Microbiota-Mediator-Host Signaling Networks in Metabolic Syndrome: From Mechanistic Insights to Therapeutic Targeting.

Metabolic syndrome (MetS) represents a growing global health burden characterized by obesity, insulin resistance, dyslipidemia, and hypertension. Increasing evidence suggests that gut microbiota-associated mediators may serve as signaling intermediates involved in host metabolic regulation. However, the mechanisms by which these mediators interact with host signaling pathways and influence metabolic responses remain incompletely understood. This review summarizes current advances in gut microbiota-associated mediators, focusing on short-chain fatty acids, bile acids, lipopolysaccharide, trimethylamine N-oxide, and branched-chain amino acids. We discuss their interactions with host metabolic and inflammatory pathways, including pathways implicated in FFAR2/3-mediated signaling, FXR/TGR5 signaling, TLR4/NF-κB-mediated inflammatory signaling, and mTORC1-associated nutrient-sensing. Furthermore, we propose a microbiota-mediator-host signaling network framework as an emerging conceptual model to integrate these molecular interactions and highlight the utility of multi-omics approaches in characterizing complex microbiota-host communication. Despite mechanistic advances, substantial challenges remain, including heterogeneous microbial signatures across populations, limited causal evidence, inter-individual variability in therapeutic responses, and barriers to clinical translation of microbiota-targeted interventions. A better understanding of microbiota-associated signaling networks may provide new insights into metabolic regulation and contribute to the rational development of microbiota-targeted strategies that complement established lifestyle interventions for MetS management.