With the shifting global disease spectrum, atherosclerosis (AS) has emerged as a leading contributor to mortality worldwide, with associated cardiovascular diseases (CVDs) representing the predominant cause of death. AS, a chronic inflammatory pathology, is mechanistically linked to oxidative stress and gut microbiota dysbiosis, which drive excessive reactive oxygen species (ROS) production and elevated levels of pro-inflammatory cytokines. Dietary polyphenols, particularly anthocyanins, are well-characterized for their dual role in modulating gut microbial communities and ameliorating chronic inflammatory conditions. Cyanidin-3-glucoside (C3G), a water-soluble flavonoid abundant in pigmented fruits and vegetables, exhibits potent antioxidant, anti-inflammatory, and anti-hypertensive bioactivities. More importantly, C3G engages in bidirectional interactions with the gut microbiota. It alters microbial composition and undergoes bacterial enzymatic metabolism to generate phenolic derivatives, including protocatechuic acid (PCA), which demonstrate enhanced systemic bioavailability and bioactivity. These metabolites improve endothelial function by augmenting nitric oxide (NO) bioavailability through endothelial nitric oxide synthase (eNOS) activation and regulating lipid homeostasis through ATP-binding cassette transporter G1 (ABCG1)-mediated pathways. Therefore, this review describes the dual mechanistic role of C3G as a phenolic bioactive compound and a prebiotic modulator, highlighting its therapeutic potential in chronic disease prevention through microbiota-dependent and -independent pathways. These insights underscore the need for advanced mechanistic studies to identify specific bacterial taxa involved in C3G biotransformation and to optimize targeted delivery systems to maximize their therapeutic efficacy.

Background: Numerous metabolic illnesses have obesity as a risk factor. The composition of the gut microbiota and endogenous metabolism are important factors in the onset and progression of obesity. Recent research indicates that cordycepin (CRD), derived from fungi, exhibits anti-inflammatory and antioxidant properties, showing potential in combating obesity. However, further investigation is required to delineate its precise impacts on endogenous metabolism and gut microbiota. Methods: In this work, male C57BL/6J mice were used as models of obesity caused by a high-fat diet (HFD) and given CRD. Mice’s colon, liver, and adipose tissues were stained with H&E. Serum metabolome analysis and 16S rRNA sequencing elucidated the effects of CRD on HFD-induced obese mice and identified potential mediators for its anti-obesity effects. Results: CRD intervention alleviated HFD-induced intestinal inflammation, improved blood glucose levels, and reduced fat accumulation. Furthermore, CRD supplementation demonstrated the ability to modulate endogenous metabolic disorders by regulating the levels of key metabolites, including DL-2-aminooctanoic acid, inositol, and 6-deoxyfagomine. CRD influenced the abundance of important microbiota such as Parasutterella, Alloprevotella, Prevotellaceae_NK3B31_group, Alistipes, unclassified_Clostridia_vadinBB60_group, and unclassified_Muribaculaceae, ultimately leading to the modulation of endogenous metabolism and the amelioration of gut microbiota disorders. Conclusions: According to our research, CRD therapies show promise in regulating fat accumulation and stabilizing blood glucose levels. Furthermore, through the modulation of gut microbiota composition and key metabolites, CRD interventions have the dual capacity to prevent and ameliorate obesity.