The influence of fatty acids, phenolic compounds, and vitamin B12 on health in an older Mediterranean population

Abstract

[eng] Chronic diseases are the leading cause of death in the world. Several of these conditions are related to the cardiovascular or cognitive system whose pathophysiology is closely linked to alterations in inflammatory processes. There are some modifiable factors that can help prevent or promote the development of these diseases, and nutrition is one of them. Mediterranean diet (MedDiet) stands out as one of the dietary patterns with more health benefits. This plant-based diet includes a balanced intake of macronutrients, and it also provides micronutrients and bioactive compounds, including vitamins and polyphenols, which are recognized for their beneficial effects. Therefore, this dissertation aimed to investigate the role of naturally occurring components of the MedDiet - fatty acids, polyphenols, and vitamin B12 - on metabolic and inflammatory pathways, as well as on cardiovascular and cognitive health. All the research was framed within the PREDIMED and PREDIMED-Plus trials, two randomized clinical trials that included an older Mediterranean population at high cardiovascular disease (CVD) risk. To achieve the first objectives of this thesis, we analyzed the plasma fatty acid composition of participants in the PREDIMED and PREDIMED-Plus trials. The first findings demonstrated that the bioavailability of saturated fatty acids, and especially palmitic acid, was impaired in diets with high consumption of fruits and vegetables. Furthermore, alterations in the estimated activities of the enzymes that metabolize fatty acids were associated with cardiometabolic risk factors. Fatty acid metabolism has a great impact on health, as depending on their degree of saturation they can exhibit antiinflammatory or proinflammatory properties. We found that saturated fatty acids, and specifically palmitic acid, increased the inflammatory molecule interleukin-6. Vitamin B12, on the other hand, was inversely associated with this inflammatory molecule and also with

C-reactive protein. In addition, wine consumption measured as its biomarker tartaric acid decreased circulating levels of adhesion molecules associated with atherosclerosis. In light of these findings, we explored the impact of wine on cardiovascular health. Wine consumption was associated with lower concentrations of LDL-cholesterol in postmenopausal women, a population at increased risk of CVD. Regarding other risk factors of CVD, a panel of urinary phenolic compounds discriminant for type-2 diabetes was described, and among them dihydrocaffeic acid and genistein diglucuronide were found to be protective. Considering the low bioavailability of polyphenols and high metabolism by the gut microbiota, a novel method was used to identify and quantify microbial phenolic metabolites (MPM) in urine. A positive association was found between them and cardiovascular health, particularly for urolithin B glucuronide and LDL-cholesterol. MPM have potential positive benefits on cognitive health; however, to exert these effects, they must overcome another challenge: crossing the blood-brain barrier. Permeability through this layer that protects the central nervous system is a requirement for compounds to exert direct biological effects on cognitive health, but the literature has only demonstrated that a select few can penetrate. In our studies, we found that MPM were associated with better global cognition, especially protocatechuic acid and enterolactone glucuronide. MPM were particularly beneficial for frontal lobe functions, and vanillic acid glucuronide showed the strongest association. Lastly, the vitamin B12 on cognition was evaluated according to the adherence to MedDiet. Only in participants with high adherence vitamin B12 was associated with better memory, while no effect was observed with low adherence. Overall, these findings highlight the role of dietary choices in supporting healthy aging and preventing chronic diseases in the context of an older Spanish population at high risk of CVD.

[cat] Les malalties cròniques són la principal causa de mort a nivell mundial, especialment les cardiovasculars i cognitives, que estan estretament vinculades a alteracions dels processos inflamatoris. La nutrició juga un paper crucial en la prevenció i desenvolupament d'aquestes malalties, amb la dieta mediterrània (MedDiet) emergint com un patró alimentari amb nombrosos beneficis per a la salut. Aquesta tesi s'ha centrat en investigar els components naturals de la MedDiet, concretament àcids grassos, polifenols i vitamina B12, i el seu impacte en les vies metabòliques, inflamatòries, i en la salut cardiovascular i cognitiva. Tots els estudis s’han dut a terme dins els assaigs clínics PREDIMED i PREDIMED-Plus, que van incloure una població mediterrània amb alt risc de malaltia cardiovascular. L'anàlisi d'àcids grassos en plasma va revelar que la biodisponibilitat dels àcids grassos saturats, especialment l'àcid palmític, es veia afectada en dietes amb elevat consum de fruites i verdures. A més, es va observar que alteracions en les activitats d'enzims que metabolitzen els àcids grassos, s’associen amb factors de risc cardiometabòlics. Els àcids grassos saturats, particularment l'àcid palmític, es van relacionar amb l'augment de la interleucina-6, una molècula inflamatòria. En canvi, la vitamina B12 va presentar una associació inversa amb aquesta molècula i amb la proteïna C-reactiva. El consum de vi, mesurat pel biomarcador àcid tartàric, es va associar amb menors nivells de molècules d'adhesió associades a l'aterosclerosi. En estudiar l'impacte del vi en la salut cardiovascular es va observar una associació inversa entre el consum de vi i el colesterol LDL en dones postmenopàusiques. Els compostos fenòlics en orina

van ser identificats com a discriminants per a la diabetis tipus 2, especialment l'àcid dihidrocafeic i la genisteïna diglucurònid. Els metabòlits fenòlics microbians (MPM) van presentar una associació positiva amb la salut cardiovascular, destacant l’associació inversa entre la urolitina B glucurònid i el colesterol LDL. Aquests MPM també van demostrar beneficis per a la salut cognitiva relacionada amb una millora de la cognició global. En resum, aquesta recerca destaca el paper de la nutrició en l’envelliment saludable i la prevenció de malalties cròniques en una població mediterrània amb alt risc cardiovascular.