Intestinal flora is an important influence on energy absorption and metabolism, and a decrease in intestinal flora diversity is associated with an increased relative risk of LMD (Rastelli et al., 2018). Studies have shown that the α diversity of intestinal flora in high-fat rats is significantly reduced, as demonstrated through a drop in the intestinal flora abundance and a decrease in the structural stability of intestinal flora (Zhao J. et al., 2022). This phenomenon is consistent with the findings on intestinal flora of patients with LMD (Mu et al., 2020), but the specific composition of intestinal flora in healthy and obese people is still debated (Kasai et al., 2015). The human intestinal flora is mainly composed of Firmicutes and Bacteroidetes, which account for more than 98% of intestinal flora abundance and are involved in lipid and BA metabolism to maintain energy balance in the host. Among them, Firmicutes can induce hepatic steatosis via regulating fatty acid inflow and lipogenesis (Chen Y. H. et al., 2019), while Bacteroidetes can suppress obesity by promoting the catabolism of BCAAs in brown adipose tissue (BAT) (Yoshida et al., 2021). In addition, Bacteroidetes also produce bile salt hydrolase (BSH), which hydrolyzes conjugated BAs and regulates BAs-mediated lipid metabolism (Tian et al., 2019). Therefore, Firmicutes are hypothesized to be positively correlated with LMD, and Bacteroidetes are negatively correlated with LMD. A lower Firmicutes/Bacteroidetes (F/B) ratio represents a healthier gut microbial environment, and the risk of obesity and LMD may be increased by an elevated F/B ratio (Magne et al., 2020). Firmicutes were increased in the intestinal tract of obese individuals compared to healthy individuals, and F/B ratio decreased with an increase in Bacteroidetes and a decrease in Firmicutes following weight loss treatment (Damms-Machado et al., 2015). Akkermansia is a mucus-degrading bacteria that reverses HFD-induced increase in adiposity, metabolic endotoxemia, and adipose tissue inflammation (Everard et al., 2013). Bifidobacterium also promotes changes in lipid metabolism and glucose homeostasis (Salazar et al., 2019). Long-term HFD-induced changes in the structure of intestinal flora in animal models, mainly in the form of a significant reduction in the content of beneficial bacteria like Akkermansia, Bifidobacterium, Lactobacillus, Blautia, and Faecalibaculum, which have the ability to alleviate LMD (Shin et al., 2014; Wang B. et al., 2020). In another study, a substantial growth in the abundance of Bacteroides and Parabacteroides was found in hyperlipidemic rats (Zhao J. et al., 2022). Bacteroides and Parabacteroides contain a large number of conditionally pathogenic bacteria that can increase the risk of infection. They can also produce acetic acid, which promotes appetite and increases food intake by activating the parasympathetic nervous system and promoting the release of insulin and ghrelin, leading to elevated TG levels, liver and muscle fat accumulation and the development of obesity-related metabolic diseases (Perry et al., 2016). LMD influenced by changes in the intestinal flora have been found extensively in animals and are also largely reflected in humans (Maruvada et al., 2017). Therefore, the management of LMD focused on the modulation of intestinal flora structure is crucial.

A normal intestinal mucosal barrier is fundamental for maintaining intestinal function. One study indicates that the pathophysiological root of LMD is a compromised intestinal barrier (Schulz et al., 2014). Damage to the tight junction proteins between intestinal epithelial cells, such as ZO-1, Occludin and Claudin1, which are essential for the intestinal mucosal barrier, leads to a rise in intercellular permeability and the admission of bacteria, endotoxins, as well as macromolecules into other tissues, organs or body circulation via the cellular bypass pathway, resulting in metabolic endotoxemia, inflammation and metabolic disorders (Zheng et al., 2022). LPS is the central aspect of Gram-negative (G-) bacteria’s outermost layer of cell wall, and is an important inflammatory stimulus that can cause severe damage to the intestinal barrier and contribute to a chronic inflammatory response in the body, leading to the development and progression of metabolic diseases (Zhang-Sun et al., 2015). It has been found that a HFD disrupts the structure of intestinal flora and increases the abundance of LPS-producing bacteria, such as Desulfovibrio, which further enhances intestinal permeability and contributes to large amounts of LPS to enter the circulation from the intestine, triggering metabolic endotoxemia (Cani et al., 2007a), which is linked to the development of LMDs including dyslipidemia, obesity, NAFLD and cardiovascular disease (Manco et al., 2010). LPS can exacerbate lipid metabolism by binding to Toll-like receptor 4 (TLR4), a receptor expressed on macrophages, hepatocytes and adipocytes, and inducing the secretion of pro-inflammatory factors like interleukin 6 (IL-6) and monocyte chemotactic protein 1 (MCP-1). Secretion, exacerbating lipid metabolic disorders (Robbins et al., 2014). Furthermore, LPS increases intestinal permeability through chronic inflammation mediated by MAPK or NF-κB pathways (Zhou et al., 2018), triggering circulating metabolic endotoxemia and leading to lipid dysfunction (Sultana et al., 2016). Myeloid differentiation factor 88 (MyD88), a central adapter molecule for most TLRs, regulates fat storage and inflammatory responses (Everard et al., 2014), influences the activity of transcription factors related to lipid metabolism and BA profiles, and is involved in regulating the body’s inflammatory response and lipid metabolism (Duparc et al., 2017). Additionally, LPS forms a triple complex with CD14 and LPS-binding protein (LBP), which activates the MyD88/NF-B pathway and increases the production of numerous inflammatory proteins. Moreover, cluster of differentiation 36 (CD36) is an important lipid absorption regulator in the intestine, and its expression is mediated by derivatives of Desulfovibrio and Clostridium. Loss of CD36 may lead to excessive lipid accumulation and activation of inflammatory factors, triggering the risk of LMD (Plociennikowska et al., 2015; Petersen et al., 2019). Thus, chronic low-level inflammation in the organism may be a key link in the pathogenesis of LMD, and disorders of intestinal flora may also contribute to chronic inflammation.

