Effects of Natural Polysaccharides on the Gut Microbiota Related to Human Metabolic Health

ABSTRACT

Natural polysaccharides (NPs) are sugar chains bound by glycosidic bonds that are composed of at least 10 monosaccharides and have broad biological activity. The human body microbiome is a complex ecosystem that plays a role in host metabolism, immunity, and other important life activities. Numerous studies have demonstrated an obvious relationship between the gut flora and the occurrence of many human diseases. Many studies have reviewed and investigated the effects of polysaccharides on the microbiome, but the underlying mechanisms remain unclear. Most of these studies have focused on the effects of NPs on microbes, as they are important “foods” for the intestinal flora. However, polysaccharides can also affect microbes by improving gut homeostasis. Therefore, the purpose of this review is to introduce recent research that looks at how NPs affect microbiomes by directly acting as fermentation substrates and enhancing gut homeostasis. In addition, this study provides a succinct summary of NP extraction, purification, and structural characteristics, as well as a discussion of their structure‒activity correlations. This study also sheds light on future directions and obstacles in the use of NPs with protective properties, with the aim of providing insights into their potential applications in disease treatment.

The graphical abstract illustrates the role of polysaccharides extracted from various natural raw materials (such as mushrooms, marine organisms, fruits, and vegetables) in modulating the gut microbiota. The process begins with the extraction and purification of polysaccharides, followed by assessing their structure‐activity relationship. Upon entering the host system, polysaccharides influence gut microbiota through three main pathways: acting as fermentation substrates, modulating gut microbiota growth via host interaction, and promoting gut homeostasis. These actions collectively contribute to beneficial effects on the host's health.

1. Introduction

Natural polysaccharides (NPs) are long polymer chains composed of more than 10 monosaccharides linked through glycoside bonds. They are commonly found in a variety of sources, including edible or medicinal plants (such as purple potato, pectin, goji berries, and reishi), microorganisms (such as fungal polysaccharides and lactic acid bacteria exopolysaccharides), and animals (such as squid, oysters, and sea cucumbers). Owing to their multiple beneficial effects, such as anti‐inflammatory, antiaging, antiviral, antitumor, and immunomodulatory effects, NPs have attracted considerable attention in recent years [1]. Numerous studies have highlighted the ability of NPs to improve the gut microbiota and overall metabolic health, thereby mitigating various diseases [2]. Investigations into the effects of NPs on the gut microbiota have focused primarily on their role as fermentation substrates, particularly for the colonic microbiota.

Recent research has highlighted the importance of polysaccharides in shaping the gut microbiota, leading to a plethora of reviews exploring this topic. However, many of these reviews tend to focus primarily on the immunomodulatory properties of polysaccharides and their involvement in gut microbiota‐facilitated intestinal mucosal repair. Other studies are limited to examining the regulatory effects of specific polysaccharide types on the gut microbiota or exploring their regulatory mechanisms in specific gut microbiota‐mediated diseases. For example, Tang et al. [3] provided a comprehensive review of the source, extraction, purification, and structural characteristics of plant polysaccharides, highlighting their regulatory role in immunity via the gut microbiota. Similarly, Ou et al. [4] discussed the regulatory mechanisms of marine polysaccharides in the treatment of gut dysbiosis. In addition, Y. Sun et al. [5] reviewed the therapeutic potential of plant polysaccharides in alleviating cognitive impairment through the modulation of the gut microbiota. This review comprehensively examines the interplay among NPs, the gut microbiota, and associated diseases, including their effects on obesity, metabolic disorders, inflammatory bowel disease (IBD), cancer, and immune function through the modulation of the gut microbiota. Furthermore, this study provides a succinct summary of NP extraction, purification, and structural characteristics, as well as a discussion of their structure‒activity correlations. Notably, the relevant literature supporting these claims was cited without restriction.

