Atherosclerosis is the underlying disease process for the emergence and progression of atherosclerotic cardiovascular diseases (ASCVD). Despite significant advancements in preventing and treating cardiovascular disease, the mortality rate from ASCVD continues to rise in China, with stroke and ischemic heart disease being the primary causes of death in the country (Zhou et al., 2019). ASCVD is responsible for approximately two-thirds of arteriosclerosis-related deaths worldwide (Stone et al., 2022). Findings from the 2019 global burden of disease (GBD) study, which analyzed data from 204 countries spanning from 1990 to 2019, revealed a significant rise in the prevalence and mortality rate of cardiovascular disease (Roth et al., 2020).

Recent studies show that the composition of gut microbiota plays a crucial role in affecting cardiovascular health (Verhaar et al., 2020). Disruptions in the balance of the intestinal microbiome have been linked to various metabolic disorders such as diabetes, obesity, dyslipidemia, and depression. In addition, these imbalances may also contribute to the development of ASCVD and its related complications (Witkowski et al., 2020; Fan and Pedersen, 2021).

Genome sequencing of fecal microbiota reveals that variations in the gut metagenome may be linked to symptomatic atherosclerosis in individuals with unstable plaque. This finding suggests that the presence of specific microbial communities and metabolites in the gut may play a role in exacerbating inflammation, leading to atherosclerosis progression and potentially increasing the risk of cardiovascular events in certain individuals (Karlsson et al., 2012). The expression and regulation of intestinal microorganisms and their metabolites are influenced by various environmental factors and pathophysiological conditions. Therefore, gaining a deeper insight into the involvement of gut bacteria and its metabolites in the prolonged progression of atherosclerosis could offer innovative therapeutic tactics to enhance the outcomes of individuals with ASCVD.

Recent research has focused on investigating drug interventions to regulate gut microbiota and metabolites for treating ASCVD. Due to their fewer adverse effects, lower cost (Yang et al., 2023), and broad structural diversity and biodiversity (Cheng et al., 2022), natural compounds are considered a promising source of leading compounds with cardiovascular protective bioactivity. Therefore, natural compounds have shown promise in the treatment of ASCVD and metabolic diseases (Zhao et al., 2021).

China is recognized as the primary region for the growth of Rhodiola, boasting 73 species, two subspecies, and seven varieties. Approximately 90% of Rhodiola within China is concentrated in the northwest, southwest, and northeast regions (Zhuang et al., 2019). As early as 200 A.D., Rhodiola was documented as a medicinal botanical drug in both Tibetan and Chinese medical texts for treating cardiovascular diseases (Zhao et al., 2021). Salidroside is a phenol glycoside found in Rhodiola (Jin et al., 2022), which could be found in all Rhodiola species with concentrations ranging from 1.3 to 11.1 mg/g (Han et al., 2022). It can be prepared commercially, such as the Koenigs-Knorr method and enzymatic catalysis method (Zhang et al., 2021). Salidroside is known for its diverse range of benefits in the body, including boosting immunity, reducing inflammation, protecting against hypoxia, lowering blood sugar levels and preventing plateau reaction (Liu et al., 2023). However, its exact mechanism of action is still not completely understood. This review detailed how salidroside effectively addresses atherosclerosis by honing in on the gut microbiota. The potential impact of gut microbiota on the diverse health benefits associated with salidroside is also emphasized.

Atherosclerosis, a chronic inflammatory condition, is linked to dysfunction in endothelial cells, infiltration of lipids, recruitment of macrophages, and vascular smooth muscle cell migration (Zhang et al., 2021). Current studies have underscored the significance of gut microbiota along with its metabolites in the advancement of atherosclerosis, proposing fresh avenues for research and promising treatment strategies (Sanchez-Rodriguez et al., 2020; Vourakis et al., 2021). Salidroside, with significant biological activity demonstrated in various in vitro and in study (Zhang et al., 2021), emerges as a promising approach to decrease the risk of atherosclerosis-related diseases (Song et al., 2021). Salidroside is capable of improving the function of endothelial cells, inhibiting the proliferation of vascular smooth muscle cells, reducing lipid peroxidation, and preventing thrombus formation. It also has a positive impact on the integrity of the intestinal barrier and the composition of gut microbiota (Fei et al., 2023).

