Elagitaninos de la dieta como herramienta para estudiar la variabilidad interindividual en el metabolismo de polifenoles

Abstract

(Poly)phenols are compounds distributed in plant foods (fruits, vegetables, etc.), potentially affecting human health. Although (poly)phenols consumption is related to the prevention or improvement of different diseases (obesity, cardiovascular diseases (CVDs), cancer, etc.), the health benefits are not observed equally in all the individuals due to the high interindividual variability determined by several factors, including the age, sex, lifestyle, physiological status, genetic makeup, gut microbiota, etc. Interindividual variability has been described in the metabolism of ellagitannins (ETs), polyphenols abundant in fruits, berries, and nuts (pomegranate, strawberries, walnuts, etc.), which are metabolized by the gut microbiota to the bioactive metabolites called urolithins. Differences in urolithin production allow stratifying the population into three metabolic phenotypes (metabotypes), according to the final type of urolithin produced: metabotype A (UM-A), characterized by the production of urolithin A, metabotype B (UM-B) that produces urolithin B and(or) isourolithin A in addition to urolithin-A, and metabotype 0 (UM-0), which does not produce these final urolithins. In this Thesis, we investigated the contribution of various factors (gut microbiota, genetic makeup, lifestyle, and health status) to the interindividual variability in (poly)phenol metabolism using dietary ETs as a tool. This multifactorial association was considered according to the individuals' development (childhood, adolescence, and adulthood), sex, and physiological status (normoweight, overweight, obesity, mothers during postpartum-lactation and metabolic syndrome (MetS) patients). Besides, the potential existence of gut microbiota metabotypes associated with the metabolism of other (poly)phenols, the proanthocyanidins (PAs), was also investigated. Three intervention studies (healthy volunteers) and 1 clinical trial (patients) were conducted, in which they consumed pomegranate juice and extract, and nuts (walnuts, almonds, and hazelnuts) as sources of ETs and PAs. Urine, feces, breast milk and(or) blood samples were analyzed by metabolomics (HPLC-DAD-ESI-Q-MS, UPLC-ESI-QTOF-MS and GC-MS), metagenomic analysis of the gut microbiome (16S rRNA gene sequencing), qPCR, determination of metabolic-inflammatory and metabolic endotoxemia markers using Luminex¿ technology and ELISA, and single-nucleotide polymorphisms (SNPs) genotyping, among other techniques. The main results obtained were: (i) there is no distinctive gut microbiota metabotypes associated with the metabolism of PAs, (ii) aging is the main factor that determines the distribution of UMs, (iii) the increase of overweight-obesity prevalence in childhood is related to being a young boy with either UM-B or UM-0, low adherence to the Mediterranean diet, and having certain SNPs, (iv) the composition and functionality of the gut microbiota differ between UMs, (v) UM-A mothers possess a more modifiable gut microbiota and faster restoration capacity of anthropometric values after one year of delivery than UM-B mothers, (vi) an analytical method for detecting urolithins in breast milk was developed and validated, (vii) gut colonization by the urolithin-producing bacterium, Gordonibacter, occurs during the first year of life, regardless of the type of delivery and feeding of the baby, (viii) there is no single distinctive taxonomic profile of the gut microbiota in SMet patients, (ix) polymedication and(or) CVD risk factors of SMet patients determine the prebiotic effects upon consumption of a pomegranate extract. This Thesis has delved into the study of metabotypes associated with the metabolism of polyphenols by the human gut microbiota. Metabotypes are potential biomarkers of the gut microbiota and predictive of human response to nutritional interventions. The identification of metabotypes could reduce interindividual variability in the context of personalized nutrition to universalize the health effects of (poly)phenol-rich functional foods or nutraceuticals.