2. Extraction and Purification of Polysaccharides

NPs can be obtained through a range of extraction techniques, including direct alcohol precipitation and extraction techniques (ultrahigh‐pressure extraction [UPE], microwave extraction [MAE], hot water extraction [HWE], and three‐phase partitioning [TPP]. Among these methods, direct alcohol precipitation has been widely used to extract polysaccharides from liquid samples because of its simplicity, speed, and ease of execution. However, chemical agents such as H₂O₂, Sevag's reagent, or trichloroacetic acid have traditionally been utilized to destain and deproteinize crude polysaccharides, and these chemical treatments result in partial hydrolysis of polysaccharides and alter their structural and biological properties. C. Li et al. [6] introduced a simple technique for destaining and deproteinizing using macroporous adsorbent resins. This method maintains the structural integrity and biological functions of polysaccharides, which can be further purified via methods such as freeze‒thaw cycles and column chromatography [3]. The resulting polysaccharides can be safely used in experiments or treatments, ensuring accurate dosing and allowing for the exploration of structure‒activity relationships. As a result, efficient polysaccharide purification can pave the way for the creation of new compounds with equivalent or enhanced biological effects.

The most common technique for purifying polysaccharides is column chromatography. Depending on the packing matrix and principle of sample partitioning and exchange, researchers have used ion exchange column chromatography, gel filtration chromatography (such as Sephadex G‐25/A‐25 columns), and affinity chromatography (such as Sephacryl S‐200/S‐300/S‐400 columns) to purify crude polysaccharides. Nevertheless, traditional polysaccharide purification methods often present several drawbacks. They often require significant amounts of solvent, which raises environmental concerns and generates toxic solvent residues [7, 8]. They are also associated with high cost and low efficiency. Undesirable processes such as isomerization and acid or base degradation are also likely to occur. Overall, integrated extraction and separation approaches, incorporating techniques such as, microwaves, ultrasonication, ultrafiltration membranes, and molecularly imprinted polymers, in addition to biological methods such as single enzymes and complex enzymes for protein removal, offer promising approaches for enhancing extraction efficiency while minimizing residual toxicity. Such comprehensive methodologies are increasingly gaining traction among researchers.

3. Analysis of Polysaccharide Structures

The biological activities of polysaccharides vary on the basis of their structural features (Table 1). For example, C. Xie and colleagues [9] reported that different purified Laminaria polysaccharide components have different abilities to bind bile acids. Notably, the components with a highly branched structure (akin to the porous arrangement of activated charcoal) had the strongest bile acid binding capacity. Thus, studying the structure of polysaccharides is crucial for elucidating their structure‒activity relationships. Advanced structural analysis methods, such as NMR and MS, can provide detailed insights into the isomerism and cyclic structures of compounds. The presence of triple helical structures within polysaccharides can be detected by Congo red staining. In addition, AFM, SEM, and TEM were utilized to examine the surface morphology of these polysaccharides. However, the comprehensive elucidation of NP structures remains challenging because of their complex nature. The absence of a unified standard for polysaccharide purity contributes to the limited accuracy of structural analyses. To overcome these challenges, Wang et al. [10] introduced the concept of the “relatively ordered structure” theory, which posits that the structures of polysaccharides follow certain consistent patterns. According to this theory, polysaccharide structures generally conform to distinct chemical groupings, such as pectin, arabinoxylan, glucomannan, glucan, or xyloglucan. In accordance with this theory, Hypsizygus marmoreus polysaccharide (SHMP), which was originally deemed a complex heteropolysaccharide, was fractionated into five subcomponents by Wang et al. [11, 12, 13, 14], thereby simplifying the monosaccharide composition. In addition, Nandita [15] proposed a method for the rapid identification of polysaccharides. This method works by depolymerizing polysaccharides to produce characteristic oligosaccharides, which are analyzed by HPLC‐QTOF MS and then compared to a marker library derived from standard polysaccharides. Therefore, the integration of different techniques, particularly NMR and LC‒MS, is crucial for the elucidation of polysaccharide structures and provides a basis for exploring the structure‒activity relationships of these molecules.