Numerous animal studies have demonstrated the potential of salidroside as a valuable therapeutic agent for ASCVD. Animal studies (Bai et al., 2019) demonstrated that salidroside could reduce atherosclerosis lesion formation, improve endothelial function and ameliorate inflammation. Six-week-old male ApoE^−/− mice were given a high-fat diet (HFD) for 8 weeks and treated with salidroside (25 and 50 mg/kg/d) at different doses for an additional 8 weeks (Xing et al., 2015). The atherosclerotic lesions, macrophage infiltration determined by CD68 immunostaining, MCP-1 and VCAM-1 expression were reduced in the salidroside (50 mg/kg/d) mice group compared with the HFD group. Salidroside, administered at a dose of 100 mg/kg/day, significantly reduced the development of atherosclerotic lesions and endothelial damage in mice with chronic intermittent hypoxia ApoE^−/− mice (Li et al., 2021). Salidroside has demonstrated its efficacy in enhancing lipid metabolism by lowering levels of fatty acids, cholesterol, and triacylglycerols in both the serum and liver of ApoE^−/− mice (Song et al., 2021). Salidroside has shown promise in slowing the advancement of atherosclerosis, but additional research is required to better understand its underlying molecular mechanisms, particularly in relation to the gut microbiota.

Studying the various pharmacological effects of salidroside on atherosclerotic diseases through the perspective of intestinal microbiota is a hopeful area of investigation. The intestinal microbiome and liver are key sites for the metabolism of salidroside (Guo et al., 2014). Most salidroside is converted to glucuronic acid, sulfate derivatives, and aglycones and transported through the blood to target tissues (Luo et al., 2016). The bioavailability of salidroside is 32.1%–98% in rat plasma after intravenous and oral administration (Yu et al., 2008; Wen et al., 2020). The bioavailability of salidroside studied in an in vitro gastrointestinal digestion model was 98.7% and the bioavailability of salidroside studied in a Caco-2 cell model ranged from 2.10% to 2.68% (Zhou et al., 2018). The absolute bioavailability of salidroside varies from 32.1% to 98% in rodents. For instance, the absolute bioavailability value of Sal is evaluated as 98.0% at doses of 25 mg/kg (po.) and 5 mg/kg (i.v) administration, while 51.97% at doses of 100 mg/kg (ig.) and 50 mg/kg (i.v) administration (Fan et al., 2020). Salidroside undergoes a low level of biotransformation in the intestinal wall (Luo et al., 2016), but it is efficiently converted by the intestinal microbiome and liver (Luo et al., 2016).

Research has shown that in rats following intragastric gavage, salidroside may undergo various metabolic reactions (Li et al., 2018). These reactions occur in two stages: Phase I and Phase II. Phase I metabolism involves various pathways such as hydrolysis, hydroxylation, deglycosylation, methylation, oxidation, and dehydrogenation. The phase I compounds M2, M6, and M7 of salidroside are biologically active, while another four phase II compounds of salidroside, M1, M3, M4, and M5, have no biological activity (Han et al., 2016). According to the results of a study, it was found that the main metabolic pathways of salidroside are glucuronidation, sulfation, and deglycosylation. Intestinal microbiomes can convert salidroside into p-Tyrosol (Luo et al., 2016). From this, we suppose that the I metabolic pathways of salidroside occur in the gut microbiota (Fan et al., 2020) (Figure 1).

Atherosclerosis, a condition characterized by the buildup of plaque in the arteries, is closely linked to various risk factors such as hypertension, abnormal cholesterol levels, smoking, diabetes, and obesity. Recent study has been established that intestinal microbiome dysbiosis is an important factor in the development of atherosclerosis (Verhaar et al., 2020). Studies have shown that certain bacteria, such as Collinsella, lactobacilli, Escherichia-Shigella, and Enterococcus, are more prevalent in patients with coronary heart disease (CHD). On the other hand, beneficial bacteria like Roseburia, Eubacterium spp., Bacteroides, and butyrate-producing bacteria such as Faecalibacterium, Roseburia, and Eubacterium rectalae are found in lower levels in individuals with atherosclerosis. This suggests that the composition of gut microbiota plays a crucial role in the development and progression of atherosclerosis (Iatcu et al., 2021). Veillonella, Haemophilus and Klebsiella had a higher abundance in coronary artery disease (CAD) patients, which could induce endotoxemia and systemic inflammation (Liu et al., 2019).