SCFAs are metabolites derived from the fermentation of undigested carbohydrates or proteins by intestinal flora and include butyrate and acetate, propionate. Among them, butyrate is primarily performed by Firmicutes, while acetate and propionate are mostly generated by bacteria belonging to Bacteroidetes (Walker et al., 2005), and they can play a crucial part in controlling host appetite, lipid metabolism, inflammatory response, and maintenance of energy balance through various pathways (Sanchez et al., 2020). SCFAs, represented by butyric acid and propionic acid, not only stimulate the release of leptin from adipose tissue, suppressing hunger and reducing host feeding activity (Naraoka et al., 2018), but also inhibit hepatic FAS activity and reduce serum lipid (TG and TC) levels (Larkin et al., 2009). As key regulators of host lipid metabolism, about 95% of SCFAs are absorbed in the intestine or utilized by intestinal flora, acting as important regulators of host lipid metabolism. These molecules not only providing the host energy, but also acting as signal transduction molecules to initiate G protein-coupled receptors 43 and 41 (GPR43 and GPR41) in intestinal epithelial cells. Activated GPR43 and GPR41 promote the secretion of peptide tyrosine-tyrosine (PYY) and glucagon-like peptide-1 (GLP-1) from enteroendocrine L cells, which reduce appetite, increase energy release and inhibit adipocyte synthesis through the “brain-gut axis” (Eslick et al., 2022). SCFAs also promote beige lipogenesis, leading to enhanced fat oxidation and energy expenditure, a process associated with the activation of GPR43 or GPR41 (Lu et al., 2016). And butyric acid also improves serum lipid metabolism by increasing fatty acid oxidation in brown adipose tissue (BAT) through thermogenesis, significantly reducing serum TG levels (Li Z. et al., 2018). In addition, SCFAs may also be involved in lipid metabolism by regulating related pathways and gene expression. For example, butyric acid downregulates the expression of proliferator-activated receptor γ (PPARγ), upregulates the expression of uncoupling protein 2 (UCP2), promotes mitochondrial proton efflux, which in turn activates the AMPK pathway, decreases lipid synthesis, and increases lipid oxidation. Acetic acid decreases SREBP-1 expression and ATP citrate lyase (ATP-CL) mRNA levels, decreases acetyl coenzyme A supply, and contributes to a decrease in cholesterol and fatty acid synthesis; it also enhances acyl-CoA oxidase (AOX) gene expression, promotes fatty acid β-oxidation, and increases energy expenditure (Fushimi et al., 2006). While another study speculated that acetate regulation of lipid metabolism may be associated with an increase in the AMPK/PGC-1α/PPARα axis (Araujo et al., 2020). Additionally, SCFAs can regulate the intestinal barrier and inflammatory levels and are indirectly implicated in lipid metabolism regulation. According to studies, SCFAs can elevate intestinal trans-epithelial resistance and reduce LPS production, thereby upregulating tight junction protein expression and mucin secretion, reducing intestinal mucosal permeability and alleviating intestinal barrier disorders (Zhao et al., 2018). Meanwhile, SCFAs inhibit the expression of TNF-α/NF-κB inflammation-related genes, reduce the secretion of pro-inflammatory molecules like IL-6 and IL-12, as well as increase the secretion of anti-inflammatory molecules like IL-10 and IL-4, alleviating chronic inflammatory response and avoiding the formation of hyperlipidemia (Chang et al., 2014; Yuan et al., 2019).

