Marine Sulfated Polysaccharides: Preventive and Therapeutic Effects on Metabolic Syndrome: A Review

Metabolic syndrome is the pathological basis of cardiovascular and cerebrovascular diseases and type 2 diabetes. With the prevalence of modern lifestyles, the incidence of metabolic syndrome has risen rapidly. In recent years, marine sulfate polysaccharides (MSPs) have shown positive effects in the prevention and treatment of metabolic syndrome, and they mainly come from seaweeds and marine animals. MSPs are rich in sulfate and have stronger biological activity compared with terrestrial polysaccharides. MSPs can alleviate metabolic syndrome by regulating glucose metabolism and lipid metabolism. In addition, MSPs prevent and treat metabolic syndrome by interacting with gut microbiota. MSPs can be degraded by gut microbes to produce metabolites such as short chain fatty acids (SCFAs) and free sulfate and affect the composition of gut microbiota. The difference between MSPs and other polysaccharides lies in the sulfation pattern and sulfate content, therefore, which is very important for anti-metabolic syndrome activity of MSPs. This review summarizes the latest findings on effects of MSPs on metabolic syndrome, mechanisms of MSPs in treatment/prevention of metabolic syndrome, interactions between MSPs and gut microbiota, and the role of sulfate group and sulfation pattern in MSPs activity. However, more clinical trials are needed to confirm the potential preventive and therapeutic effects on human body. It may be a better choice to develop new functional foods containing MSPs for dietary intervention in metabolic syndrome.


Introduction
Cardiovascular diseases have become the leading killer of human beings [1]. Many risk factors contribute to cardiovascular disease, such as genetics, aging, smoking, and metabolic syndrome [2]. Genetics and aging cannot be modified, and metabolic syndrome can be addressed by lifestyle modifications or pharmacologic treatment. Metabolic syndrome mainly includes obesity, insulin resistance, atherogenic dyslipidemia, and hypertension [3]. Modern diets and lifestyles, such as high intake of sugar, fat and salt, and less exercise have led to an increasing incidence of metabolic syndrome (Figure 1) [4]. Dietary change is the main strategy for the treatment of metabolic syndrome, and the development of functional food components is an important method. In recent years, marine sulfate change is the main strategy for the treatment of metabolic syndrome, ment of functional food components is an important method. In recent fate polysaccharides (MSPs) have shown to be effective in the prevent of metabolic syndrome [5,6]. Sulfated polysaccharides (SPs) are sulfated derivatives of polysacc multifunctional active compounds formed by substituting some hydrox osaccharide molecules in the chain of polysaccharides by sulfate radi special environment of the sea, polysaccharides from marine organism more sulfate groups than polysaccharides from terrestrial microorgani plants [8,9]. A variety of MSPs have been isolated from seaweed and ma as fucosylated chondroitin sulfate, chondroitin sulfate, fucoidan, kerata sulfate, carrageenans, and ulvans [10,11]. The diverse biological activitie ing antiobesity, anticoagulant, immunomodulating, antihyperlipidem tive, have attracted remarkable interest. Among various functions, the a drome function of MSPs was only discovered in recent years [6,12-shown that MSPs can treat metabolic syndrome by regulating the dysb biota and the production of related metabolites [15]. Therefore, elucid MSPs on gut microbiota, especially the mechanism of MSPs interaction ota, will help to explain the mechanism of MSPs against metabolic synd promote their application.
MSPs cannot be digested directly by the human body but can onl utilized through the fermentation of gut microorganisms [16]. Gut micr term for the microbial community living in the human gut. It is one of research focuses in the fields of microbiology, medicine, and geneti Sulfated polysaccharides (SPs) are sulfated derivatives of polysaccharides, which are multifunctional active compounds formed by substituting some hydroxyl groups of monosaccharide molecules in the chain of polysaccharides by sulfate radical [7]. Due to the special environment of the sea, polysaccharides from marine organisms tend to contain more sulfate groups than polysaccharides from terrestrial microorganisms, animals, and plants [8,9]. A variety of MSPs have been isolated from seaweed and marine animals, such as fucosylated chondroitin sulfate, chondroitin sulfate, fucoidan, keratan sulfate, heparin sulfate, carrageenans, and ulvans [10,11]. The diverse biological activities of MSPs, including antiobesity, anticoagulant, immunomodulating, antihyperlipidemic and antioxidative, have attracted remarkable interest. Among various functions, the antimetabolic syndrome function of MSPs was only discovered in recent years [6,[12][13][14]. Studies have shown that MSPs can treat metabolic syndrome by regulating the dysbiosis of gut microbiota and the production of related metabolites [15]. Therefore, elucidating the effects of MSPs on gut microbiota, especially the mechanism of MSPs interaction with gut microbiota, will help to explain the mechanism of MSPs against metabolic syndrome and further promote their application.
MSPs cannot be digested directly by the human body but can only be absorbed and utilized through the fermentation of gut microorganisms [16]. Gut microbiota is a general term for the microbial community living in the human gut. It is one of the most attractive research focuses in the fields of microbiology, medicine, and genetics in recent years [17,18]. Many scientists refer to the gut microbiota as the body's organ due to its large number and complex interaction with the human body [19]. Gut microbiota is closely related to human health, which can help digestion, regulate immunity, avoid pathogen invasion, regulate mood, etc. Evidence has shown that gut microbiota dysbiosis is related to obesity, diabetes, cardiovascular diseases, and cancer [20]. The interaction between MSPs and gut microbiota plays an important role in metabolic syndrome. The establishment of relevant dietary intervention strategies has become a hot research topic in the field of functional food.
More than 30,000 research papers from 2000 to 2021 were found in PubMed by searching keywords such as sulfate polysaccharides, metabolic syndrome, gut microbiota, obesity, insulin resistance, atherogenic dyslipidemia, and hypertension, etc., and effects of MSPs on metabolic syndrome, regulation of MSPs on gut microbiota, utilization of MSPs in gut microbiota, mechanism of MSPs in treatment/prevention of metabolic syndrome, and therapeutic methods and dietary intervention.

