Polyphenols as Modulators of Gastrointestinal Motility: Mechanistic Insights from Multi-Model Studies

Background/Objectives: Dietary polyphenols are recognized as crucial modulators of gastrointestinal motility, holding therapeutic promise for conditions like irritable bowel syndrome, postoperative ileus, and functional dyspepsia. However, their reported effects are heterogeneous, ranging from spasmolytic to prokinetic. This review aims to clarify these inconsistencies by synthesizing experimental evidence on structure–activity relationships and underlying mechanisms. Methods: We conducted a structured literature review spanning January 1990 to January 2025 across PubMed, Scopus, and Web of Science. Our search utilized keywords such as "polyphenols," "flavonoids," "gastrointestinal motility," "smooth muscle," and specific compound names. Results: Across various experimental models, polyphenols function as multi-target modulators of gastrointestinal smooth muscle. The primary mechanisms identified involve the blockade of voltage-dependent L-type Ca2+ channels, activation of K+ channels (BK, KATP), and modulation of the NO/cGMP and cAMP/PKA pathways. Flavones and multiple flavonols consistently demonstrate spasmolytic activity via Ca2+ channel antagonism. In contrast, flavanones engage BK and KATP channels to induce membrane hyperpolarization. Complex extracts from plants like ginger and turmeric exhibit mixed pro- or antimotility effects, reflecting the diverse profiles of their constituent compounds. While robust ex vivo pharmacology and some in vivo and human data exist, a high degree of dataset heterogeneity and inconsistent reporting impedes direct translational efforts. Conclusions: Polyphenols are promising, multi-mechanistic modulators of gastrointestinal motility with clear structure-activity patterns. To advance their clinical application, future research must focus on establishing standardized in vivo pharmacokinetics, conducting targeted structure-activity studies, employing bioassay-guided fractionation, and designing rigorous clinical trials.