The synthesis of BAs is the main pathway of cholesterol degradation and metabolism in humans, which is regulated by intestinal flora. The majority of primary BAs are converted from cholesterol by the enzymatic action of three cholesterol hydroxylases, CYP7A1, CYP8B1 and CYP27A1 in the liver (classical pathway), and a small proportion is processed by CYP27A1 and CYP7B1 in extrahepatic sites (alternative pathway). Primary BAs, which including cholic acid (CA) and chenodeoxycholic acid (CDCA), can bind to glycine or taurine to form conjugated BAs like glycocholic acid (GCA), glycochenodeoxycholic acid (GCDCA), taurocholic acid (TCA) and taurochenodeoxycholic acid (TCDCA). The bile salt export pump (BSEP) or ATP-binding cassette subfamily G member 5 (ABCG5)/ABCG8 subsequently actively transfers these conjugated BAs into the bile, where they contribute to lipid emulsification when the food enters the intestine (Jia et al., 2018). The apical sodium-dependent bile acid transporter (ASBT) reabsorbs around 95% of BAs from the intestine; The apical sodium-dependent bile acid transporter (ASBT) reabsorbs around 95% of BAs from the intestine; these are subsequently released into the portal circulation by the organic solute transporter α/β (OST α/β), which finally transports them back to the liver (Vourakis et al., 2021). Intestinal flora can reduce cholesterol levels by producing BSH and CYP7A1, which decouple conjugated BAs into unconjugated BAs including deoxycholic acid (DCA) and lithocholic acid (LCA), preventing their reabsorption through ASBT and promoting BAs excretion through the feces (Wahlström et al., 2016). It is known that BSH-producing bacteria include Bacteroides, Bifidobacterium, Clostridium, Eubacterium and Lactobacillus, while Clostridium and Eubacterium also possess 7α-dehydroxylation activity (Vourakis et al., 2021). BAs can also act as signaling molecules, such as conjugated BA T-βMCA, unconjugated BAs CDCA and LCA, which regulate lipid metabolism by interacting to the BA receptors like FXR and Takeda G protein-coupled receptor 5 (TGR5) to regulate BA self-synthesis, transport, as well as lipid digestion and absorption (Schoeler and Caesar, 2019). In summary, BAs play an important part in lipid metabolism homeostasis. Increasing intestinal BA production can block the reverse cycle from BA to cholesterol; it can also accelerate the transformation of cholesterol to BA, lowering serum TC levels. It is worth noting that the synthesis and excretion of BAs are related to the regulation of intestinal flora.

Trimethylamine oxide (TMAO) is an intestinal flora-dependent metabolite formed by the oxidation of trimethylamine (TMA) in the liver by flavin-containing monooxygenase (FMO), especially FMO3 (Chen Y. et al., 2019). Studies have shown that serum TMAO levels are determined by genetics, diet and intestinal flora, and may be a biomarker of AS (Randrianarisoa et al., 2016; Canyelles et al., 2018). Another observational study found that TMAO levels were positively and significantly related with body mass index (BMI), fatty liver index and visceral obesity index, and could be used as a predictor of NAFLD and metabolic syndrome (Barrea et al., 2018). Additionally, 8 consecutive weeks of supplementation with a high TMAO diet may lead to elevated the levels of plasma TC, TG and LDL-C and induce hyperlipidemia (Koeth et al., 2013). Knockdown of FMO3 may downregulate circulating TMAO levels and acts as a preventive measure against hyperlipidemia (Miao et al., 2015). As a result, intestinal flora metabolite TMAO is essential for lipid metabolism. The underlying mechanism of TMAO-induced disruption of lipid metabolism is unknown; however, it may be associated with host cholesterol and BA metabolism. It has been investigated that TMAO reduces the expression of CYP7A1 and CYP27A1, two key enzymes necessary for the synthesis of BAs, and various BA transport proteins, decreases BA biosynthesis, inhibits the reverse cholesterol transport (RCT) pathway, and affects BA metabolism and cholesterol homeostasis in the hepatic-intestinal tract (Koeth et al., 2019). In turn, BAs can also lead to an increase in serum TMAO by mediating the upregulation of FMO3 expression by FXR (Bennett et al., 2013). Moreover, TMAO is able to induce CD36 and scavenger receptor A1 (SR-A1), which are involved in stimulating macrophages to bind ox-LDL, promoting macrophage foaminess and causing intracellular cholesterol accumulation (Wang et al., 2011). This process may also be mediated through MAPK and NF-κB signaling pathways that promote vascular inflammation, one of the earliest cellular signals in the atherosclerotic process (Ma et al., 2017; Geng et al., 2018).

Obesity, NAFLD and AS are frequently associated with LMD. Therefore, for the efficient implementation of atherosclerotic cardiovascular disease (ASCVD) preventive and treatment methods, early diagnosis of dyslipidemia and monitoring changes in its levels are key foundations.

Routine lipid testing to identify the “hidden” high-risk groups will not only facilitate better treatment decisions, but more importantly, it will provide early intervention for these high-risk individuals or patients with LMD, so that they can have more cardiovascular benefit. The basic items of clinical lipid monitoring are TC, TG, LDL-C and HDL-C. It is noteworthy that LDL-C is an important causative factor of ASCVD and has an important significance in lipid monitoring. More and more clinical laboratories are using ApoAⅠ, ApoB, and Lp(a) as routine lipid testing items. In addition, the clinical testing items of oxLDL, FFA and non-HDL-C are also receiving increasing attention. In recent years, assays for intestinal flora and its metabolites have also been increasingly used to assist in monitoring lipid levels. Usually healthy people have low F/B ratio, while patients with LMD tend to have high F/B ratio (Human Microbiome Project, 2012). The main core of LMD such as hyperlipidemia is chronic low-level inflammation in the body, which is also caused by intestinal flora, often manifested as elevated serum LPS levels (Dai and Fu, 2019). SCFA is inversely correlated with lipid levels and can reduce serum TG and TC levels by inhibiting FAS activity (Larkin et al., 2009). BA is produced by cholesterol conversion, and its increased synthesis and impaired transport frequently lead to the development of LMD (Haeusler et al., 2016). Serum TMAO levels predict the risk of cardiovascular disease and are closely related to the regulation of cholesterol (Chen et al., 2019). Therefore, the detection of intestinal flora and its metabolites can also be used as a reference item for clinical lipid monitoring, but it still needs to be combined with the items of lipid testing for comprehensive assessment, so it is not yet popular in the clinic.

