Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Indirect pharmacology of phytopolyphenols: The role of intermediate substances in cross-organ regulation and phenotypic outcomes.
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Linh Tran Chi, Duc Chong Kim Thien
Аннотация
BACKGROUND: Dietary polyphenols exhibit diverse biological activities, yet many parent compounds rarely reach peripheral target organs at pharmacologically relevant concentrations following oral intake. This discrepancy highlights the need to understand how these compounds exert systemic efficacy.
PURPOSE: This review aims to critically evaluate the concept of "indirect pharmacology" in the context of dietary polyphenols, referring to mechanisms in which biological effects are mediated predominantly through gut microbiota-dependent biotransformation and intermediary signaling molecules rather than direct systemic exposure of the intact parent compounds at pharmacologically relevant concentrations.
STUDY DESIGN: A comprehensive narrative review and conceptual synthesis of current evidence regarding polyphenol-microbiota interactions and their interorgan signaling pathways.
METHODS: The study evaluates key mechanisms, including microbial biotransformation, the modulation of the intestinal barrier, and the multi-layered signaling network of shared mediators across major cross-organ axes. Evidence from in vitro systems, animal models, metabolomic analyses, and available human intervention studies was comparatively evaluated to assess the mechanistic and translational strength of current evidence.
RESULTS: Current evidence suggests that unabsorbed polyphenols undergo extensive microbial biotransformation to generate bioactive mediators, including short-chain fatty acids (SCFAs), secondary bile acids, and specific phenolic derivatives. Together with the modulation of the microbial architecture itself, these mediators reinforce the gut barrier to reduce endotoxemia. By entering the systemic circulation, these metabolites may influence host receptor signaling and interorgan communication across the gut-liver, gut-adipose, and gut-brain axes, thereby contributing to the regulation of systemic inflammation and glucose-lipid metabolism. However, in many cases, causal validation remains incomplete, and the relative contribution of direct versus microbiota-mediated mechanisms is still unresolved.
CONCLUSION: The physiological efficacy of dietary polyphenols is heavily driven by a multi-target, microbiota-mediated regulatory network. Although the indirect pharmacological framework provides an integrative perspective for understanding microbiota-mediated polyphenol activity, substantial translational challenges remain, including interindividual microbiome variability, limited causal validation, and insufficient long-term clinical evidence.
PURPOSE: This review aims to critically evaluate the concept of "indirect pharmacology" in the context of dietary polyphenols, referring to mechanisms in which biological effects are mediated predominantly through gut microbiota-dependent biotransformation and intermediary signaling molecules rather than direct systemic exposure of the intact parent compounds at pharmacologically relevant concentrations.
STUDY DESIGN: A comprehensive narrative review and conceptual synthesis of current evidence regarding polyphenol-microbiota interactions and their interorgan signaling pathways.
METHODS: The study evaluates key mechanisms, including microbial biotransformation, the modulation of the intestinal barrier, and the multi-layered signaling network of shared mediators across major cross-organ axes. Evidence from in vitro systems, animal models, metabolomic analyses, and available human intervention studies was comparatively evaluated to assess the mechanistic and translational strength of current evidence.
RESULTS: Current evidence suggests that unabsorbed polyphenols undergo extensive microbial biotransformation to generate bioactive mediators, including short-chain fatty acids (SCFAs), secondary bile acids, and specific phenolic derivatives. Together with the modulation of the microbial architecture itself, these mediators reinforce the gut barrier to reduce endotoxemia. By entering the systemic circulation, these metabolites may influence host receptor signaling and interorgan communication across the gut-liver, gut-adipose, and gut-brain axes, thereby contributing to the regulation of systemic inflammation and glucose-lipid metabolism. However, in many cases, causal validation remains incomplete, and the relative contribution of direct versus microbiota-mediated mechanisms is still unresolved.
CONCLUSION: The physiological efficacy of dietary polyphenols is heavily driven by a multi-target, microbiota-mediated regulatory network. Although the indirect pharmacological framework provides an integrative perspective for understanding microbiota-mediated polyphenol activity, substantial translational challenges remain, including interindividual microbiome variability, limited causal validation, and insufficient long-term clinical evidence.