TABLE 1.

The structure and activity of common natural polysaccharides.

Source	Monosaccharide composition	Backbone	Molecular weight	Surface morphology	Biological activities	Reference
Chinese wolfberry	Ara:Gal:Rha = 55.6:35.5:8.0	A main chain consisting of a repeated unit of →6)‐β‐Galp(1 → residues with branches composed of α‐Araf, β‐Galp and α‐Rhap residues at position C‐3	112.97 kDa	—	LBP‐W exhibits anti‐obesity effects by modulating the composition of intestinal flora and the metabolism of short‐chain fatty acids (SCFAs).	[16]
Crassostrea gigas	Glc:Man:GlcN:Xyl = 96.97:1.15:0.97:0.91	The main chain consists of a repeated unit of →6)‐β‐Galp(1→ residues with branches composed of α‐Araf, β‐Galp, and α‐Rhap residues at position C‐3	5.56 ×106 Da	—	OPS significantly alleviates weight gain, dyslipidemia, and metabolic endotoxemia in obese mice induced by a high‐fat diet (HFD)	[17]
Wild Morels	D‐Man: D‐Glc: D‐Gla: L‐Rha = 43.15: 19.56: 20.25: 1	The main chain consists of a repeated unit of →6)‐β‐Galp(1→ residues with branches composed of α‐Araf, β‐Galp, and α‐Rhap residues at position C‐3	3.974×103 kDa	—	MP stimulates lymphocyte proliferation and may improve gut microbiota composition and SCFA production	[18]
Ganoderma amboinense	Glc:Man:Gal:Fuc = 52.54:15.78:27.16:4.21	—	—	—	GAP has a regulatory effect on the gut microbiota of HFD‐mice. Effective in preventing weight gain and fat accumulation. Improves glucose tolerance. Reduces serum and liver lipid concentrations and inflammation.	[19]
Atractylodes macrocephala	Man:Glc:Rha:Gal:Ara = 60.67:14.99:10.61:8.83:4.90	1, 3 linked β‐D‐Galp and 1,6‐linked β‐D‐Galp residues	2.325×103 kDa	Cluster and have a complex polymer structure network	RAMPtp can protect against DSS‐induced intestinal injury through a novel lncRNA ITSN1‐OT1	[20, 21]
Purple sweet potato	D‐Rha:D‐Ara:D‐Gal:D‐Glc:D‐Xly:D‐Man:GlcA = 4.3:6.3:16.5:10.8:1:1.8:16	α‐pyranose containing 1→2, 1→2,6, 1→4, 1→4,6 glycosidic bonds	1.66×103 kDa	—	PSPP alleviates diarrhea and improves structural damages in the ileum caused by lincomycin hydrochloride. Decreases levels of IL‐1β, IL‐6, and TNF‐α, but increases IL‐10 in the intestines of mice Changes the composition and diversity of the intestinal flora of mice with AAD. Increases the content of short‐chain fatty acids (SCFAs).	[22]
Spirulina	D‐Rib:L‐Rha:L‐Ara:L‐Fuc:D‐Glc = 1:0.70:1.03:2.1:6.59	β‐pyran polysaccharide with 1→2, 1→3, and 1→4 glycosyl bonds	623.02 kDa	Linear filament structure with a width of 34.132 nm and a height of 819.169 pm	Promotes intestinal barrier function by preventing oxidative stress‐induced disruption of Caco‐2 monolayers. Inhibits proliferation of Caco‐2 and HepG2 cells.	[11]

