Chronic Exposure to Short-chain Fatty Acids Modulates Transport and Metabolism of Microbiome-derived Phenolics in Human Intestinal Cells

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.