Identification of the absorption mechanisms and pre-systemic metabolism of monotropein and monotropein esters from Gaultheria berries

• Applicant: Dr. Felipe Jimenez Aspee
• Subject Area: Nutritional Sciences
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 504936438

Epidemiological studies demonstrate that the consumption of fruits and vegetables has significant positive health effects on the human body. These benefits are ascribed to bioactive food compounds, which are non-nutritional constituents in foods that are effect changes in consumer´s health status. However, to have health-promoting effects, a bioactive food component needs to be absorbed before reaching the systemic circulation. Among bioactive food compounds are iridoids, a group of secondary metabolites that can be found in berries from the Vaccinium and Gaultheria genus. Iridoids, and in particular monotropein, have demonstrated their anti-inflammatory, cytoprotective and health promoting properties in vitro and in vivo. However, scarce information about the mechanism of absorption of iridoids can be found in literature, and it is unknown to what extent these compounds are bioavailable for the organism. Another gap in our knowledge about iridoid´s pharmacokinetics concerns the pre-systemic metabolism of these compounds, specifically how the gut microbiota and phase I and II enzymes can change the structures of these compounds and thus affect their absorption and overall bioavailability. In preliminary results, I have found that monotropein-esters are stable under simulated in vitro digestion conditions and that they are taken up by Caco-2 cells, but the mechanisms describing this absorption process are still unknown. The present project will investigate the absorption and pre-systemic metabolism of monotropein and monotropein esters. Moreover, the in vivo bioavailability will also be evaluated in humans. The effect of the gastrointestinal system will be simulated through an in vitro gastrointestinal digestion model and colonic fermentation. Active and passive absorption, as well as possible efflux of monotropein and its esters will be identified through Caco-2/HT-29 cellular trans-epithelial transport studies and a Parallel Artificial Membrane Permeability Assay. By using pharmacological inhibitors, the role of transporters will be confirmed. Pre-systemic metabolism will be studied using mass spectrometric analysis of colonic fermentation samples, as well as those metabolites derived from liver microsomes and LS174/HepG2 cell cultures. Finally, we will compare the in vitro results with in vivo bioavailability studies with human volunteers. The results of this research will provide novel insights into the molecular mechanisms involved in the absorption of iridoids and will disclose the metabolic reactions involved in the pre-systemic metabolism of monotropein and its esters, providing helpful information to understand the pharmacokinetics of this group of compounds.

• DFG Programme: Research Grants