4. Polysaccharides Affect the Biological Barrier (Gut Microbiome) as Fermentation Substrates

Prebiotics are a class of food components that cannot be digested by human enzymes. They selectively promote the growth and activity of beneficial microorganisms in the gut, thereby providing health benefits to the host. Prebiotics help maintain gastrointestinal health by inhibiting pathogens and stimulating the immune system. They can also prevent various diseases caused by gut microbiota dysbiosis by modulating the composition and activity of the gut microbiota and altering the gut environment. By serving as prebiotics, polysaccharides facilitate a favorable environment for the growth of probiotic strains in the gut while inhibiting the proliferation of potential pathogens such as Clostridium [23]. Inulinfructan (ITF) has been shown to improve the intestinal environment by inhibiting the growth of Clostridium difficile, a pathogen associated with severe diarrhea, colitis, and mortality, as demonstrated in vitro [24]. Consequently, this adaptation influences the composition of the gut microbiota and helps to restore the disrupted gut barrier function caused by broad‐spectrum antibiotics. Buckwheat pollen polysaccharide (WFPP) has also been studied by researchers, who reported its ability to increase sIgA secretion, suppress inflammatory responses, and alleviate antibiotic‐induced microbiota dysbiosis [25].

Polysaccharides also contribute to the accumulation of SCFAs in the colon. SCFAs are synthesized by carbohydrate fermentation as direct energy substrates for IECs, where SCFAs promote their proliferation and strengthen the gut biological barrier. Prebiotics such as inulin have been used to treat metabolic disorders and ulcerative colitis (UC) in mice by potently increasing SCFA concentrations [26]. In addition, the mechanism of action of durian peel polysaccharides, Scutellaria baicalensis polysaccharides, and Lycium barbarum polysaccharides in IBD in mice involves an increase in SCFA levels. Therefore, the reported studies have recognized the importance of SCFAs in maintaining epithelial integrity and restoring biological barrier function, and the mechanisms may include (1) lowering the pH of the intestinal environment and inhibiting the reproduction of pathogenic bacteria (Goldsmith et al. [27]); (2) regulating cell permeability and solute trafficking by regulating the expression of tight junction protein (TJ protein) (Mörkl et al. [28]); and (3) butyric acid, which has been shown to induce the production of antimicrobial peptides (AMPs), which are important substances produced by IECs to maintain intestinal biological barrier function (Zhao et al. [29]) (Figure 1).

FIGURE 1.

The composition of the gut microbiota is related to diet and host control of microbial growth. CO₂, carbon dioxide; FAs, fatty acids; O₂, oxygen (cited from []).

5. Polysaccharides Affect the Gut Microbiome by Improving Gut Homeostasis

In addition to their role as nutrients, polysaccharides can influence the gut microbiome by improving its balance. The dietary choices and host factors that govern microbial proliferation determine the structure and functionality of the adult gut microbiota (Figure 2). In the small intestine lumen, the host supplies oxygen and nitrate, promoting bacteria that generate energy through respiration. Conversely, in the colon, a community of bacteria specializing in fermentation for growth is favored by the host, which limits the availability of oxygen and nitrate [30, 31]. While diet shapes the composition of the microbiota, a poor diet weakens the host regulatory mechanisms that oversee the microbiota. Polysaccharides can improve the intestinal balance by maintaining intestinal epithelial barrier integrity, which is achieved by inhibiting oxidative stress, regulating the expression of inflammatory cytokines, increasing the expression of TJ proteins, and indirectly modulating intestinal immunity. Consequently, polysaccharides may influence the gut microbiome by improving intestinal equilibrium.

FIGURE 2.

Protective effects of natural polysaccharides on intestinal barrier injury. AMP, antimicrobial peptide; GPx, glutathione peroxidase; GSH, reduced glutathione; IFN, interferon; MDA, malon dialdehyde; MUC, mucin; MyD88, myeloid differentiation factor 88; NF‐κB, nuclear factor κB; ROS, reactive oxygen species; slgA, secretory IgA; SOD, superoxide dismutase; TLR, toll‐like receptor (cited from Huo et al. [108]).

