Background/Objectives: Chronic low-grade inflammation, underpinned by persistent activation of the NLRP3 inflammasome, is a central pathological mechanism in noncommunicable diseases including cardiovascular disease, type 2 diabetes, inflammatory bowel disease, and neurodegeneration. Dietary polyphenols have been consistently associated with reduced inflammatory burden; however, the mechanisms underlying these effects remain incompletely understood. This review aims to characterize the gut microbiota–polyphenol–NLRP3 inflammasome axis as a central regulatory network through which diet modulates innate immune signaling and chronic inflammatory tone. Methods: A comprehensive narrative review of the available literature was conducted, integrating evidence from mechanistic studies in cell culture and animal models, microbiome research, metabolomics, and human epidemiological and interventional data. Results: The gut microbiota emerges as a critical biochemical intermediary that transforms dietary polyphenols into bioactive metabolites, including urolithins, phenyl-γ-valerolactones, protocatechuic acid, and short-chain fatty acids, with enhanced bioavailability and potent inflammasome-modulating properties. These compounds suppress NLRP3 activation through multiple converging mechanisms, including inhibition of NF-κB-dependent priming, mitochondrial quality control via mitophagy, Nrf2 mediated antioxidant responses, and HDAC inhibition. Evidence across cardiovascular, metabolic, neurological, and respiratory disease models supports the translational relevance of this axis. Conclusions: The microbiota–polyphenol–NLRP3 axis functions as an integrated, self-regulated network in which each component simultaneously shapes and is shaped by the others: dysbiosis primes NLRP3 and depletes protective metabolites, while inflammasome hyperactivation further destabilises microbial ecology; polyphenol biotransformation by specific taxa interrupts this feed-forward loop at multiple nodes, restoring homeostasis.
The Gut Microbiota–Polyphenol–NLRP3 Inflammasome Axis: A Key Regulatory Network Linking Diet to Chronic Inflammation
Stefania D’AngeloConceptualization
;
2026-01-01
Abstract
Background/Objectives: Chronic low-grade inflammation, underpinned by persistent activation of the NLRP3 inflammasome, is a central pathological mechanism in noncommunicable diseases including cardiovascular disease, type 2 diabetes, inflammatory bowel disease, and neurodegeneration. Dietary polyphenols have been consistently associated with reduced inflammatory burden; however, the mechanisms underlying these effects remain incompletely understood. This review aims to characterize the gut microbiota–polyphenol–NLRP3 inflammasome axis as a central regulatory network through which diet modulates innate immune signaling and chronic inflammatory tone. Methods: A comprehensive narrative review of the available literature was conducted, integrating evidence from mechanistic studies in cell culture and animal models, microbiome research, metabolomics, and human epidemiological and interventional data. Results: The gut microbiota emerges as a critical biochemical intermediary that transforms dietary polyphenols into bioactive metabolites, including urolithins, phenyl-γ-valerolactones, protocatechuic acid, and short-chain fatty acids, with enhanced bioavailability and potent inflammasome-modulating properties. These compounds suppress NLRP3 activation through multiple converging mechanisms, including inhibition of NF-κB-dependent priming, mitochondrial quality control via mitophagy, Nrf2 mediated antioxidant responses, and HDAC inhibition. Evidence across cardiovascular, metabolic, neurological, and respiratory disease models supports the translational relevance of this axis. Conclusions: The microbiota–polyphenol–NLRP3 axis functions as an integrated, self-regulated network in which each component simultaneously shapes and is shaped by the others: dysbiosis primes NLRP3 and depletes protective metabolites, while inflammasome hyperactivation further destabilises microbial ecology; polyphenol biotransformation by specific taxa interrupts this feed-forward loop at multiple nodes, restoring homeostasis.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