Obesity
Obesity is a state of pathological and physiological changes caused by excessive accumulation of fat in the human body. Obesity not only affects physical beauty, but also brings inconvenience to life. In addition, it can also cause a variety of diseases, including cardiovascular diseases, joint soft tissue damage, psychological disorders, diabetes, fatty liver, etc. [36]. Drug treatment for obesity, so far, mainly involves blocking the absorption of food or increasing metabolism. Drug use may cause side effects and drug resistance, and drug treatment must be carefully selected. Therefore, food-derived natural products with obesity prevention and treatment functions are of interest to researchers, and among them, MSPs are more promising. MSPs from Cymodocea nodosa effectively reduced weight and inhibited lipase activity in obese mice [21], and MSPs from brown seaweed Ascophyllum nodosum could pass through the upper digestive tract and could be degraded by gut microbe, thus regulating the composition of gut microbiota and reducing the risk of obesity [22]. MSPs of abalone gonad could improve the metabolic syndrome and gut microbiota dysbiosis induced by high fat diet and could affect nutrient absorption and energy metabolism [23]. SP from sea cucumber has a good therapeutic effect on dietinduced obesity mice; it could reduce the levels of fat, serum lipid and inflammatory cytokines, and had a good preventive effect on metabolic syndrome [24]. A variety of MSPs from different sources showed positive effects in the prevention and treatment of obesity, and they seem to be potential ingredients for the development of new drugs and dietary treatment of obesity. However, current research only stays in the animal experiment stage, and further clinical trials are needed to verify their role and safety in human obesity.

Insulin Resistance
The decrease in the efficiency with which insulin promotes glucose uptake and utilization is known as insulin resistance. It is one of important pathogenesis of cardiovascular diseases and type 2 diabetes [37]. Insulin resistance promotes cardiovascular disease by increasing the vascular stiffness. Elevated plasma insulin level, along with a concomitant decrease in bioavailable nitric oxide, plays an important role in the pathogenesis of impaired vascular relaxation and vascular stiffness in patients with cardiovascular disease [38]. Fucoidan, a favorable MSP, has a promising therapeutic effect on insulin resistance [39,40]. Fucoidan exists in a variety of marine organisms and is mainly composed of L-fucose and sulfate groups. However, the structure of fucoidan varies according to its source [5]. Fucoidan from Sargassum fusiforme improved insulin resistance by activating the Nrf2 pathway, regulating the structure of gut microbiota, and reducing intestinal inflammation [25]. However, fucoidan extract from Fucus vesiculosus showed no marked effect on insulin resistance in obese, nondiabetic subjects [26]. This might be due to the different structure of fucoidan from different sources. In addition to fucoidan, fucosylated chondroitin sulfatedominated polysaccharide fraction from Cucumaria frondosa improved insulin resistance by activating IRS/PI3K/AKT signaling and regulating GSK-3β gene expression in T2DM rats [27]. In summary, various MSPs from different sources have therapeutic potential against insulin resistance; however, the treatment of insulin resistance might have to use an appropriate and specific MSP.