5.1. Host Factors Influence and Guide the Growth of Microbes

5.1.1. Redox Reactions Select Successful Metabolic Strategies for Microbial Communities

Bacterial proliferation relies on adenosine triphosphate (ATP) to fuel biosynthetic activities, which are generated by redox reactions involving the transfer of electrons from an electron donor (such as glucose) to an electron acceptor (such as O₂). Bacteria can be grouped into different metabolic categories on the basis of the redox reactions they use to produce ATP, with each group using similar resources in analogous ways []. For example, facultatively anaerobic bacteria are capable of producing ATP utilizing oxygen or nitrate (NO₃‐) but are able to switch to fermentation in the absence of these electron acceptors. Another important metabolome is that of obligate anaerobic primary fermentation bacteria, which cannot grow under aerobic conditions. These organisms generate ATP by oxidizing carbohydrates via internal electron acceptors such as pyruvate or phosphoenolpyruvate. Microbes that efficiently optimize ATP production in their respective environments are more likely to grow rapidly and become dominant within their microbial communities. Thus, in natural environments, the composition of bacterial communities is predominantly influenced by redox reactions that produce the greatest amount of free energy [32]. The oxygen level in the intestine decreases from the duodenum to the colon. Facultatively anaerobic bacteria that use oxygen as an electron acceptor with the highest redox potential are predominant in the small intestine. When oxygen levels are low, these bacteria switch to oxidizing organic compounds via nitrate, the next most favorable electron acceptor after oxygen [33]; in the colon, owing to the limited availability of oxygen and nitrate, obligate anaerobic primary fermenters become dominant. The composition of the gut microbial community is influenced by the preference for oxygen or nitrate. As a result, the low‐density microbial community in the small intestine is dominated by facultatively anaerobic bacteria belonging to the class Bacilli (phylum Firmicutes) and the order Enterobacterales [ord. nov. [30], phylum Proteobacteria], whereas obligately anaerobic primary fermenters belonging to the classes Bacteroidia (phylum Bacteroidetes) and Clostridia (phylum Firmicutes) dominate the high‐density microbial community in the large intestine [31, 34].

5.1.2. The Host Selects which Metabolic Groups Dominate the Gut Microbiota

It is generally believed that microbial oxygen consumption is primarily determined by the availability of electron acceptors in the gut. This finding suggested that as the contents of the small bowel pass through the large intestine, facultatively anaerobic bacteria create an oxygen gradient by progressively depleting this electron acceptor, thus maintaining anaerobic conditions in the large intestine [35]. However, certain observations challenge this idea. For example, the luminal level of oxygen in the duodenum of germ‐free mice is very similar to the tissue level, suggesting that oxygen is derived from the circulation and diffuses freely from the tissue into the lumen of the duodenum. In contrast, the host maintains a state of physiological hypoxia (less than 1% O₂) in the colonic epithelium to restrict the diffusion of oxygen into the colon [36]. This mechanism creates an effective anaerobic state that is maintained in the cecum of germ‐free mice by regulating the luminal oxygen concentration in the cecum to approximately 0.6%. This study suggests that the host is responsible for the establishment and maintenance of the oxygen gradient along the longitudinal axis of the intestinal lumen rather than microbial oxygen consumption alone.

The host actively regulates the levels of oxygen and nitrate within the intestinal lumen, maintaining elevated oxygen levels in the proximal small intestine and supplying nitrate to the distal small intestine. This distribution of electron acceptors influences the dominance of microbial communities in the gut. In the small intestine, where oxygen and nitrate are readily available, facultatively anaerobic bacteria thrive [31]. Conversely, in the colon, where access to oxygen and nitrate is limited, obligate anaerobic primary fermenters, including members of the Bacteroidia and Clostridia classes, become dominant. These investigations underscore the role of the host in controlling the availability of oxygen and nitrate in the gut by modulating epithelial hypoxia and the production of inducible nitric oxide synthase (iNOS) [37]. By modulating the availability of these electron acceptors along the length of the intestine, the host dictates which microbial metabolic strategies predominate in the small and large intestines. This regulatory mechanism is consistent with the thermodynamic principles that govern the composition of bacterial communities in natural settings.

