Achieving glucose-lowering and appetite-suppressing effects through dietary strategies depends not only on the presence of active compounds but also on the timing and rate of nutrient release from the food matrix. This highlights the need for mechanistic research employing physiologically relevant models that accurately mimic the environment experienced by intestinal epithelial and enteroendocrine cells in the body. In this study, we hypothesised that whole apples and pomace (a by-product from juice/cider processing with hydrocolloid properties), offer dual but distinct cardiometabolic benefits by modulating glucose homeostasis and appetite regulation. To test this hypothesis, physiologically relevant in vitro digesta from whole apple and apple pomace were prepared using the upper gastrointestinal INFOGEST protocol coupled to a novel laboratory-implementable solubilization and purification method that doubled polyphenol concentrations without inducing cytotoxicity. These purified digesta were incubated with differentiated Caco-2 cell monolayers and with STC-1 enteroendocrine cells. Samples collected at the end of the gastric and intestinal phases represented pre- and post-intestinal chyme. By concentrating bioaccessible polyphenols and removing cytotoxic constituents from digesta, the resulting digesta from whole apple and apple pomace (mostly consisting of cell walls impregnated with polyphenols) were suitable for both mass spectrometry analysis and direct application to Caco-2 and STC-1 cells. This integrated approach enabled mechanistic investigation of physiologically relevant bolus and chyme.

LC-ESI-QTOF-MS/MS analysis of 48 polyphenols across apical, intracellular, and basolateral compartments showed predominant apical retention, except for flavanols. Whole apple and pomace significantly inhibited glucose transport, primarily driven by dihydrochalcones and hydroxybenzoic acids (Spearman ρ>0.70). Notably, although phloridzin alone inhibited GLP-1 secretion, gastric digestates of both apple and pomace enhanced secretion by 50%. However, only the pomace digestate retained this effect after intestinal digestion, increasing GLP-1 levels by 250% compared to the control.

Although both apples and their by-product pomace may offer cardiometabolic protection, the mechanisms appear to differ due to variations in polyphenol profiles and bioaccessibility (Figure 1). Whole apple digesta strongly inhibited transepithelial glucose transport in both pre- and post-intestinal chyme, suggesting persistent activity throughout the upper gastrointestinal tract. In contrast, pomace showed moderate glucose transport inhibition at the gastric phase, which was lost after intestinal digestion. However, while both apple and pomace gastric digesta stimulated GLP-1 secretion, only pomace retained this effect following intestinal digestion - highlighting its unique potential as a functional ingredient for appetite suppression and lowering food intake.

The distinct mechanisms by which whole apple and apple pomace exert glucose-lowering and appetite-suppressing effects, respectively, underscore the need for greater precision in evaluating how specific food components influence physiological responses. These findings support a shift toward more targeted nutritional strategies, moving beyond generalized dietary recommendations to leverage the unique functional properties of individual food matrices with hydrocolloid properties. They also highlight the vast, largely untapped complexity of food systems as a resource for designing tailored interventions to prevent chronic diseases.