Dyslipidemia
Dyslipidemia is an abnormal metabolism of lipoprotein in human body, and it is one of important factors leading to atherosclerosis and an independent risk factor for coronary heart disease and ischemic stroke [41]. Studies have shown that MSPs have hypolipidemic effects. Fucoidan is effective in reducing dyslidemia and atherosclerosis, inducing lipoprotein lipase activity, and suppressing inflammatory and oxidative stress in mice [28]. The administration of MSP from Sargassum vulgare to obese rats could inhibit lipase activity, regulate lipid profile, and limit lipid peroxidation [29]. The sulfate of MSPs may have a significant effect on the hypolipidemic effect. MSPs from sea cucumbers Pearsonothuria graeffei dominated with a 4-O-sulfation pattern had a significant effect on lipid regulation; however, MSPs from sea cucumbers Isostichopus badionotus dominated with a 2-O-sulfation pattern showed limited effects [30]. In another work, Ulvan PU3 from Ulva pertusa with the highest uronic acid and sulfate content exhibited stronger antioxidant activities than other ulvans in the model of hyperlipidemic Kunming mice [31]. Therefore, the sulfation pattern and sulfate content in MSPs might contribute to the regulation of dyslipidemia.

Hypertension
Hypertension is the most common chronic disease and the most important risk factor for cardiovascular and cerebrovascular diseases. Because high blood pressure requires lifelong treatment, safe and reliable medications are important. Low molecular weight fucoidan seems to have a good effect on hypertension, and studies showed that it could improve basic hypertension in type 1 and type 2 diabetic rats [32,33]. In rat experiments, fucoidan from Undaria Pinnatifida was found to effectively and consistently reduce high blood pressure, even after the drug was stopped, indicating its excellent potential in the treatment of hypertension [34]. Carrageenan might also have potential for the treatment of hypertension, as its producer Sarconema filiforme was effective in improving diet-induced metabolic syndrome. Systolic blood pressure was significantly reduced in rats with dietinduced metabolic syndrome after 5% S. filiforme supplementation [35].

Mechanism of MSPs in Treatment/Prevention of Metabolic Syndrome
MSPs treat or prevent metabolic syndrome through regulating glucose or lipid metabolism based on microbiota-targeting strategies. The scope for MSPs involved in source, characteristics, effect on health, and its mechanism was shown in Figure 2. Metabolites such as dihydroxyacetone phosphate, acetyl coenzyme A, and NADPH are generated during glucose metabolism, which provide precursors for lipid metabolism. However, when cells are blocked from using glucose, the body uses fat oxidation for energy and generate acetyl coenzyme A, thus entering the tricarboxylic acid cycle and affecting glucose metabolism. Therefore, the regulation of glucose and lipid metabolism by MSPs may be a cyclic pathway.

Regulating Glucose Metabolism
Although a number of studies have shown that MSPs have significant effects in the treatment of metabolic syndrome, it should be noted that most of the studies focus on the function of MSPs, and the research on the mechanism is still in progress, which is related to the complex mechanism of MSPs in the treatment of metabolic syndrome. Some studies focus on the effects of MSPs on the key enzyme activities related to metabolic syndrome, for example, fucoidan is an inhibitor of α glucosidase, which can reduce postprandial hyperglycemia [42]. High molecular weight fucoidan from F. vesiculosus can also indirectly reduce postprandial hyperglycemia through the inhibition of dipeptidyl peptidase-IV (DPP-IV) [43]. DPP-IV is an enzyme that is involved in the inhibition of the rapid degradation of incretin hormones, which prevents postprandial hyperglycemia. Inhibiting DPP-IV prolongs the action of incretins, which reduces glucose production and increases insulin production [44]. Additionally, some studies have examined changes in metabolic syndrome-related signaling pathways and gene expression following MSPs intake. The sulfated rhamnose polysaccharides from Enteromorpha prolifera have significant effects on glycemic control by activating the insulin receptor/insulin receptor substrate-2/phosphoinositide 3-kinase/protein kinase B/glycogen synthase kinase 3β (IR/IRS-2/PI3K/PKB/GSK-3β) signaling pathway, which is related to glycogen synthesis, to improve glucose metabolism and enhance glucose transport through glucose transporter 4 translocation [45]. MSPs from sea cucumber also improve glucose metabolism by activating the insulin-mediated PI3K/PKB/GSK-3β signaling pathway, improving insulin resistance and promoting glycogen accumulation [27,46]. Low molecular weight fucoidan activates adenosine monophosphate-activated protein kinase to prevent metabolic syndrome by controlling endoplasmic reticulum stress-dependent pathways [47]. Repairing islet cells to increase insulin secretion and increasing glycogen synthesis to increase glucose utilization are beneficial to reducing blood glucose content. The MSPs from U. pinnatifida have a strong α-glucosidase inhibitory activity, which can improve glucose intake, reduce islet cell damage, and promote liver glycogen synthesis [48].