5.2. Effects of Polysaccharides on Improving Gut Homeostasis

Research indicates that NPs serve a vital function in safeguarding the gut barrier and promoting overall health. Research has explored the mechanisms by which NPs affect the intestinal barrier, focusing on three key aspects.

5.2.1. Protective Effects on the Intestinal Mechanical Barrier

Inhibition of oxidative stress and protection of the antioxidant system. Various studies have highlighted the detrimental effects of oxidative stress on IECs, which are characterized by an imbalance between oxidation and antioxidation processes leading to the overproduction of reactive oxygen species (ROS). The excessive release of ROS derivatives is a major contributor to tissue injury, promoting lipid peroxidation and increasing malondialdehyde (MDA) levels, which can consequently lead to damage of the intestinal mechanical barrier through interactions with various amino acid groups [38]. In particular, studies have demonstrated the ability of NPs to reduce ROS and MDA levels, thereby attenuating intestinal injury in IBD patients [39]. For example, polysaccharides from Hypnea musciformis (PLS) have been shown to decrease MDA levels within the colonic tissues of rats with TNBS‐induced IBD, in addition to suppressing the overproduction of inducible iNOS and peroxynitrite [40]. In addition, mushroom polysaccharides have shown protective effects against lipopolysaccharide (LPS)‐induced IBD in chickens by lowering the transcript levels of iNOS and cyclooxygenase‐2 in the jejunal mucosa [41]. Furthermore, dysregulation of the antioxidant defense system, which includes both enzymatic (like superoxide dismutase and glutathione peroxidase) and nonenzymatic (e.g., ascorbic acid, glutathione) components, is a central mechanism underlying IBD Research indicates that Enteromorpha polysaccharides can enhance intestinal function in various animal models by increasing the activities of antioxidant enzymes such as SOD, GPx, and CAT [42]. Similarly, oat fiber β‐glucan has been shown to increase the activity of antioxidant enzymes and modulate the redox balance in the spleens of rats with LPS‐induced enteritis. This antioxidant effect of polysaccharides is attributed to the presence of heteroatoms such as hydrogen, which act as radical scavengers [43]. These findings suggest the ability of these compounds to protect the intestinal epithelium from damage caused by ROS through the combined activity of enzymatic and nonenzymatic antioxidant mechanisms.

Preventing inflammatory disruption of the structural and functional integrity of the intestinal epithelial barrier can disrupt the balance of the mucosal immune system, leading to an inflammatory response that exacerbates barrier dysfunction. Polysaccharides have been shown to attenuate the levels of proinflammatory agents, which are often induced by dendritic cells (DCs) and macrophages through interactions with the symbiotic microbiota and Toll‐like receptor (TLR) pathways. For example, lactulose has demonstrated efficacy in alleviating TNBS‐induced colitis in rats by downregulating TNF‐α levels, thereby ameliorating epithelial cell damage and mucosal ulceration [44]. [. Moreover, Zizyphus jujuba cv. Muzao polysaccharide (ZJP) was shown to protect against intestinal epithelial barrier dysfunction in mice subjected to cecal ligation and perforation sepsis by lowering the levels of proinflammatory cytokines (TNF‐α, IL‐1β, and IL‐6) and blocking the activation of TLR4/NF‐κB signaling (Zhou et al. 2020b). These studies showed that polysaccharides modulate several pathways to reduce inflammatory cytokine expression and protect against gut barrier dysfunction. Additionally, polysaccharides alleviate inflammation by increasing the expression of anti‐inflammatory factors (; [45, 46]). Interleukin‐10 (IL‐10) is a regulatory cytokine that inhibits antigen presentation and the release of proinflammatory cytokines. It also enhances the expression of anti‐inflammatory molecules, such as IL‐1 receptor antagonists, soluble TNF‐α receptors, and tissue inhibitors of matrix metalloproteinases. These actions serve to alleviate inflammation and maintain the integrity of the intestinal epithelial barrier [47, 48, 49]. Daguet et al. [50] reported that an arabinogalactan with a molecular weight of 200 kDa improved the transepithelial electrical resistance (TEER) of Caco‐2 cells. It also reduced NF‐κB activity, induced IL‐10 production, and inhibited the increase in distal colonic permeability. Another study by Majumder et al. [51] revealed that isomaltodextrin enhances IL‐10 expression in mice with DSS‐induced colitis by suppressing TLR4 expression, suggesting that TLR4 inhibition represents a promising approach for mitigating inflammation.

