Cyanidin-3-glucoside: targeting atherosclerosis through gut microbiota and anti-inflammation

Abstract

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.

Keywords: C3G; anthocyanins; atherosclerosis; chronic inflammation; gut microbes; vascular endothelial cells.

Figure 1

Chemical structure of C3G. C3G has a molecular weight of 449.4 g/mol, and it consists of o-glycosylated anthocyanins with two hydroxyl groups in the third aromatic ring.

Figure 2

The digestive pathway of C3G. A small portion of C3G is metabolized by microorganisms in the oral cavity to the corresponding chalcone. The stomach then rapidly absorbs a large portion of C3G, while the remaining C3G is absorbed through passive diffusion in the small intestine and broken down by microorganisms in the colon. The metabolites of C3G also enter the liver through the enterohepatic circulation and blood circulation to form methyl- and sulfate-conjugated metabolites.

Figure 3

Pathways by which gut microbes attenuate the inflammatory response. Gut microorganisms inhibit butyric acid-mediated HDAC by synthesizing SCFAs, thereby reducing the transcriptional activity of the NF-κB pathway and decreasing the inflammatory response.

Figure 4

C3G reduces inflammation through gut flora. C3G alleviates inflammation by increasing the relative abundance of gut microbiota, which improves the intestinal environment. In conjunction with its metabolite protocatechuic acid, C3G enhances the expression of tight junction proteins in the intestinal epithelium, thereby reducing intestinal permeability and restoring the mucosal barrier, ultimately exerting therapeutic effects on the AAD mouse model.

Figure 5

The relationship between obesity and inflammation. Expanded adipose tissue stroma results in the recruitment and accumulation of activated macrophages and T-cells. In an obese state, adipose tissue produces large amounts of pro-inflammatory factors and vascular function is reduced.

Figure 6

Pathways through which C3G reduces inflammation. C3G can attenuate LPS-induced pro-inflammatory cytokine production, and empty plaque formation, by inhibiting the activation of the NF-κB pathway and p65 translocation.

Figure 7

The role of ATP-binding cassette transporter protein G1 in AS. Asprosin inhibits macrophage lipid accumulation and reduces the atherosclerotic load by up-regulating ABCA1 and ABCG1 expression through the p38/Elk-1 pathway.