Cranberry Proanthocyanidin and Its Microbial Metabolite 3,4‐Dihydroxyphenylacetic Acid, but Not 3‐(4‐Hydroxyphenyl)‐Propionic Acid, Partially Reverse Pro‐Inflammatory microRNA Responses in Human Intestinal Epithelial Cells

The molecular basis underlying the anti-inflammatory and anticarcinogenic properties of cranberries is incompletely understood. The effects of a cranberry proanthocyanidin-rich extract (PAC) and two of its gut microbial metabolites, 3,4-dihydroxyphenylacetic acid (DHPAA) and 3-(4-hydroxyphenyl)-propionic acid (HPPA), on intestinal epithelial cells microRNA (miRNA) expression and their downstream pathways at homeostasis and in inflammatory conditions, are investigated.The expression of 799 miRNAs is quantitatively assessed in differentiated Caco-2BBe1 cells pre-treated with PAC, DHPAA, or HPPA and stimulated with interleukin (IL)-1β or not. PAC, DHPAA, and HPPA generate subsets of shared and distinct miRNA responses. At homeostasis, miRNAs affected by the metabolites, but not PAC, targeted genes enriched in kinase, Wnt, and growth factor signaling, cell growth and proliferation, apoptosis, and specific cancer pathways. In an inflammatory environment, PAC and DHPAA, but not HPPA, reverses the expression of 16 and two IL-1β-induced miRNAs, respectively, regulating inflammatory and cancer pathways.miRNA modulation is a novel mechanism for PAC bioactivity in the gut. The gut microbiota may be necessary to unlock these effects at homeostasis and partially in inflammation.