Regulation of TJ protein expression and recombination. TJs are crucial for maintaining the selective permeability of the intestinal barrier. Typically, modulating the expression of TJ proteins (either downregulating or upregulating) or translocating them through different intracellular pathways can alter the selective permeability of the intestine [52, 53]. Using tissue mounted via the Ussing chamber technique, the barrier function of TJs and intestinal permeability can be directly assessed in vitro. As quantifiable indicators of gut barrier integrity, a reduction in TEER and an increase in the paracellular flux of macromolecules such as dextran, phenol red, or mannitol are measured [54]. Polysaccharides from Plantago asiatica L., adlay bran, and spirulina have been shown to play a protective role in intestinal cells by maintaining epithelial barrier integrity [55, 56, 57]. The assessment of intestinal barrier function can also be carried out indirectly by the analysis of TJ proteins or by the serological detection of LPS and D‐lactate in the blood [58, 59]. Studies by Wang et al. [60] have shown that Astragalus polysaccharides, xylooligosaccharides, and their complexes can improve the growth of broilers by strengthening the intestinal epithelial barrier, which is commonly compromised by disease, nutrition, or environmental factors. The results revealed reduced levels of D‐lactic acid and diamine oxidase in broiler blood plasma and increased gene expression levels of occludin, claudin‐3, and claudin‐1 in the jejunum. Overall, polysaccharides can increase the expression of TJ proteins through the activation of relevant pathways to repair intestinal barrier damage and maintain intestinal barrier integrity. However, further exploration is needed to elucidate the specific regulatory mechanisms and receptors associated with polysaccharide‐mediated promotion of TJ protein expression.

5.2.2. Effects on Intestinal Immunity

The gastrointestinal tract functions as an important immune organ that harbors a diverse repertoire of immune cells, including B cells, T cells, and innate lymphoid cells [61]. Polysaccharides exhibit robust immunomodulatory effects by modulating various immune cell types, such as antigen‐presenting cells, neutrophils, DCs, macrophages, B cells, T cells, and various cytokines, thereby playing a pivotal role in immune responses [47, 62, 63]. These polysaccharides can initiate signaling cascades by binding to TLRs, eventually leading to the upregulation of relevant gene expression and protein synthesis. In macrophages, the major signaling pathways that regulate the immune response include the MAPK and NF‐κB pathways [64, 65]. Numerous polysaccharides have been shown to activate macrophages and increase the production of nitric oxide and other proinflammatory cytokines by activating signaling proteins such as ERK and p38 [3, 66–68]. For example, a polysaccharide derived from Lepidium meyenii (LMP‐1) obviously upregulates the expression of TLR4 and TLR2, leading to immune cell activation. In addition, LMP‐1 increases the expression of p65 in both the cytoplasm and nucleus, thereby activating the TLR/NF‐κB signaling pathway and enhancing immunity [69]. Similarly, polysaccharides from Dendrobium huoshanense promote IL‐12 secretion and regulate the immune response in lamina propria cells (LPCs) by directly interacting with intestinal epithelial cells (IECs) via TLR4 [70, 71]. 72

