ABSTRACT: The molecular basis underlying the known anti-inflammatory and anticarcinogenic properties of cranberries is incompletely understood. We investigated the microRNA (miRNA)-modulatory effects of cranberry proanthocyanidin (PAC) and two of its main gut microbial metabolites, 3,4-dihydroxyphenylacetic acid (DHPAA) and 3-(4-hydroxyphenyl)-propionic acid (HPPA), in intestinal cells at homeostasis and in inflammatory conditions. Differentiated Caco-2BBe1 cells were pre-treated with PAC, DHPAA, or HPPA then stimulated with IL-1ß or not. Total RNA was used to profile the expression of 799 miRNAs. PAC, DHPAA, and HPPA generated subsets of shared and distinct miRNA responses. At homeostasis, miRNAs affected by the metabolites, but not by PAC, targeted genes enriched in kinase, Wnt, and growth factor signaling, cell growth and proliferation, apoptosis, and specific cancer pathways. In an inflammatory environment, pre-treatment with PAC and DHPAA, but not HPPA, reversed the expression of 16 and two IL-1ß-induced miRNAs, targeting genes enriched in inflammatory and cancer pathways. These data suggest that in the absence of inflammation, PAC may be reliant on its transformation by the gut microbiota for its miRNA-modulatory effects, while in an inflammatory environment, both PAC and DHPAA counter inflammatory miRNA responses. This work provides a novel mechanism to characterize the bioactivity of cranberry and will inform cranberry utilization in nutritional strategies for the maintenance of intestinal homeostasis.