In patients with acute myocardial infarction (AMI), the presence of Parabacteroides merdae was found to be more prominent. A. muciniphila, E. hallii, and Roseburia hominis were decreased in AMI (Liu et al., 2022). The levels of Firmicutes were lower in AMI patients compared to healthy controls, while Bacteroidetes showed a slight increase (Han et al., 2021). HFD-fed mice showed dramatic enrichment in Desulfovibrio, Lachnospiraceae_NK4A136_group, which were positively correlated with reactive oxygen species (ROS) (Wang et al., 2020). Additionally, the metabolic syndrome (MetS) mice model showed an increase in vascular inflammation and cardiovascular disease, which was linked to a lower ratio of Firmicutes/Bacteroidetes (Rovella et al., 2021). Compared to healthy controls, the gut microbiota of hypertensive patients showed the reduced abundance of Lactobacilli and increased the abundance of Prevotella and Klebsiella species compared with healthy controls (Al Samarraie et al., 2023). In addition, the increased abundance of Prevotellaceae and Peptococcaceae showed a correlation with stroke severity (Sorboni et al., 2022).

The inhibition of salidroside on disease-related microbiota growth shows its potential to help restore a balanced gut microbiota (Xie et al., 2020). In a research experiment utilizing a mouse model with gut microbiota disturbance induced by antibiotics, the effects of salidroside on promoting the restoration of gut microbiota richness, diversity, and community structure were examined (Sun et al., 2022). Specifically, it was noted that salidroside stimulated the proliferation of advantageous genera such as Bacteroides, Actinobacteria, Parabacteroides, Lactobacillus, and Bifidobacterium. This ability to promote the growth of beneficial bacteria, particularly Lactobacillus and Bifidobacterium, suggests that salidroside may have prebiotic functions that can offer various health benefits to the host (Sun et al., 2022). Additionally, salidroside has been shown to inhibit the growth of disease-associated genera including norank_f_Muribaculaceae, Helicobacter, and Ruminococcus_torques_group. By balancing the microbiota composition, salidroside has the potential to contribute to the maintenance of a healthy gut microbiota. Treatment with salidroside supplement for 15 days resulted in a changed gut microbiota composition, along with the regeneration of the liver in mice exposed to furan (Yuan et al., 2019). It was notable that 20 mg/kg/day salidroside administration remarkably enhanced the abundance of phyla Verrucomicrobia suppressed by LPS and reduced the abundance of phyla Proteobacteria promoted by LPS. Experiments administering salidroside (100 mg/kg/day) to mice for 4 weeks revealed that salidroside increased the relative abundance of beneficial microbes: Alistipes, Rikenellaceae, Parabacteroides, and Lactobacillus, while decreasing the relative abundance of harmful bacteria such as Candidatus Arthromitus (Zhu et al., 2023). Wang et al. sought to determine whether salidroside could mitigate the symptoms of colitis induced by dextran sulfate sodium (DSS)-induced colitis (Wang et al., 2021). Mice with colitis were orally administered salidroside at doses of 125, 250, and 500 mg/kg/day for 14 days. Salidroside treatment could reverse the microbial dysbiosis induced by DSS, leading to an increase in abundance of Turicibacter, Lactobacillus, Clostridia_UCG-014, Bifidobacterium, Bacteroides_acidifaciens, and Bacteroides_thetaiotaomicron in the salidroside-treated groups. Conversely, levels of Staphylococcus, Prevotellaceae_UCG-001, Parasutterella, and norank_f_norank_o_Clostridia_UCG-014 were decreased.

Disruption of the gut microbiota exacerbates inflammation, which is crucial in starting and advancing atherosclerosis (Sun et al., 2021). Although it is currently unclear how salidroside exerts its protective effects against atherosclerosis through modulation of gut microbiota-mediated inflammation, several studies have been conducted in other models of chronic inflammatory diseases. Inflammatory bowel disease (IBD), characterized as a state of chronic inflammation, confers a higher risk of developing ASCVD (Stone, 2020). A lot of studies discovered that IBD could be treated by salidroside through regulating the gut microbiota. Systemic inflammation in patients with IBD contributes to oxidative stress and increased levels of inflammatory cytokines, like TNF-α, that can lead to the development of atherosclerosis and cardiovascular disease (Jucan et al., 2022).

Salidroside as a small polyphenolic molecule can interfere with or degrade RNA (Birtić and Kranner, 2006), which may interfere with the result of gut microbiota. However, nowadays most studies on intestinal flora use the 16S rDNA method for detection, and the experimental results have a certain degree of reliability. The potential for salidroside to mitigate the progression of atherosclerosis through the manipulation of gut microbiota is a promising prospect. However, it is essential to conduct additional research, including human clinical trials, to substantiate the efficacy and understand the therapeutic mechanisms of salidroside in regulating gut microbiota (Figure 2).

