Role of dietary (poly)phenols on cardiometabolic risk associated with menopausea multi-omics approach

  1. Sánchez Martínez, Lorena
Supervised by:
  1. María Jesús Periago Gastón Director
  2. Rocío González Barrio Director

Defence university: Universidad de Murcia

Fecha de defensa: 04 December 2024

Committee:
  1. Francisco A. Tomás Barberán Chair
  2. Begoña Cerdá Martínez-Pujalte Secretary
  3. Alice Rosi Committee member

Type: Thesis

Abstract

Menopause is a critical stage in woman's life, characterized by a sudden decline in estrogen levels, leading to cardiometabolic alterations such as insulin resistance, hypertension, dyslipidemias, and/or gut dysbiosis. These changes increase the risk of cardiometabolic diseases (R-CMBs), among which cardiovascular diseases (CVDs) stand up. In fact, it has recently been identified that CVDs are the leading cause of mortality in women, due to intrinsic factors in their physiology, among menopause stands up. The development of new strategies to alleviate the R-CMBs of postmenopausal women using natural compounds, has become one of the main challenges of the scientific community. In this sense, plant-based diets rich in fruit and vegetables could play a fundamental role, due to its high content in (poly)phenols, which are recognized by its antioxidant, anti-inflammatory, prebiotic and gene expression-regulating properties. Therefore, the aim of this research was to develop a dietary intervention trial with postmenopausal women, to evaluate by multi-omics approach, the effect of daily intake of (poly)phenol-rich foods (PP-rich foods) during 2 months on cardiometabolic risk biomarkers, (poly)phenol bioavailability, gut microbiota, and gene expression related to R-CMBs. In order to achieve this aim, a 3-month dietary trial was carried out in 25 postmenopausal women, with a control period of 1 month during which the participants followed their habitual diet, and an experimental period of 2 months during which the diet of participants was supplemented daily with dark chocolate, green tea and fruit juice (containing pomegranate, berries and orange juices). During the dietary trial, anthropometric, body composition and blood pressure (BP) measurements were assessed. Blood, plasma, urine, and feces samples were also collected. Moreover, 24-h food recall questionnaires and the Mediterranean diet adherence questionnaire were completed by participants. The study aimed to analyse cardiometabolic risk biomarkers, characterize gut microbiota and phase II-derived metabolites, evaluate short-chain fatty acids (SCFAs), determine the gut microbiota profile and assesses changes in global gene expression of postmenopausal women following the daily intake of PP-rich foods. Dietary intervention showed a slight improvement in BP, lipid profile, oxidative stress biomarkers, endothelial function biomarkers and inflammatory biomarkers. However, this improvement was only significant for TBARs. Moreover, significant increases in urinary excretion of gut microbiota and phase II-derived metabolites were observed, after the daily consumption of PP-rich foods. Due to the excretion of glucuronides and/or sulfates of phenyl-γ-valerolactones, phenylvaleric acids, phenylacetic acids, benzoic acids and urolithins. Furthermore, a significant increase in the fecal excretion, including phenyl-γ-valerolactones, phenylvaleric acids, cinnamic acids, benzoic acids, benzenes and urolithins, were observed. Whereas no significant differences were observed in the production of SCFAs. Gut microbiota analysis revealed beneficial changes in gut composition after the dietary intervention, due to a significant increase in Lachnospiraceae, Burkholderiaceae and Ruminococcaceae families, as well as in Dorea, NK4A214 group, Ralstonia, Eubacterium eligens, Agathobacter, Ruminococcus and Faecalibacterium genera, whose presence in the large intestine exerts a cardioprotective effect on the body. Results from gene expression analysis revealed that the dietary intervention with PP-rich foods was able to module global gene expression profiles of the participants. A total of 2,272 genes were significantly affected, not only protein coding genes but also protein non-coding RNA. Pathway analysis indicated that these differentially expressed genes were involved in several biological processes. Moreover, 19 transcription factors were significantly associated with the protein-coding genes regulated by the dietary intervention. In silico docking analyses showed that the major interactions were generated between FOXA1, PURA, RUNX3, RXRA and glucuronidated phenolic metabolites. Furthermore, gene expression profile after the dietary intervention, negatively correlated with gene expression profiles of patients with cardiometabolic diseases, which could suggest a positive effect on cardiometabolic health in postmenopausal women. Daily consumption of PP-rich foods improved cardiometabolic health in postmenopausal women by reducing oxidative stress, modulating gut microbiota, and regulating gene expression associate with R-CMBs. Therefore, the consumption of PP-rich foods during menopause could be a promising dietary strategy to reduce the adverse effects associated with this pivotal stage of woman's life, and in particular to reduce the risk of cardiometabolic events of postmenopausal women. However, the observed cardioprotective effect varied significantly among individuals, highlighting the influence of the inter-individual variability. Therefore, further research is needed to elucidate these differences and develop strategies based on personalized nutrition for optimizing the effectiveness of PP-rich diets for menopausal women's health.