Currently, the guidelines recommend three main classes of lipid-lowering drugs (Du, 2022): 1) Statins, which reduce cholesterol synthesis in hepatocytes mainly through competitive inhibition of endogenous cholesterol synthesis rate-limiting enzymes, leading to a significant decrease in blood cholesterol levels, and are the cornerstone of primary prevention of ASCVD. 2) Ezetimibe, which reduces cholesterol by inhibiting the absorption of cholesterol in the intestinal tract. 3) Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, which lower cholesterol levels by inhibiting the binding of PCSK9 to LDL receptors and preventing LDL receptor degradation, are the most potent cholesterol-lowering drugs available and have a good safety profile, offering another option for high-risk patients who are statin intolerant (Koren et al., 2019). The intestinal flora and its metabolites serve as a key link in lipid metabolism, and the therapeutic effect of lipid-lowering drugs may be related to the regulation of intestinal flora. Statins were found to modulate the abundance of SCFA, SBA, TMAO and LPS-producing intestinal flora, which in turn affected AMPK-SREBP, FXR, PXR, FFAR2 and TLR4-Myd88 signaling pathways, acting to regulate cholesterol metabolism and LDL-C levels (Sun et al., 2022). In addition, different statins, such as atorvastatin, simvastatin and resevastatin, have different effects on different intestinal flora. Desulfurization was negatively correlated with TG and HDL-C levels, and desulfurization was significantly reduced after ezetimibe intervention (Jin et al., 2022). Desulfovibrio was considerably decreased following ezetimibe treatment and had a negative correlation with TG and HDL-C levels (Jin et al., 2022). PCSK9 inhibitors can promote the clearance of LDL-C and LPS from the blood, regulate intestinal microecology, alleviate intestinal inflammation and endotoxemia, and reduce the risk of cardiovascular disease (Morelli et al., 2019). Furthermore, probiotic supplementation alone was able to significantly reduce plaque area in the full-length aorta and aortic sinus, lower plasma TMAO and cecum TMA levels, improve lipid disorders, reduce serum oxLDL and inflammatory factor levels in mice, increase cecum acetate and butyric acid levels, and reduce inflammatory responses in the aorta and liver of mice by inhibiting the levels of key proteins in the TLR4/MyD88/NF-kB/NLRP3 pathway (Wang, 2022). In contrast, mice on diets supplemented with choline or TMAO showed increased cholesterol levels in peritoneal macrophages, elevated TMAO plasma levels, and enhanced aortic atherosclerotic plaques (Wang et al., 2011). Thus, intestinal flora and its metabolites also play an important role in the treatment of LMD, but further studies are needed to validate this in order to maximize the clinical benefits of drugs.

TCM treatment encourages the development of beneficial intestinal bacteria by increasing the diversity of intestinal flora, while inhibiting the growth of harmful bacteria (Ding K. et al., 2019; Ling et al., 2022). It was found that intervention with Zexie Tang (ZXT) (Xu et al., 2017), Shenlingbaizhu Powder (SLBZ) (Hong, 2021), Ganoderma lucidum polysaccharide (GLP) (Sang et al., 2021), G. lucidum polysaccharide and chitosan (PC) (Tong et al., 2020), Pueraria lobata starch (PLS) (Yang Y. et al., 2022), Luteolin (Liu, 2022), Naringin (Wang F. et al., 2020), Inulin (Bao, 2021; Cui et al., 2022), Epigallocatechin gallate (EGCG) (Zuo, 2020), RSV (Chen et al., 2016) greatly enriched the abundance of Bifidobacterium in the intestinal tract; Modified Xiongdan yinchen granules (MXYG) (Wu et al., 2021), Tian Huang Formula (THF) (Pang, 2021), Tea seed saponins (Lin et al., 2020), Kaempferol (Wang T. et al., 2020), Green Brick Tea (Zhou T. T. et al., 2021) were able to upregulate the relative abundance of Lactobacillus; the intervention of Yunpi Huazhuo granules (YPHZ) (Kou et al., 2022), Qinggan Qushi Huoxie prescription (QGQSHX) (Zhang X. Y. et al., 2022), Jiangzhi Ligan Decoction (JZLG) (Tang et al., 2016), Modfied Yinchen Wuling San (MYCWL) (Xu et al., 2019), Purple yam (Dioscorea alata L.) resistant starch (PYRS) (Li T. et al., 2019) and PLS (Yang Y. et al., 2022) also increased the abundance of intestinal Bifidobacterium and Lactobacillus, resulting in an increase in the proportion of beneficial bacteria and a corresponding increase in its metabolites, such as acetate and lactate, thus lowering the PH in the intestine and greatly inhibiting the development of harmful bacteria such as Parabacteroides, Desulfovibrio, Escherichiacoli, Enterococcus and Helicobacter. Interestingly, we also found that Alistipes had a negatively relationship with serum lipid profile, while PC (Tong et al., 2020) and Porphyran (Wang X. et al., 2022) were able to reduce lipid levels by upregulating the abundance of Alistipes. Blautia was negatively correlated with visceral fat area, and the number of Blautia was noticeably increased by Ilex pubescens triterpenoid saponins (IPTS) (Ba et al., 2021) treatment. Akkermansia was negatively correlated with inflammation levels, while Alisma orientale extract (Li L. S. et al., 2019), Jaboticaba peel and seed powder (JPSP) (Soares et al., 2021) were able to elevate the relative abundance of Akkermansia and reduce inflammation levels and lipid accumulation. Faecalibaculum, a SCFAs-producing bacteria, while Burdock inulin (Wang, 2020) and Yinchenhao Decoction (Li Z. H. et al., 2019) can upregulate the relative abundance of Faecalibaculum to promote the production of SCFAs and alleviate inflammation to improve lipid metabolism. In contrast, the opposite result was observed after Caffeic acid (Mu et al., 2021) treatment, which showed a decrease in the abundance of Faecalibaculum. This suggests that it may be the role of multiple intestinal flora in regulating lipid metabolism and inflammation levels, and that Faecalibaculum may not be a core flora.

