Mucus Barrier Weakens the Inhibitory Activity of Pyrogallol-Based Polyphenols Against α-Glucosidase

Scope: Polyphenols reportedly possess strong in vitro α-glucosidase inhibitory activity, even higher than acarbose, but their in vivo regulation on postprandial hyperglycemia is poor. So far this typical problem of polyphenols remains unsolved, greatly hindering their application as α-glucosidase inhibitors. Methods and results: Here, we identify the small intestinal mucus layer acts as a barrier to significantly reduce in vivo α-glucosidase inhibitory activity of epigallocatechin gallate, prodelphinidin B digallate (proDB DG), and proanthocyanidins from Chinese bayberry leaves. Multispectroscopy, rheology, solvent method, and molecular docking analysis showed that these pyrogallol-based polyphenols, especially proDB DG strongly interacted with small intestinal mucins through hydrogen bonding, hydrophobic interactions, and electrostatic interactions. These interactions block polyphenols from penetrating the mucus layer, resulting in their low binding rates with α-glucosidase in vivo. Besides, polyphenol-driven aggregation of the mucins enhanced the barrier function and reduced the permeability of the mucus layer, resulting in delayed digestion and absorption of carbohydrates. Conclusions: The mucus barrier weakens the inhibitory activity of pyrogallol-based polyphenols against α-glucosidase. Hence, overcoming the mucus barrier is a promising strategy to improve the regulation of pyrogallol-based polyphenols against postprandial hyperglycemia in vivo, which helps them to become novel α-glucosidase inhibitors in the clinic.