Wine polyphenols as modulators of oral microbiota in periodontitis, and neuronal dysfunction. Human metabolome and metabotyping after moderate wine consumption

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Química Física Aplicada. Fecha de lectura: 19-02-2018Esta tesis tiene embargado el acceso al texto completo hasta el 19-02-2023The health benefits associated to moderate wine intake have been widely reported, however the mechanisms of protection involved in certain disorders are still unclear. During this thesis, novel in vitro and in vivo approaches have been applied with the final aim of elucidating the actions of red wine and its phenolic constituents in the management of oral diseases and brain function, as well as to evaluate the human individual metabolism in response to wine consumption. Regarding oral microbiota and health, the anti-adhesive properties of wine polyphenols against periodontal and cariogenic pathogens adherence (P. gingivalis, F. nucleatum and S. mutans) to human gingival fibroblasts have been proved, and the evaluation of oral metabolism confirmed both, bacterial and cellular metabolism of wine polyphenols. Also, reciprocal benefits of these compounds together with a recognized oral probiotic has been revealed for the first time at oral level, as well as the bactericidal action of red wine, dealcoholized red wine and oenological extracts against periodontal pathogens (P. gingivalis, F, nucleatum and A. actynomycetemcomitans) in a six-species model of subgingival biofilm. In order to characterize metabolic changes after moderate wine consumption, an untargeted metabolomics approach (UHPLC-TOF MS) has been applied to the study of urine samples from a human intervention study based on moderate red wine consumption in healthy subjects. This analysis confirmed a strong impact of red wine consumption in the overall urinary metabolome, as well as biomarkers associated to wine consumption have been proposed, including specific wine components (tartaric acid) and microbial-derived phenolic metabolites (γ- valerolactones and valeric acids derivatives). A stratification of the population into different “metabotypes” or wine-metabolizing phenotypes has been perceived depending on the ability to produce specific amounts of selected bioactive compounds. Glutaric acid derivatives, procyanidins, catechins and epicatechins, and some microbial derived metabolites of valeric acids, were the compounds mainly involved in this classification. To our knowledge, this is the first work in which consistent metabotypes have been described in healthy volunteers after moderate wine consumption, pointing out the value of the urinary metabolome for characterizing inter individual responsiveness to a dietary intervention. Abstract/Resumen 4 Finally, in regard to brain function, several novel and noteworthy features have been addressed. The study of the protective role of phenolic metabolites and aroma compounds in a situation of nitrosative-induced stress in neuroblastoma cells confirmed a modulation by these compounds of mitogen-activated protein kinase route (MAPK) as well as of caspase-3 pro-apoptotic protein expression. An in vitro cellular model of mice primary hippocampal neurons mimicking neuroticism alterations was used to explore the restoration of synaptic plasticity by wine phenolic metabolites, through modulation of genes involved in protein translation. Finally, the promotion of resilient phenotype to social stress after consumption of a diet containing grape polyphenols and PMI5011 botanical extract, in a mice model of social defeat, confirmed a positive modulation of synaptic plasticity and prevented neuroinflammation, through epigenetic mechanisms