Chronic exposure to short-chain fatty acids modulates transport and metabolism of microbiome-derived phenolics in human intestinal cells

Abstract

Dietary fiber-derived short-chain fatty acids (SCFA) and phenolics produced by the gut microbiome have multiple effects on health. We have tested the hypothesis that long-term exposure to physiological concentrations of SCFA can affect the transport and metabolism of (poly)phenols by the intestinal epithelium using the Caco-2 cell model. Metabolites and conjugates of hesperetin (HT) and ferulic acid (FA), gut-derived from dietary hesperidin and chlorogenic acid, respectively, were quantified by LC-MS with authentic standards following transport across differentiated cell monolayers. Changes in metabolite levels were correlated with effects on mRNA and protein expression of key enzymes and transporters. Propionate and butyrate increased both FA transport and rate of appearance of FA glucuronide apically and basolaterally, linked to an induction of MCT1. Propionate was the only SCFA that augmented the rate of formation of basolateral FA sulfate conjugates, possibly via basolateral transporter up-regulation. In addition, propionate enhanced the formation of HT glucuronide conjugates and increased HT sulfate efflux toward the basolateral compartment. Acetate treatment amplified transepithelial transport of FA in the apical to basolateral direction, associated with lower levels of MCT1 protein expression. Metabolism and transport of both HT and FA were curtailed by the organic acid lactate owing to a reduction of UGT1A1 protein levels. Our data indicate a direct interaction between microbiota-derived metabolites of (poly)phenols and SCFA through modulation of transporters and conjugating enzymes and increase our understanding of how dietary fiber, via the microbiome, may affect and enhance uptake of bioactive molecules.

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

“…In this study, the placebo treatment consisted of cellulose, which can increase the production of SCFA . Recently, Van Rymenant et al . have demonstrated that SCFA alter in vitro bioavailability and phase II conjugation of hesperetin and ferulic acid in chronically pre‐treated Caco‐2 cell cultures, although in vivo studies supporting this observation are currently lacking.…”

“…In addition, to elucidate the mechanisms of hesperidin conversion throughout the gastrointestinal tract, various batch and continuous luminal digestion models simulating enzymatic and microbial degradation were set up. In another in vitro approach, absorption and phase II metabolism of hesperetin in Caco‐2 cells as a model for the gut epithelium have also been studied extensively, and the impact of microbial fermentation products such as short chain fatty acids on hesperetin transport and phase II metabolism in Caco‐2 cells was recently demonstrated . Similar experiments for the microbial degradation products are however scarce.…”

Bioengineered Systems and Designer Matrices That Recapitulate the Intestinal Stem Cell Niche

“…The use of a Transwell insert also provides a robust strategy to form microbial-product gradients across intestinal epithelial monolayers; however, the vast majority of these studies have focused on the response of tumor cells to microbial metabolites. 128 , 129 , 130 , 131 Although these models provide useful insights, recently established primary intestinal epithelial monolayer cultures in these inserts are expected to replace the intestinal cancer models. 23 , 26 , 27 , 132 For example, a mouse primary colonic monolayer was used to show that interferon-γ (IFN-γ) did not increase IgA-receptor expression or transcytosis as IFN-γ did in tumor cells.…”

Impacts of Dietary Pleurotus eryngii Polysaccharide on Nutrient Digestion, Metabolism, and Immune Response of the Small Intestine and Colon—An iTRAQ‐Based Proteomic Analysis

“…Four proteins belonging to the UDP‐glucuronosyltransferase isoforms (Ugt1a7c, Ugt1a6, Ugt1a1, and Ugt2b34) were all decreased in the PEP gavage group and annotated with the metabolism of toxic xenobiotics and endogenous compounds, along with the glucuronidation process. This would enhance the excretion of these compounds from the body and the decreased expressions might be due to the SCFAs concentrations increasing effects of PEP on the GIT contents …”