In addition, the effectiveness of TCM in reversing the elevated F/B ratio in animals with a HFD has been experimentally confirmed. It was found that some natural medicine extracts, proprietary Chinese medicines and Chinese herbal formulas reduce F/B ratio by decreasing Firmicutes abundance and increasing Bacteroidetes abundance, such as Guizhi Tang (GZT) (Yuan et al., 2021), Naoxintong Capsule (NXT) (Lu et al., 2022), Huanglian Jiedu Decoction (HLJD) (Jiang et al., 2021), Quyu Huatan Tongmai Prescription (QYHTTM) (Miao et al., 2022), Danggui Shaoyao San (DGSY) (Yu et al., 2021), Laminaria japonica polysaccharide (LJP) (Zhang et al., 2021d), Porphyran-derived oligosaccharides (PYOs) (Wang X. et al., 2021), Ethyl Acetate Extract of Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. [Araliaceae, Acanthopanacis senticosi radix et rhizoma seu caulis] (Jia et al., 2022) and Lonicera caerulea L. berry polyphenols (LCBP) (Wu et al., 2018). In contrast, the abundance of Firmicutes and Bacteroidetes were not mentioned after applying interventions such as Jieyu Qutan Huazhuo Prescription (JYQTHZ) (Li N. et al., 2021; Li N. et al., 2022), Shenerjiangzhi formulation (SEJZ) (Zhang et al., 2022c), Jian Pi Tiao Gan Yin (JPTGY) (Dong et al., 2022), Shanmei (SM) Capsule (Du et al., 2022), Tongxinluo (TXL) Capsule (Qi et al., 2022), Hugan Qingzhi Tablet (HGQZ) (Tang et al., 2018; Tang, 2019), Compound Danshen Dripping Pills (Zhang Y. Y., 2020), Jiangan Jiangzhi Pill (JGJZ) (Zhao Z. et al., 2022), Jiangzhi Granules (JZG) (Wang R. R. et al., 2021), Procyanidin B2 (PB2) (Xing et al., 2019), Resistant starch (RS) (Shou, 2021), Tea polyphenol (TP) (Wang et al., 2018) and Gynostemma pentaphyllum (Thunb.) Makino [Cucurbitaceae; Gynostemmatis herba] (GP) (Huang et al., 2018), and only a decrease in F/B ratio was reported. It has been suggested that one of the pathways in which TCM regulates LMDs is through a relative decrease in the F/B ratio of the intestine. However, it remains to be further investigated exactly by which bacteria are regulated, or which of the many genera affected by TCM have the greatest effect on F/B ratio by alteration.

Studies have found that TCMs are effective in improving the inflammatory response related to dyslipidemia, possibly by maintaining intestinal barrier and reducing the release of inflammatory factors. Some natural medicine extracts, proprietary Chinese medicines and Chinese herbal formulas, such as Xiexin Decoction (XXD) (Chen, 2021), Biejia Jian Wan (BJJW) (Qiu et al., 2017), RSV (Yao, 2017) increased occludin mRNA expression; Dengzhan Shengmai Capsules (DZSM) (Guo et al., 2022), Senna tora (L.) Roxb. [Fabaceae; Cassiae semen] (ST) (Luo et al., 2021), Astragalus mongholicus polysaccharides (mAPS) (Zhong M. et al., 2022), Lycium barbarum polysaccharide (LBPs) (Gao et al., 2021), Inulin (Perez-Monter et al., 2022), EGCG (Zuo, 2020), Usnea diffracta Vain. [Usneaceae; U. diffracta] (UD) (Zhang L. D. et al., 2021) and Momordica charantia L. [Cucurbitaceae; Fructus momordicae] (MC) (Bai, 2019) also significantly enhanced occludin and ZO-1 expression, thus significantly enhancing intestinal barrier integrity. Huayu Qutan Formula (HYQT) (Zheng et al., 2022), Gegen Qinlian Decoction (GGQL) (Liu, 2019), Diammonium glycyrrhizinate (DG) (Li Y. et al., 2018) and GLP (Sang et al., 2021) significantly upregulated Claudin-1, Occludin and ZO-1 expression, which repaired intestinal mucosal barrier and prevented the development of chronic inflammation and LMD. Moreover, WIP (Sun et al., 2019) and JZG (Wang R. R. et al., 2021) elevated the expression of mucosal integrity protein Muc5 in addition to ZO-1 and occluding has also been reported to increase the expression of Muc2 and Muc4, maintain intestinal mucosal integrity, and improve intestinal inflammation (Li W. et al., 2019). Akkermansia, a mucin-degrading bacteria present in the mucosal layer, it can produce certain enzymes that affect the expression of mucins and tight junction proteins to regulate the intestinal barrier function. RSV (Chen, 2019; Chen et al., 2020), BBR (Zhu et al., 2018) and Rosa roxburghii Tratt polysaccharide (RTFP) (Zhang p. et al., 2022) were able to enrich the abundance of Akkermansia, and increase the colonic mucus layer thickness and intestinal tight junction proteins expression, thus reducing intestinal hypometabolic endotoxemia. Therefore, all of these TCMs can enhance intestinal barrier integrity and reduce intestinal permeability, thereby improving intestinal inflammation and abnormal lipid metabolism.