Regulating Glucose Metabolism
Although a number of studies have shown that MSPs have significant effects in the treatment of metabolic syndrome, it should be noted that most of the studies focus on the function of MSPs, and the research on the mechanism is still in progress, which is related to the complex mechanism of MSPs in the treatment of metabolic syndrome. Some studies focus on the effects of MSPs on the key enzyme activities related to metabolic syndrome, for example, fucoidan is an inhibitor of α glucosidase, which can reduce postprandial hyperglycemia [42]. High molecular weight fucoidan from F. vesiculosus can also indirectly reduce postprandial hyperglycemia through the inhibition of dipeptidyl peptidase-IV (DPP-IV) [43]. DPP-IV is an enzyme that is involved in the inhibition of the rapid degradation of incretin hormones, which prevents postprandial hyperglycemia. Inhibiting DPP-IV prolongs the action of incretins, which reduces glucose production and increases insulin production [44]. Additionally, some studies have examined changes in metabolic syndrome-related signaling pathways and gene expression following MSPs intake. The sulfated rhamnose polysaccharides from Enteromorpha prolifera have significant effects on glycemic control by activating the insulin receptor/insulin receptor substrate-2/phosphoinositide 3-kinase/protein kinase B/glycogen synthase kinase 3β (IR/IRS-2/PI3K/PKB/GSK-3β) signaling pathway, which is related to glycogen synthesis, to improve glucose metabolism and enhance glucose transport through glucose transporter 4 translocation [45]. MSPs from sea cucumber also improve glucose metabolism by activating the insulin-mediated PI3K/PKB/GSK-3β signaling pathway, improving insulin resistance and promoting glycogen accumulation [27,46]. Low molecular weight fucoidan

Regulating Lipid Metabolism
A number of experimental studies have shown that most MSPs are effective in lipid metabolism. MSPs could regulate lipid metabolism by affecting lipid absorption and improving antioxidant capacity. Goto et al. found that sacran, an MSP mainly from Aphanothece sacrum, could reduce the increase in serum triglyceride induced by corn oil in SD rats and had the potential of reducing lipids absorption into blood [49]. It could also reduce the level of oxidative stress in serum and hepatic injury, accompanied by increased levels of transforming growth factor-β and tumor necrosis factor-α. Chondroitin sulfate from salmon nasal cartilage inhibited fat storage in mice fed a high-fat diet, possibly by inhibiting pancreatic lipase activity and fatty acid uptake through the brush border membrane, thus inhibiting the absorption of dietary fat in the small intestine [50]. MSP from Cystoseira crinita could inhibit lipase activity in plasma and small intestine, leading to a significant decrease in blood triglyceride in rats fed a high fat diet [51]. In mice induced by high fat diet, it was found that polysaccharides from abalone viscera not only decreased blood lipid but also significantly increased the activity of malondialdehyde and superoxide dismutase, suggesting that it might play a role in the antioxidant pathway to improve the lipid metabolism disorder [52]. Ethanol extract from Hypnea musciformis could modulate lipid peroxidation in mammary carcinogenesis [53]. MSPs also affect lipid metabolism by regulating the expression of related genes. Reportedly, 200 mg kg −1 MSP from E. prolifera could significantly reduce the expression of hydroxy methylglutaryl coenzyme A (HMG-CoA) reductase and sterol regulatory element binding protein-2 (SREBP-2) in the liver of non-alcoholic fatty liver disease rats induced by a high-fat diet, in which SREBP-2 is a key transcription factor of cholesterol metabolism, while inhibiting HMG-CoA reductase could hinder cholesterol synthesis [54]. Fucoidan has been extensively studied on the mechanism of lipid regulation. It mainly transferred lipids from blood to liver and promoted lipid metabolism by regulating the expression of genes related to reverse cholesterol transport and lipid metabolism in hyperlipidemic C57BL/6J mice, such as low-density lipoprotein receptor, scavenger receptor B type 1, cholesterol 7 alpha-hydroxylase A1, peroxisome proliferator-activated receptor (PPAR) α, liver X receptor β, ATP-binding cassette transporter A1, and sterol regulatory element-binding protein 1c [55]. Fucoidan also decreased the expression of PPARγ (peroxisome proliferator-activated receptor γ, major transcription factors associated with adipocyte differentiation) in the liver of apolipoprotein E-deficient mice fed a high-fat diet [56]. Another study showed that sea cucumber fucoidan significantly increased the expression of Wnt/β-catenin pathway related genes and decreased the expression of key transcription factors such as SREBP-1c, CCAAT/enhancer binding protein-α (C/EBPα) and PPARγ in the high-fat-high-fructose diet mice. β-catenin inhibited the expression of PPARγ and C/EBPα, thus slowing adipocyte differentiation, while SREBP-1c had the opposite effect [57].

