cells, we will be able to provide even more causal relationships.

Societal relevance of outcomes

This work package particularly adds to the mechanistic understanding of multi-domain lifestyle intervention effects. However, the work can also lead to the identification of novel biomarkers that serve as early predictors of the intervention response. Particularly, we will assess the same non-invasive measures as in WP1 and can subsequently link them to our more invasive markers in MRI, blood, and faeces. This way, we will be able to validate the biological relevance of non-invasive markers of lifestyle intervention success. Such validated markers can subsequently be used to give relevant feedback to the user in an e-Health setting, as will be done in WP4.

Moreover, by specifically targeting the gut microbiome in our gut-health intervention, we can elucidate the relevance of gut health for cognitive aging. This could lead to new, targeted interventions for preventing cognitive decline in aging.

Involved partners

Academic partners:

Industrial partners:

  • DSM Nutritional Products; Dept. Human Nutrition and Health
    • Ateequr Rehman (impact leader)
  • Reckitt/Mead Johnson Nutrition


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