Investigation of in Vivo Endogenous and/or Exogenous Production of Phenolic Metabolites in People With an Ileostomy Using an Oral (Poly)Phenol Challenge Test

Plant (poly)phenols are a diverse family of compounds encompassing flavonoids (e.g., flavonols, flavanones, flavones, isoflavones, anthocyanidins, flavan-3-ols) and non-flavonoids (e.g., phenolic acids, lignans, stilbenes, hydrolysable tannins), typically present in foods as glycosides. Converging evidence from cohort studies and randomised trials associates modest, long-term (poly)phenol intake with reduced risk of cardiometabolic diseases (CMD) and improved intermediate risk factors including blood pressure, endothelial -function and insulin sensitivity.

Following ingestion, only a minor fraction of aglycones and small, hydrophilic forms is absorbed in the small intestine; most dietary (poly)phenols reach the colon, where gut microbiota (GM) convert them into a wide array of low-molecular weight metabolites (LMWP) that enter the circulation predominantly as phase II conjugates (glucuronides, sulfates, methylated forms). These circulating LMWP often present at higher concentrations than parent compounds and are increasingly considered the mediators of biological effects. However, bioavailability shows striking inter-individual variability (15-99% recovery as diverse metabolites), reflecting differences in absorption, distribution, metabolism, and excretion (ADME). Genetic variation may explain up to ~50% of variability in flavonoid ADME, with remaining variability largely determined by lifestyle factors, (patho)physiology, and GM composition/function. GMdependent- transformations generate distinct metabolic phenotypes (metabotypes) characterised by the presence/absence and relative abundance of specific catabolites. Importantly, metabotypes are associated with baseline cardiometabolic risk and intervention responsiveness and can inform stratified or personalised nutrition approaches.

Interpreting LMWP profiles is complicated by biochemical convergence between dietary and endogenous pathways. For example, hippuric acid - a major endpoint of many (poly)phenols - is also formed via glycine conjugation of benzoate in glycine deportation; benzoic acid itself arises from both (poly)phenol catabolism and aromatic amino acid (phenylalanine/tyrosine) metabolism. These overlaps, together with interindividual variability in GM and host genetics, underscore the need to carefully map circulating LMWP, quantify exposure, and apportion sources to understand diet-health relationships.

Studying people without a colon (ileostomates) offers a powerful in vivo model to disentangle small intestinal absorption and phase II conjugation from colonic microbial metabolism. Sampling ileal effluent will allow for (i) direct assessment of parent compounds which escape from the small intestine, (ii) characterisation of early conjugated metabolites entering circulation independent of colonic metabolism, and (iii) clearer attribution of LMWP to endogenous versus dietary origins whilst accounting for inter-individual variability.

In sum, while plant (poly)phenols are linked to cardiometabolic benefits, substantial heterogeneity in ADME - shaped by GM, genetics, and endogenous pathway overlap - limits understanding of their role in nutrition and health. Integrating metabotyping concepts with the ileostomy model can resolve key uncertainties in true internal exposure and source attribution of LMWP, strengthening causal inference about diet-metabolite-health pathways and will improve our understanding on the determinants of the responsiveness to (poly)phenols, being able to predict their health effects at individual level.