Understanding the role of the gastrointestinal tract and the gut microbiome on the biotransformation, absorption and bioavailability of xenobiotics

Ondertitel:chlorogenic acid as model compound

During the past decade, researchers have shown an increased interest in the fate of orally ingested exogenous compounds, such as food supplements and pharmaceuticals in the gastrointestinal system. The gastrointestinal tract contains diverse compartments with varying physiological properties which could influence the bioavailability, activity and/or toxicity of these compounds. Until recently, it was believed that the biotransformation of xenobiotics occurs mainly by the cytochrome P450 enzyme system (CYP450) in the liver. However, recent data clearly show that the gut microbiome play a significant role in the biotransformation of oral administered xenobiotics, leading to a potential influence of this microbiotic biotransformation on activation, inactivation and possible toxicity of these compounds. A thorough knowledge on how the gut microbiome influences the bioavailability of xenobiotics and if the microbiotic biotransformation varies between individuals and different disease-states is essential further research on formulation and dosing strategies. Application of relevant in vitro gastrointestinal models can aid in the development of this research field. In the first part of this work a ready-to-use in vitro gastrointestinal platform, including (i) the gastrointestinal dialysis model with colon phase (GIDM-Colon) and (ii) bioanalytical strategies to elucidate the gastrointestinal biotransformation of xenobiotics, was optimized using chlorogenic acid as a model compound. The influence different incubation media and different incubation times on bacterial composition and concentration of the pooled fecal slurry suspension were evaluated. The use of a sterile phosphate buffer and a one-hour incubation time ensured a closer resemblance to the in vivo composition. Furthermore, different sample preparation procedures and data-analysis workflows were evaluated and optimized. Secondly, the in vitro gastrointestinal platform was successfully applied to investigate inter-population differences in microbiotic biotransformation of xenobiotics between a lean and obese population. The obese gut microbiome presented a lower metabolic activity in comparison to the lean population. The presented results in this thesis confirmed that changes in gut microbiota related to obesity are associated with differences in microbiotic biotransformation of xenobiotics. Finally, the in vitro gastrointestinal platform was expanded with an in vitro intestinal permeability assay using a Caco-2 cell line and an in vitro intestinal first-pass biotransformation assay using human intestinal microsomes and cytosol respectively. The involvement of an active efflux mechanism was observed for the intestinal absorption of both chlorogenic acid and quinic acid. Regarding the intestinal first-pass effect, no phase I biotransformation products of chlorogenic acid, caffeic acid and quinic acid were observed. For both chlorogenic acid and caffeic acid two sulfate-conjugate isomers and low-abundance features corresponding to the glucuronide-conjugates were identified. No phase II biotransformation products of quinic acid were detected.

Jaar van publicatie:2021

Trefwoorden:Doctoral thesis

Toegankelijkheid:Open