Regulation of MSPs on Gut Microbiota
In recent years, the study of gut microbiota has aroused widespread interest and provided a new idea for the study of the mechanism of MSPs in the prevention and treatment of metabolic syndrome. The interaction between MSPs and gut microbiota has been found in many studies [16,58]. MSPs can be metabolized by gut microbiota and its metabolites in turn affected the gut microbiota. The gut microbiota plays an important role in the metabolic syndrome, which was confirmed in human and animal experiments [59,60]. The clinical characterization of metabolic syndrome is the proliferation of potentially harmful bacteria and the inhibition of beneficial ones. Therefore, MSPs regulation of metabolic syndrome begins with gut microbial degradation, acts on the dysbiosis of gut microbiota, and has far-reaching effects beyond the gut. Representative studies on the regulation of MSPs on gut microbiota are listed in Table 2.  Chondroitin sulfate/fucosylated chondroitin sulfate usually showed powerful effects on the gut microbiota in mice. Shang et al. found that chondroitin sulfate had a positive regulation effect on gut microbiota, which was gender dependent [61]. Chondroitin sulfate significantly increased the number of Bacteroides acidifaciens, which indirectly played its role in gut immune regulation and improved the stress-induced intestinal inflammation [70]. Fucosylated chondroitin sulfate from sea cucumbers generally had the function of alleviating metabolic syndrome and gut microbiota dysbiosis, which could reduce the ratio of Firmicutes to Bacteroidetes and increase the abundance of beneficial bacterium Megamonas, Bacteroides, Fusobacterium, Parabacteroides, Prevotella, Faecalibacterium [62,63]. The ratio of Firmicutes to Bacteroidetes is generally regarded as an important indicator of obesity, and obese patients generally have a higher ratio [36].
Studies found that fucoidan could improve the dysbiosis of gut microbiota by increasing the abundance of Lactobacillus and Ruminococcaceae [64]. Lactobacillus are traditional probiotics, which have a variety of functions, while arterial stiffness correlates negatively with the abundance of Ruminococcaceae [71]. Another study in mice with gut microbiota dysbiosis caused by antibiotics showed that fucoidan not only increased the abundance of Ruminococcaceae, but also increased the abundance of Akkermansia, which was consistently correlated with metabolic syndrome and considered as the next generation probiotic [72]. Fucoidan could also reduce the Firmicutes to Bacteroidetes ratio in obese mice induced by high fat diet [25]. In diabetic mouse models, S. fusiforme fucoidan could relieve diabetic symptoms by regulating gut microbiota, and increasing the abundance of benign bacteria, such as Bacteroides, Faecalibacterium, and Blautia [65,66].
Carrageenan also has the effect of regulating gut microbiota in the treatment of metabolic syndrome, but its efficacy and safety need to be further studied, which may be related to its degree of polymerization [35,67]. A number of studies have shown that carrageenan induces colitis and is related to the gut microbiota of the host [68,73]. Porphyran and ulvans also have some anti-metabolic syndrome function, but there are few studies on related mechanism and its effect on gut microbiota [69,74].