Accumulating evidence suggests that metabolites produced by the gut microbiome, such as trimethylamine N-oxide (TMAO), lipopolysaccharide (LPS), and short-chain fatty acids (SCFAs), impact cardiovascular health (Kasahara and Rey, 2019; Anto and Blesso, 2022; Cao et al., 2023). TMAO can promote the progression of atherosclerosis through cholesterol accumulation, pro-inflammatory pathways activation, endothelial dysfunction and thrombosis (Zhen et al., 2023). LPS enhances atherosclerosis by stimulating chronic systemic inflammation (Wang et al., 2022). Meanwhile, SCFAs show anti-atherosclerosis effects, including gut immune system modulation, intestinal barrier restoration, vascular inflammation inhibition, and oxidative stress amelioration (Yao et al., 2022). Salidroside alleviates LPS-induced human umbilical vein endothelial cells (HUVECs) injury by activation of autophagy and inhibition of the NLRP3 pathway (You et al., 2021). Salidroside could increase SCFAs production, which could contribute to the repair of antibiotic-induced intestinal damage (Sun et al., 2022). According to the above, salidroside may play the role of arteriosclerosis by regulating the metabolites of the intestinal microbiome, such as TMAO, LPS, etc.

Recent evidence has been a growing body of evidence highlighting the significance of gut microbiota in the development and advancement of atherosclerosis (Kazemian et al., 2020; Li et al., 2024b; Mao et al., 2024). Oscillatory spp. has been shown to efficiently absorb cholesterol from various intestinal sources in humans and convert this cholesterol into ketones, glycosylated cholesterol, and hydroxycholesterol, which may impact lipid homeostasis and cardiovascular health (Li et al., 2024). Mendelian randomization studies in two samples suggested that complex networks may exist among gut microbes, and interactions between bacteria, viruses, and fungi jointly influence the occurrence and progression of atherosclerosis (Jiang et al., 2024). Desulfovibrioceae showed a stable and significant negative correlation with ApoB levels (Teng et al., 2024), which was associated with increased TG levels (Takeda et al., 2023). The traditional Chinese herbal prescription (Yu et al., 2024), serum sex hormones (Peters et al., 2023), and structure of the gut virome (Li et al., 2024c) play an important role in slowing down the progression of atherosclerosis by regulating altered intestinal microbiota and perturbed metabolites.

The mechanisms by which salidroside could regulate the intestinal microbiome in atherosclerosis are as follows: 1) Salidroside has been shown to have a positive impact on the gut microbiome by promoting the growth of beneficial bacteria and suppressing the growth of harmful bacteria. 2) Salidroside can reduce liver phosphatidylcholine absorption, which can suppress the production of TMAO by gut bacteria. 3) By obstructing the ROS-mediated PI3K/AKT/mTOR pathway and impeding the Notch signaling pathway, salidroside can inhibit the production of LPS. 4) Salidroside has the capability to elevate the production of SCFAs, specifically butyric acid and acetic acid. 5) By elevating the levels of ZO-1 and occludin proteins, salidroside could enhance the integrity of the intestinal barrier and enhance intestinal permeability. 6) Salidroside may reduce the activation of NLRP3 to protect the balance of intestinal microecological, further reducing systemic levels of TMAO and LPS.

Salidroside has the ability to directly reshape the gut microbiota (Shi et al., 2022) and also indirectly influence them through reducing inflammation (Liu et al., 2023), enhancing gut and mucus layer integrity (Wang et al., 2021), promoting appropriate immune responses (Yang et al., 2024), and increasing antimicrobial peptide production (Soroudi et al., 2024). However, there is currently a lack of in vitro studies investigating whether and how salidroside selectively alters bacterial function or competitiveness. In-vitro models of the human gut microbiota, such as Transwell culture models (Biagini et al., 2023), could be an effective approach to delineate the specific mechanisms through which salidroside protects against atherosclerosis by interacting with the gut microbiota and its metabolites.

In conclusion, the anti-atherosclerotic effect of salidroside can be partially attributed to its influence on intestinal microbiota and metabolites, which leads to a decrease in systemic inflammation and modulation of lipid metabolism. While research has shown that salidroside can alter the gut microbiota in animal models, a definitive connection between salidroside’s effects on gut microbiota and atherosclerosis remains unclear. Furthermore, further research is necessary to delve into the specific pathways through which salidroside protects against atherosclerosis by interacting with the gut microbiota and its metabolites. These studies will help enhance our understanding of the mechanisms underlying the beneficial effects of salidroside in preventing atherosclerosis (Table 1).