(Poly)Phenol metabolites antinflammatory role in blood-brain barrier – microglia crosstalk

• Main Author: Matos, Sara
• Publication Date: 2025
• Format: Master thesis
• Language: eng
• Source: Repositórios Científicos de Acesso Aberto de Portugal (RCAAP)
• Download full: http://hdl.handle.net/10362/181041
• topic: Neurodegenerative disorders; (Neuro)inflammation; Blood-brain barrier; Microglia; (Poly)phenol metabolites; Nutrition; Saúde

Abstract: With increasing life expectancy, we stand at the cusp of a global health crisis: the rising incidence of age-associated neurodegenerative diseases (NDDs), that remain cureless, deeply affecting the quality of life of patients and causing a substantial socio-economic burden. Preventive nutritional strategies are gaining attention, particularly surrounding (poly)phenol rich diets, which have revealed significant benefits towards brain health. Recently, low molecular weight (poly)phenol metabolites (LMWPMs), produced through gut microbiotacatabolism of dietary (poly)phenols, are suggested to be the real biological effectors with neuroprotective capabilities. Still, a major knowledge gap remains concerning their mode of action, especially in relevant models of (neuro)inflammation/NDDs that contemplate brain complexity and cell crosstalk. Therefore, this thesis aims to shed light on the anti-inflammatory potential of six LMWPMs, particularly in the context of blood-brain-barrier (BBB)-microglia crosstalk, implementingmore complex and physiologically relevant human cell models. Additionally, samples from an animal intervention study of neuroinflammation with berry supplementation were used to validate our hypothesis from in vitro systems. We showed that some LMWPMs attenuated IL 6 release and reduced zonula occludens-1 membrane gaps in human brain microvascular endothelial cells (HBMEC). We also observed that they attenuated IL-8 release and suppressed NF-κB nuclear translocation in human microglia (HMC3). Furthermore, we implemented two novel co-culture models of systemic inflammation, containing HBMEC and HMC3, in static (transwell) and dynamic (biochip) conditions, evidencing crosstalk between the different cell populations and system compartments. Finally, we demonstrated that supplementation with a berry-enriched diet modulated LPS-induced inflammatory responses in vivo, reducing microglial proliferation/hyper-ramification and potentially mitigating brain vascular damage. Overall, the present work highlights LMWPMs’ neuroprotective effects at the BBB/microglial level and generating knowledge concerning physiologically relevant in vitro models of (neuro)inflammation, that can be used to further dissect cell-cell interactions and potential novel preventive and/or therapeutic approaches against NDDs.