Utilization of MSPs by Gut Microbiota
Non-digestible polysaccharides are rarely digested by the human body itself but can be degraded by gut microbiota to produce short chain fatty acids (SCFAs) and other substances that can be absorbed by the human body. SCFAs can be used as an energy source of intestinal epithelial cells and have functions such as regulating gut microbiota dysbiosis and resistance to pathogen invasion [75]. The utilization of MSPs by gut microbiota was showed in Figure 3. Previous studies suggested that, unlike non-SPs, MSPs were poorly fermentable, which might be related to the degree of sulfation [76,77]. However, recent studies showed that small molecular weight MSPs (<30 kDa) could be degraded by human gut microbes and produce large amounts of SCFAs, which regulate the balance of gut microbiota [78]. MSPs from pacific abalone could be degraded by intestinal Bacteroidetes in an in vitro fermentation model, and it was species dependent [79]. These different results may have something to do with the fact that the gut microbiota of the Chinese, who traditionally consume kelp and other algae, is more suitable for the degradation of MSPs. MSPs from A. nodosum also showed strong in vitro digestibility and fermentability, and the total SCFA content increased significantly after the digestion [22]. Similar results could also be found in animal experiments. Feeding fucoidan from Acaudina molpadioides significantly increased the content of SCFAs and the abundance of SCFA producing bacteria Coprococcus, Rikenella, and Butyricicoccus in the gut of mice [80]. Therefore, it is of great significance to study the digestion of MSPs in gut to understand the mechanism of MSPs in the treatment of metabolic syndrome. group in obese mice [85]. SCFAs act as an active signaling molecule that interacts with Gprotein-coupled free fatty acid receptors and has a wide range of effects on glucose and lipid metabolism [86]. SCFAs can improve glucose homeostasis and insulin sensitivity and directly reduce the secretion of adipose tissue-derived pro-inflammatory cytokines and chemokines [87]. More and more evidence shows that SCFA, as a metabolic tool, has a potential role in preventing and counteracting metabolic syndrome. Therefore, regulating SCFAs produced by the gut microbiota through the ingestion of MSPs is a useful tool for the prevention of metabolic syndrome. Apart from the utilization of MSPs by gut microbiota, MSPs can be directly absorbed into the human body through the intestinal tract. There are many studies on the absorption and pharmacokinetics of MSPs by human body [88,89]. The absorption and pharmacokinetics of MSPs should be considered in correct doses and treatment schemes selection of metabolic syndrome. Studies have shown that high molecular weight fucoidans can be absorbed by rat intestinal epithelial cells but cannot accumulate in blood and urine [88]. MSPs can be detected in urine after ingestion in human bodies, and dietary habit is a factor in the absorption of MSPs [89]. The absorption rate of fucoidan via the intestine using subjects is 0.6% [90]. The pharmacokinetic and tissue distribution of fucoidan exhibit considerable heterogeneity. Fucoidan first accumulates in kidney (AUC0-t = 10.74 μg•h/g; Cmax Gut microbes have a series of genes encoding the binding and subsequent degradation of MSPs, including genes encoding glycoside hydrolase, polysaccharide lyase, glycosyltransferase, and other related enzymes such as sulfatases [81]. These genes can be found in human gut microbes such as Streptococcus, Eubacterium, Bifidobacterium, Faecalibacterium, and Bacteroides, among which Bacteroides is the most important degrader [76], because it is dominant in the human gut, and genes mentioned above in Bacteroides form a tightly regulated colocalized gene clusters [82]. After degradation of MSPs, oligosaccharides, monosaccharides, SCFAs, and other metabolites are produced, some of which can be directly absorbed by the human body, while others can be used by other microbes through the cross-feeding mechanism.
SCFAs have a strong regulatory effect on gut microbiota, thus affecting the onset and development of metabolic syndrome. There are many SCFA-producing bacteria in gut microbiota, such as Bacteroides, Alloprevotella, Clostridium, Eubacterium, Faecalibacterium, Roseburiam and so on [83]. Different types of MSPs selectively increased the abundance of SCFA producing bacteria. For example, MSPs from sea cucumber significantly increased the abundance of Bacteroides, Allobaculum, Alloprevotella, Roseburia, and Turicibacter in BALB/c mice [84]. Nevertheless, fucosylated chondroitin sulfate from A. molpadioides increased the abundance of Lactobacillus, Bifidobacterium, and Lachnospiraceae NK4A136 group in obese mice [85]. SCFAs act as an active signaling molecule that interacts with G-proteincoupled free fatty acid receptors and has a wide range of effects on glucose and lipid metabolism [86]. SCFAs can improve glucose homeostasis and insulin sensitivity and directly reduce the secretion of adipose tissue-derived pro-inflammatory cytokines and chemokines [87]. More and more evidence shows that SCFA, as a metabolic tool, has a potential role in preventing and counteracting metabolic syndrome. Therefore, regulating SCFAs produced by the gut microbiota through the ingestion of MSPs is a useful tool for the prevention of metabolic syndrome.
Apart from the utilization of MSPs by gut microbiota, MSPs can be directly absorbed into the human body through the intestinal tract. There are many studies on the absorption and pharmacokinetics of MSPs by human body [88,89]. The absorption and pharmacokinetics of MSPs should be considered in correct doses and treatment schemes selection of metabolic syndrome. Studies have shown that high molecular weight fucoidans can be absorbed by rat intestinal epithelial cells but cannot accumulate in blood and urine [88]. MSPs can be detected in urine after ingestion in human bodies, and dietary habit is a factor in the absorption of MSPs [89]. The absorption rate of fucoidan via the intestine using subjects is 0.6% [90]. The pharmacokinetic and tissue distribution of fucoidan exhibit considerable heterogeneity. Fucoidan first accumulates in kidney (AUC 0-t = 10.74 µg·h/g; C max = 1.23 µg/g after 5 h), spleen (AUC 0-t = 6.89 µg·h/g; C max = 0.78 µg/g after 3 h), and liver (AUC 0-t = 3.26 µg·h/g; C max = 0.53 µg/g after 2 h), and stays in the blood with a mean residence time (6.79 h) [91]. Studies on pharmacokinetics of fucoidan is useful for understanding the molecular mechanism of biological activity and correct selecting therapeutic doses.