The abundance of Desulfovibrio, a producer of LPS, was positively correlated with inflammation and LMD. Danlou Tablet (DLT) (Sun et al., 2020), DZSM (Guo et al., 2022), GQD (Liu, 2019), SLBZ (Zhang et al., 2018), DG (Li Y. et al., 2018), Chitooligosaccharide (COSM) (Feng et al., 2022), Rhizoma Coptidis (RC) alkaloids (He et al., 2016), Baicalin (Liu, 2016), Quercetin (Porras et al., 2017) and BBR (Xu, 2013) might ameliorate LMD by decreasing the abundance of Desulfovibrio to reduce LPS into the blood and inflammatory factors secretion. Notably, DLT (Sun et al., 2020), Gastrodin (Liu F. Y. et al., 2021) could downregulate the levels of inflammatory markers IL-1β, ICAM-1 and TNF-α, favoring the reversal of periaortic inflammation and reduction of plaque area in AS mice. By reducing LPS levels, EGCG (Li, 2020; Zuo, 2020), Citrus Peel Powder extract (CPP) (Wang H. et al., 2022), HGQZ (Tang et al., 2018), Si Ni San (SNS) (Zhu et al., 2019), Rosa Laevigata Michx. Fruits Polysaccharides (RLPs) (Zhang X. J., 2020), Honokiol (Ding Y. et al., 2019), Fucoidan (Huang J. L., 2021) and ST (Luo et al., 2021) were found to inhibit the excessive production of inflammatory cytokines (mainly TNF-α, IL-6, IL-1β and MCP-1). In contrast, Alisma orientalis Beverage (AOB) (Zhu, 2021), Chaihu Shugan san (CHSG) (Xie et al., 2021), RSV (Chen, 2019), ST (Luo et al., 2021), Zhibitai Capsule (ZBT) (Pan et al., 2020), Xiaoyao San (XYS) (Zhou, 2020), JGJZ (Zhao Z. et al., 2022), Qinghua Fang (QHF) (Wang Y. et al., 2021), RTFP (Zhang p. et al., 2022), LBPs (Gao et al., 2021), Noni fruit polysaccharide (NFP) (Yang et al., 2020), Inulin (Bao, 2021; Wang L. J. et al., 2021), Quercetin (Wu et al., 2019), BBR (Wu et al., 2020), GP (Shen et al., 2020), CPP (Hu et al., 2021), Paeonol (Pae) (Jiang, 2019) and Blackberry leaf and fruit extracts (BLF) (Park et al., 2019) had effective antagonistic effects on the secretion of pro-inflammatory factors (e.g., IL-6, IL-1β and TNF-α) although the effects on LPS levels were not mentioned. In addition to this, some natural medicine extracts also have a promoting effect on anti-inflammatory cytokines IL-10, such as RSV, LBPs, NFP, COSM, BBR and Inulin.

Numerous experimental studies have demonstrated that TCMs achieve improvement of LMD by down-regulating inflammation-related signaling pathways (Li, 2015). Huazhi-Rougan formula (HZRG) (Li C. et al., 2022), DZSM (Guo et al., 2022), mAPS (Zhong M. et al., 2022), Luteolin (Liu, 2022) and Myricetin (Sun et al., 2021) markedly reduced metabolic endotoxemia and chronic hypo-inflammation associated with LPS, downregulated TLR4 mRNA and protein expression, inhibited IKKβ phosphorylation, and prevented p65 NF-κB translocation to the nucleus by modulating the TLR4/NF-κB pathway. CA (Mu et al., 2021) decreased LPS/TLR4, an LPS-mediated inflammatory pathway, and reduced TNF-α, IL-6 levels, thereby inhibiting dysregulation of lipid metabolism. LBPs (Gao et al., 2021) and COSM (Feng et al., 2022) inhibited indicators related to hepatic LPS/TLR4/NF-κB signaling pathway and attenuated the level of inflammation. HQT (Tang, 2019) and Compound Danshen Dripping Pills (Zhang Y. Y., 2020) selectively targeted TLR4 and inhibited LPS-induced inflammatory mediator production by attenuating the LPS/TLR4/MyD88 pathway. SLBZ (Zhang et al., 2018) and polyphenol-rich loquat fruit extract (LFP) (Li W. et al., 2019) also exhibited downregulation of the TLR4/MyD88 pathway and its downstream molecules, thereby inhibiting the overproduction of serum lipids. While, Qiang Gan formula extract (QGE) (Li et al., 2020), GLP (Sang et al., 2021) and EGCG (Zuo, 2020) regulated lipid metabolism-related processes by reducing the expression of LPS, LBP, and CD14, inhibiting TLR4/MyD88/NF-κB signaling pathway, reducing inflammatory factors secretion, and improving endotoxemia. Si Miao Formula (SMF) (Han et al., 2021), TXL (Qi et al., 2022) and Pae (Liu, 2021) inhibited the expression of NLRP3 inflammatory vesicles and their downstream factors including IL-18, IL-1β and caspase-1, alleviated the inflammatory response and reduced lipid levels. Furthermore, MC also inhibited LPS intestinal leakage, elevated intestinal tight junction protein expression, and protected intestinal mucosal integrity, which was associated with inhibition of the intestinal NF-κB/JNK/MAPKs pathway (Bai, 2019). Notably, Luffa cylindrica (L.) Roem [Cucurbitaceae; Luffa aegyptiaca Miller] (LC) (Zhang et al., 2019) and Berberrubine (BRB) (Yang S. et al., 2022) resulted in genes associated with hepatic lipid metabolism expression reduction, including fatty acid synthase (FAS), fatty acid synthesis protein (FABP), fatty acid transport protein (FATP), SREBP-1c and CD36, thus acting to reduce lipid levels.

