A Critical Evaluation of In Vitro Hesperidin 2S Bioavailability in a Model Combining Luminal (Microbial) Digestion and Caco‐2 Cell Absorption in Comparison to a Randomized Controlled Human Trial

Abstract

In the combined in vitro model, smaller phenolics strongly accumulated, whereas in humans, hesperetin conjugates were the main bioavailable compounds. Future in vitro model development should focus on simulating faster polyphenol absorption and elimination of smaller phenolics to improve their predictive value of in vivo polyphenol bioavailability.

The Intestinal Fate of Citrus Flavanones and Their Effects on Gastrointestinal Health

“…Data from in vitro studies using various GI digestion models have provided additional information. In vitro digestion of hesperidin, naringin, and their aglycones has been carried out either in batch-like settings using incubations with fecal slurries or isolated bacteria [37,40,41], or in more comprehensive models, such as the TNO in vitro model of the colon (TIM-2) and the simulator of the human intestinal microbial ecosystem (SHIME) [42,43]. These in vitro studies, listed in Table 1, show quite consistently that during colonic microbial fermentation, hesperidin and naringin are first metabolized into their aglycones hesperetin and naringenin and subsequently into various phenolics, including dihydrocaffeic acid, isoferulic acid, 4-hydroxyphenylacetic acid, dihydroferulic acid, ferulic acid, resorcinol, phloroglucinol, 2,4-dihydroxyphenylacetic acid, 4-hydroxybenzoic acid, phloretic acid, phloroglucinic acid, hydrocinnamic acid, 3-(3′-hydroxyphenyl)propionic acid, protocatechuic acid, and hippuric acid.…”

“…In addition to the type of metabolites formed, a recent study by Van Rymenant et al provided information about the location of citrus flavanone metabolism. Using a digestion model comprising compartments representing the ascending, transverse, and descending colon (SHIME) inoculated with a fecal sample from a healthy volunteer, the metabolites formed upon hesperidin conversion were found at the highest concentrations in the compartments representing the ascending and transverse colon, while lower concentrations were measured in the descending colon [42]. These in vitro results suggest that microbial metabolism predominantly takes place in the more proximal parts of the colon.…”

Search for Natural Compounds That Increase Apolipoprotein A‐I Transcription in HepG2 Cells: Specific Attention for BRD4 Inhibitors

“…In future experiments, bioavailability can therefore be addressed by using a transwell system that combines intestinal and hepatic cells. Moreover, by using the Simulator of the Human Intestinal Microbial Ecosystem (SHIME), the in vivo situation could be better mimicked (Van Rymenant et al, ). Also, more structural derivatives of the main structures that were presented could be tested.…”

Insight into Polyphenol and Gut Microbiota Crosstalk: Are Their Metabolites the Key to Understand Protective Effects against Metabolic Disorders?

“…Similarly, olive oil polyphenol glycosides, including oleuropein (glycoside of elenolic acid linked to hydroxytyrosol) underwent rapid and time-dependent hydrolysis, yielding appreciable amounts of free hydroxytyrosol and tyrosol, probably through nucleophilic attack [ 66 ]. On the contrary, other studies, using the same in vitro model, along with oral administration of polyphenols to humans, showed stability of a variety of polyphenols in the acidic milieu [ 67 , 68 , 69 , 70 , 71 , 72 , 73 ]. Interestingly, the incubation of apple phloretin and quercetin for 5 min with native saliva resulted in the production of the respective aglycones, likely by oral bacterial flora as the process was blocked by antibiotics [ 68 ].…”

“…Although valuable for screening polyphenol bioavailability, caution should be used when interpreting the data obtained from the Caco-2 cellular model in terms of predictability. Indeed, even if in vitro smaller phenolic derivatives of hesperidin 2S were absorbed, hesperidin conjugates were the main bioavailable moieties in a randomized human controlled study [ 69 ].…”