Role of Sulfate Group and Sulphation Pattern
The function of MSPs is closely related to its sulphation patterns and sulfate group, and the sulfate group plays a special role in the interaction with gut microbiota [30,31,76]. The content of sulfate group is significantly different with different extraction methods and sources, which leads to significant differences in the activity of MSPs from different sources or even the same source. MSPs from abalone have a variety of fragments, and their activity is related to molecular weight and sulfate content [92,93]. A fraction named AGP33 with sulfates occur at 3-O-and 4-O-positions showed a better anticoagulant activity than its desulfated product [93]. MSPs from abalone viscera also exhibited significantly hypolipidemic and anti-atherogenic activities [52]. Another abalone SP (AGSP) and its desulfated product D-AGSP can inhibit fat accumulation and improve lipid metabolism balance and gut microbiota dysbiosis in mice fed with high fat diet [94]. However, there were significant differences in relative abundance of Oscillibacter and Helicobacter in gut microbiota between AGSP and D-AGSP groups, and the butyrate content in feces of mice in D-AGSP group was significantly lower than that in AGSP group, indicating that the sulfate group did not have a decisive effect on the hypolipidemic activity of AGSP, but it might affect the inhibitory effect on metabolic syndrome by regulating the composition of gut microbiota and the expression of their metabolites [94]. There are few studies relating to the effect of sulfate group in MSPs on metabolic syndrome, which might partly determine the activity of MSPs through gut microbiota; however, the specific mechanism is still unclear and needs further study.
After MSPs are degraded in the gut, they might generate free sulfate that is used by sulfate-reducing bacteria, such as Desulfovibrio, to form hydrogen sulfide [95]. Although hydrogen sulfide in the gut may protect the gut microbiota from reactive oxygen species, high concentration of hydrogen sulfide might be toxic to the host [95]. It seems important to control the abundance of sulfate-reducing bacteria as well as H 2 S levels in the intestines of people on high MSPs diet. However, whether sulfate-reducing bacteria is beneficial or harmful is still debated, and its role in the pathogenesis of metabolic diseases such as obesity remains unclear [96]. Therefore, tracking the free sulfate content of MSPs after degradation in gut to clarify the release of sulfate in MSPs and studying the physiological functions of sulfate reducing bacteria by colonizing germ-free mice is of great importance so as to understand the mechanism of sulfate group determining the activity of MSPs.