Although the strong connection between intestinal flora, SCFAs and LMDs are still unclear, an increasing number of studies have shown that LMDs are directly correlated with both the number of SCFA-producing bacteria and the level of SCFAs. To play its part in treating LMDs, TCM can control the prevalence of bacteria that produce SCFAs and encourage the generation of SCFAs. LC (Zhang et al., 2019), DLT (Sun et al., 2020), NXT (Lu et al., 2022), IPTS (Ba et al., 2022), LJP (Zhang et al., 2021d), LBPs (Gao et al., 2021), Zanthoxylum bungeanum Maxim. [Rutaceae; Zanthoxyli pericarpium] (ZB) (You, 2016), Ginkgo biloba extract (GbE) (Wang Y. et al., 2022), Inulin (Bao, 2021; Wang L. J. et al., 2021), NFP (Yang et al., 2020), TP (Wang et al., 2018), Bilberry anthocyanins (Nakano et al., 2020) and COSM (Feng et al., 2022) significantly improved serum lipid levels (TC, TG) as well as reducing lipid accumulation, which may be associated with modifying intestinal flora and increasing SCFAs levels. In-depth research revealed that Compound Danshen Dripping Pills (Zhang Y. Y., 2020) and JZG (Wang R. R. et al., 2021) intervention elevated the abundance of Lachnospiraceae; Qingxin Jieyu Granule (QXJY) (Wang, 2019) and water insoluble polysaccharide WIP (Sun et al., 2019) intervention increased Clostridium abundance; Macroalgae Laminaria japonica (MLJ) (Zhang Q. et al., 2020), Quercetin (Porras et al., 2017), Myricetin (Sun et al., 2021), MC (Bai, 2019) and GLP (Sang et al., 2021) administration improved the abundance of Allobaculum; Erchen decoction (ECD) (Liu H. et al., 2021) and EGCG (Zuo, 2020) administration enhanced the abundance of Roseburia; HGQZ (Tang, 2019) and DG (Li Y. et al., 2018) treatment increased the abundance of Ruminococcaceae; SLBZ (Hong, 2021) and DZSM (Guo et al., 2022) administration enriched the abundance of Bifidobacterium, Lactobacillus; Guanxinning Tablet (GXNT) (Yang Q. et al., 2022), Black tea polyphenols (BTP) (Henning et al., 2018) and RLPs (Zhang X. J., 2020) treatment all increased the relative abundance of Prevotella; G. pentaphyllum saponins (GPS) (Zhong F. W. et al., 2022) administration enriched the abundance of Bacteroides. The above mentioned Ruminococcaceae, Lachnospiraceae, Clostridium, Allobaculum, Bifidobacterium, Lactobacillus, Prevotella, Roseburia, Bacteroides are all SCFAs-producing bacteria. In addition, TCM can promote the synthesis of key synthetic enzymes of SCFAs to elevate the level of SCFAs, or mediate SCFAs to regulate energy metabolism and inflammation-related pathways to improve LMD. GXNT treatment was also found to promote the production of butyrate kinase, propionate kinase, the key synthetic enzymes of SCFAs, thereby increasing the levels of butyric acid and propionic acid (Yang Q. et al., 2022). BTP treatment increased the level of SCFAs and activated the AMPK signaling pathway to increase energy expenditure, thus exerting a fat-lowering and weight-reducing effect (Henning et al., 2018). WIP treatment enhanced intestinal butyric acid levels, improved intestinal mucosal integrity, and regulated PPAR-γ pathway in the intestine (Sun et al., 2019). Dingxin Recipe IV (DXR) intervention promoted acetate, butyrate, propionate production, inhibited LXR-α/SREBP1 pathway and improved lipid metabolism (Zhang et al., 2021c). The mechanism through which GLP intervention ameliorated LMD may be indirectly engaged in regulating lipid metabolism by promoting the production of acetate and butyrate, activating the GPR43 receptor and modulating the intestinal barrier and inflammatory response (Sang et al., 2021).

