Metaboliti umani dei (poli)fenoli della dieta: interazione con il microbiota e nutricinetica comprensiva

(Poly)phenols are the most consumed phytochemicals in the western diet, and their intake, mainly associated with that of fruits and vegetables, has been correlated with a multitude of preventive and beneficial actions against several chronic diseases. The potential health benefits of (poly)phenols are strongly attributable to their capability to be efficiently absorbed and metabolized, and in producing bioavailable metabolites able to reach target districts at concentration levels high enough to be bioactive. This Doctoral Thesis comprehensively assessed the production of metabolites from the main dietary (poly)phenols in the framework of their absorption, distribution, metabolism and excretion (ADME) in humans. This work investigated: I) the interaction of flavan-3-ols, hydroxycinnamic acids (HCAs), quercetin and cranberry (poly)phenols with gut microbiota; II) blood nutrikinetics and urinary excretion profiles of flavan-3-ol and HCA metabolites through a systematic review based-approach; III) the metabolic efficiency (aka stoichiometry) in the production of the main flavan-3-ol colonic catabolites and main urinary HCA metabolites; IV) the bioavailability of ingested (poly)phenols. The results of this Doctoral Thesis highlighted that: I) in vivo, flavan-3-ols and HCAs are metabolized in up to 97 and 41 phase-2 conjugates of colonic catabolites and 22 and 8 colonic catabolites, respectively. If the flavan-3-ol structure (i.e. degree of polymerization, different subunit linkages (A-/B-type), and the presence of galloyl moieties) seems to influence the profile of (phenyl)-?-valerolactones (PVLs) and phenylvaleric acids (PVAs) produced in vitro, the presence of a delivery system, namely phytosome, did not affect the profile of these C6-C5 catabolites resulted from flavan-3-ol colonic metabolism of cranberry. On the other hand, phytosome affected the quantitative profile of phenolic catabolites produced from the interaction of quercetin with gut microbiota in vitro; II) data analysis of 96 intervention studies (n=1267, total sample size) demonstrated that after flavan-3-ol and HCA intake, up to 180 and 105 metabolites circulate in biofluids, respectively. Their blood concentration levels ranged from 37 to 1493 nmol/L, and metabolites were excreted in urine in amounts ranging from 0.3 to 11 % of intake; III) stoichiometric balances calculated in the production of PVLs and PVAs from cumulative urinary data were in line with those obtained from in vitro colonic fermentation of flavan-3-ol monomers and B-type dimers. Monomers are more prone to producing metabolites than oligomer flavan-3-ols. Instead, a specific heterogeneity was found in the stoichiometry for the main urinary metabolites of HCAs (n=16), with phenylpropanoic acids having the highest metabolic yield; IV) although flavan3-ols and HCAs appear to be moderately bioavailable (31% and 25%, respectively), intra- and inter-source differences in bioavailability values for both (poly)phenol classes emerged. In conclusion, this work represents a starting point for improving and harmonising the available knowledge on the interaction of dietary (poly)phenols with gut microbiota and their nutrikinetic profiles in humans. This Doctoral Thesis could strongly support understanding the fate of ingested (poly)phenols in humans, besides metabolic pathways associated with the production of (poly)phenol metabolites, and their circulating levels in biofluids, which represent pivotal steps for underlying the beneficial effects observed after ahigher adherence to plant-based dietary pattern.