Therapeutic Methods and Dietary Intervention
A number of studies indicate that most MSPs have anti-metabolic syndrome effects, and most of them are based on animal experiments. However, few clinical trials have been carried out on fucoidan as an anti-metabolic syndrome drug (Table 3). Previous studies showed that 5 weeks administration of 400 mg fucoidan could effectively shorten lysis time of the thrombus [97], and three months 500 mg of fucoidan daily taking for obese and overweight people could lower diastolic blood pressure and low-density lipoprotein cholesterol and raise insulin levels [98]. The combination of fucoidan and fucoxanthin can improve hepatic steatosis, inflammation, fibrosis, and insulin resistance in non-alcoholic fatty liver disease patients [99]. However, a recent randomized controlled trial of obese patients showed no significant differences in insulin resistance or other measures of cardiometabolic health between the two groups given 90 days 500 mg of fucoidan and placebo [26]. In a clinical trial of carrageenan, carrageenan failed to reduce glycosylated hemoglobin and homeostasis model assessment-insulin resistance in prediabetic patients, while a diet without carrageenan improved insulin signaling and glucose tolerance [100]. Therefore, MSPs still need further research and development as anti-metabolic syndrome drugs. However, fucoidan, as an MSP entering clinical studies, is promising for its safety and effectiveness in managing metabolic syndrome.  [94] Abbreviations: ↑, increase; ↓, decrease; HOMA: homeostasis model assessment.
Recently, there has been great interest in the appropriate use of MSPs to achieve maximum health benefits [7], and they seem to have important application in dietary intervention of metabolic syndrome as functional foods. For metabolic syndrome such as obesity and dyslipidemia, scientific and reasonable diet intervention combined with exercise is the safest and most effective basic treatment at present. However, the traditional low-calorie meal replacement mode is a disguised diet, which is not only uncomfortable and has poor compliance, but also easily causes a decline in immunity, stress gastritis, and other problems. Adding MSPs to a normal or even high-fat diet can prevent or alleviate metabolic syndrome [6,15,94], and this not only ensures the supply of energy and nutrition, but also achieves the purpose of reducing fat, blood glucose, and insulin resistance. It is especially suitable for people who are easy to regain weight and is not suitable for exercise, obese and overweight children, pregnant women, and people with type 2 diabetes. In addition, direct consumption of MSPs-rich seafood also has some remission effect on metabolic syndrome. Red seaweed S. filiforme and Kappaphycus alvarezii, the producers of carrageenan, can be used as functional foods to relieve metabolic syndrome [35,101]. Many brown seaweeds also have good effects on metabolic syndrome management, owing to high amounts of MSPs in the total dry mass [102]. Sea cucumbers, abalone, and other animal seafood are rich in MSPs and other functional components, and they can also alleviate the metabolic syndrome induced by a high-fat diet [62,94]. Eating more of these seafoods seems to be beneficial for health, but too simple a diet is harmful for metabolic syndrome. Dietary intervention through intake of MSPs is a good way to prevent and alleviate metabolic syndrome and can provide reference for the development of functional foods in the future.

Conclusions and Future Perspectives
Metabolic syndrome is a universal health problem facing the world, and its incidence is increasing rapidly. It aggravates metabolic abnormalities and is associated with a marked increase in type 2 diabetes and early onset of cardiovascular and cerebrovascular risk. Interventions for metabolic syndrome are mainly lifestyle changes and necessary medication. MSPs are natural compounds in food, with a variety of biological activities, especially in the prevention and treatment of metabolic syndrome. Compared with traditional drugs, MSPs are safe and have low side effects, and they have been shown to have positive effects on obesity, insulin resistance, dyslipidemia, and hypertension.
The mechanism of MSPs prevention or treatment of metabolic syndrome may be through its regulation of glucose metabolism and lipid metabolism, and these regulation effects may be derived from the digestive products of MSPs in the gut and its effect on gut microbiota. MSPs can reduce the ratio of Firmicutes to Bacteroidetes, thus reducing the risk of obesity. In addition, it can increase the abundance of Akkermansia and other beneficial bacteria. After MSPs are degraded in the gut, SCFAs are generated; thus, the content of SCFAs and the abundance of SCFA-producing bacteria increase. SCFAs further affect glucose and lipid metabolism through complex mechanisms. It is generally believed that MSPs have higher activity due to their high sulfate content and sulphation patterns, and they are essential to the activity of MSPs. Intestinal sulfate-reducing bacteria may play an important role in the functioning of MSPs, but the effect and mechanism are still unclear.
MSPs have the potential to prevent and treat metabolic syndrome, which has a high value for drug development. At present, some clinical trials targeting fucoidan have been carried out, but other MSPs still need more animal and clinical trials to verify their function and safety. In addition, it is still not clear what role MSPs play in anti-metabolic syndrome and the mechanisms necessary for development of MSPs drugs. At present, there are still many difficulties in developing MSPs as drugs, but most MSPs can be added into the daily diet as functional food for dietary intervention to prevent and alleviate metabolic syndrome. In the future, it will be of great value to develop more MSPs formula foods for special medical use with clear function.