Studies have shown that GXNT (Yang Q. et al., 2022) and Quercetin (Nie et al., 2019) can reduce serum or intestinal BAs levels. HYQT (Sui et al., 2021b), HZRG (Li C. et al., 2022), Proanthocyanidin (Fu et al., 2013), Theabrownins (Huang et al., 2019), Radix scutellariae water extract (Zhao et al., 2021), ZB (You, 2016), GbE (Wang Y. et al., 2022), QGE (Li et al., 2020) and Pae (He, 2021) promoted the conversion of cholesterol to BA and significantly increased the excretion of BA in feces. In-depth studies have revealed that the hypolipidemic effects of TCM are closely related to the modulation of BA synthesis and transport pathways. Among them, HYQT can increase BA synthesis-related genes expression, upregulate hepatic CYP7A1 expression, promote BA biosynthesis, and reduce serum lipid levels (Sui et al., 2021b). XXD may be achieved hypolipidemic effects by upregulating CYP8B1 expression (Lei, 2020), and Baicalein exhibited the same effects (Li P. et al., 2022). HZRG aimed to reduce serum TC and TG levels mainly by decreasing the expression of BA transporter-related genes ASBT and OSTβ mRNA and reducing the reabsorption of harmful BA such as LCA, DCA and HCA (Li C. et al., 2022). QGE promoted BA transport in the liver by increasing BSEP expression and hepatic TGR5 receptor expression to attenuate the inflammatory response and regulate lipid metabolism in the liver (Li et al., 2020). RC alkaloids reduced lipid and TBA levels involving multiple BA receptor pathways, and were associated with reduced ASBT expression and elevated CYP7A1 and TGR5 expression (He et al., 2016). NXT decreased BSH enzyme activity, modulated the BA profile in the intestine, and reduced lipid deposition, but the exact mechanism has not been elucidated (Lu et al., 2022). It was found that treatment with THF (Yang L. et al., 2022), WESB (Zhao et al., 2021), HQF (Sui et al., 2021b), TB (Huang et al., 2019), Pae (He, 2021), Naringin (Wang F. et al., 2020) and Penthorum chinense Pursh. (PCP) extract (Li X. et al., 2022) decreased the abundance of intestinal flora that produces BSH and BSH enzyme activity, leading to a weakened hydrolysis of BAs, increased the level of FXR antagonist T-βMCA, decreased FXR agonist CDCA and LCA levels, inhibited FXR/FGF15 axis in the intestine, activated CYP7A1 and CYP7B1 expression in the liver, and promoted hepatic BA synthesis, thereby reducing serum and hepatic TC levels. In addition, RSV enhanced BSH enzyme activity via boosting the number of BSH-producing bacteria, including Bifidobacterium and Lactobacillus, to promote BA catabolism and fecal excretion in the intestine, downregulated OSTα, OSTβ expression to reduce BA reabsorption transport, and reduced CDCA content to suppress enterohepatic FXR/FGF15 axis in order to promote hepatic BA synthesis (Chen et al., 2016).

It was found that serum lipid and TMAO levels were significantly decreased in HFD-induced AS model animals after treatment with Ginkgolide B (GB) (Lv et al., 2021), Eucommia ulmoides extract (Sun, 2020), HYQT (Sui et al., 2021a) and AOB (Zhu, 2021). The possible mechanism is to reduce TMA production, decrease hepatic FMO3 expression and inhibit the oxidation of TMA to TMAO by adjusting intestinal flora, which is a process consistent with the study of Xiangsha Liujunzi Decoction (XSLJZ) for the treatment of hyperlipidemia model rats (Wang J. et al., 2022). BBA reduces TMAO biosynthesis by decreasing the abundance of TMAO-related enzymes, such as carnitine oxygenase (CntA), choline-trimethylamine lyase (CutC), FMO and betaine reductase, effectively reducing serum TMAO levels (Wu et al., 2020; Li X. et al., 2021; Ma et al., 2022). The content of TMAO in the blood was shown to be associated to the severity of AS. Treatment with Tongmai Zhuyu decoction (TMZY) (Ji et al., 2020) or Tanyutongzhi Formula (TYTZ) (Wang, 2016) led to the reduction of TMAO levels as well as the decrease of atherosclerotic plaque area in AS model animals, and its anti-AS effect may be connected with TMAO reduction and the reduction of endothelial damage and inflammation levels. Another study showed that GXNT treatment was effective in reducing the production of TMAO, a TMA metabolite, lowering ox-LDL levels and inhibiting macrophage foaminess, while reducing NF-κB expression in AS plaques and alleviating the inflammatory response, thus preventing and preventing the formation of AS, which was correlated with reduced Escherichia abundance (Yang Q. et al., 2022). Furthermore, Jianpi Huazhuo Tiaozhi Granule (JPHZTZ) (Huang Q., 2021) and RSV (Chen et al., 2016) also exerted significant efficacy in anti-AS by a mechanism that may be achieved by inhibiting the enterohepatic FXR/FGF15 pathway, upregulating hepatic CYP7A1 expression, promoting BA biosynthesis, reducing TMAO production, and maintaining cholesterol metabolic homeostasis.