Despite the high human interindividual variability in response to (poly)phenol consumption, the cause-and-effect relationship between some dietary (poly)phenols (flavanols and olive oil phenolics) and health effects (endothelial function and prevention of LDL oxidation, respectively) has been well established. Most of the variables affecting this interindividual variability have been identified (food matrix, gut microbiota, single-nucleotide-polymorphisms, etc.). However, the final drivers for the health effects of (poly)phenol consumption have not been fully identified. At least partially, these drivers could be (i) the (poly)phenols ingested that exert their effect in the gastrointestinal tract, (ii) the bioavailable metabolites that exert their effects systemically and/or (iii) the gut microbial ecology associated with (poly)phenol metabolism (i.e., gut microbiota-associated metabotypes). However, statistical associations between health effects and the occurrence of circulating and/or excreted metabolites, as well as cross-sectional studies that correlate gut microbial ecologies and health, do not prove a causal role unequivocally. We provide a critical overview and perspective on the possible main drivers of the effects of (poly)phenols on human health and suggest possible actions to identify the putative actors responsible for the effects.

Scope: Some polyphenol‐derived metabolites reach human breast cancer (BC) tissues at concentrations that induce cell senescence. However, this is unknown for isoflavones, curcuminoids, and lignans. Here, their metabolic profiling in normal (NT) and malignant (MT) mammary tissues of newly‐diagnosed BC patients and the tissue‐occurring metabolites’ anticancer activity are evaluated.Methods and results: Patients (n = 26) consumed 3 capsules/day (turmeric, red clover, and flaxseed extracts plus resveratrol; 296.4 mg phenolics/capsule) from biopsy‐confirmed diagnosis to surgery (5 ± 2 days) or did not consume capsules (n = 13). NT and MT, blood, and urine are analyzed by UPLC‐QTOF‐MS using targeted metabolomics. Anticancer activity was tested in MCF‐7 and MDA‐MB‐231 BC cells. Mainly phase‐II metabolites were detected (108, 84, 49, and 47 in urine, plasma, NT, and MT, respectively). Total metabolite concentrations reached 10.7 ± 11.1 and 2.5 ± 2.4 µmol L^–1 in NT and MT, respectively. Free curcumin, but not its glucuronide, was detected in the tissues (1.1 ± 1.8 and 0.2 ± 0.2 µmol L^–1 in NT and MT, respectively). Breast tissue‐occurring metabolites’ antiproliferation was mainly exerted in p53‐wild‐type MCF‐7 cells by curcuminoids through cell cycle arrest, senescence, and apoptosis induction via p53/p21 induction, while isoflavone‐derived metabolites exerted estrogenic‐like activity.Conclusion: Curcuminoids could be coadjuvants that might help fight BC upon regular consumption.

The Aryl Hydrocarbon Receptor (AHR) is a ligand-dependent transcription factor able to control complex transcriptional processes in several cell types, which has been correlated with various diseases, including inflammatory bowel diseases (IBD). Numerous studies have described different compounds as ligands of this receptor, like xenobiotics, natural compounds, and several host-derived metabolites. Dietary (poly)phenols have been studied regarding their pleiotropic activities (e.g., neuroprotective and anti-inflammatory), but their AHR modulatory capabilities have also been considered. However, dietary (poly)phenols are submitted to extensive metabolism in the gut (e.g., gut microbiota). Thus, the resulting gut phenolic metabolites could be key players modulating AHR since they are the ones that reach the cells and may exert effects on the AHR throughout the gut and other organs. This review aims at a comprehensive search for the most abundant gut phenolic metabolites detected and quantified in humans to understand how many have been described as AHR modulators and what could be their impact on inflammatory gut processes. Even though several phenolic compounds have been studied regarding their anti-inflammatory capacities, only 1 gut phenolic metabolite, described as AHR modulator, has been evaluated on intestinal inflammatory models. Searching for AHR ligands could be a novel strategy against IBD.