5.2.3. Inhibiting Apoptosis

NPs have been shown to protect the intestinal epithelial barrier through preventing apoptosis. Research has demonstrated that G. lucidum spore polysaccharides protect intestinal epithelial barrier integrity both in vivo (in mice) and in vitro (in IEC‐6 cells) by inhibiting apoptosis through the inhibition of microtubular polymerization [72]. Research has additionally demonstrated that low‐molecular‐weight chitosan (LMWC) reduces jejunal and ileal epithelial cell apoptosis in enterotoxigenic Escherichia coli (ETEC)‐infected weaned piglets. Apoptosis, which can be split into endogenous (mitochondrial) and exogenous (death receptor) pathways, is a genetically regulated cell death process. The endogenous apoptosis pathway is stimulated by various intracellular stresses, modulated by Bcl‐2 and its counterparts, and results mainly in the activation of caspase‐9 [73]. Conversely, the activation of death receptors (such as Fas and TNFR1) on the cell membrane by homologous ligands of the TNF superfamily results in the recruitment of caspase‐8 via FADD, thereby initiating exogenous apoptosis. Both pathways lead to the activation of caspase‐3, which then triggers the caspase cascade, ultimately leading to apoptosis. According to Wan et al. [74], LMWC supplementation in weaned ETEC‐infected piglets decreased TNFR‐1 and FADD mRNA levels and cleaved caspase‐3 and ‐8 protein levels in the jejunum and ileum. Thus, LMWC may attenuate ETEC‐induced intestinal barrier injury by inhibiting TNFR1‐mediated intestinal epithelial cell apoptosis.

5.2.4. Other Methods

Studies have shown that high‐viscosity polysaccharides can form a protective layer on the intestinal mucosa similar to intestinal mucus, a property that allows it to preserve intestinal barrier function. For example, Piqué et al. [75] extracted a natural polysaccharide, xylan, from tamarind seeds because its “mucin‐like” adhesion properties give xylan a barrier‐like function in the gastrointestinal tract, thereby reducing bacterial adhesion and invasion. Therefore, Xylan is expected to be a safe and effective alternative to drugs for the treatment of gastrointestinal disorders because of its film‐forming protective barrier properties.

6. Polysaccharides, the Intestinal Flora, and Diseases

Recently, the pathogenesis of diseases such as obesity, diabetes, and IBD has been reported to be related to dysbiosis of the GM Polysaccharides can improve these diseases by regulating the intestinal flora, and the main effects and mechanisms are shown in Table 2.

TABLE 2.

Effects of natural polysaccharides on the gut microbiota and the control of related diseases.

Source	Polysaccharide	Disease control	Intestinal flora	Metabolite	Reference
Chinese wolfberry	Homogeneous polysaccharide	Anti‐obesity	Increase the relative abundance of Lactobacillus and reduce the relative abundance of Proteus, Firmicutes, and Bacteroides	Increase in the output of acetic acid, propionic acid and butyric acid	[16]
Rosa roxburghii	Water‐soluble polysaccharide	Anti colitis	Reduce the ratio of Firmicutes/Bacteroides, and significantly increase the abundance of beneficial bacteria (Ruminococcus caeae, Muribaculeae, and Akkermaniacaea)	All SCFA levels increased significantly	[84]
Masson pine pollen	Heteropolysaccharides	Anti‐colitis	The relative abundance of Bacteroides (Bacteroidaceae, Muribagulaceae, Rikenellaceae, Prevotella), Actinomyces (Bifidobacteriaceae) and Lachnospira	Increase in the production of acetic acid and propionic acid	[83]
Radix Pseudostellariae	Water‐soluble polysaccharide	Regulate immunity	Restore the relative abundance of Odoribactor and Mucispirillum, and reduce the relative abundance of Sporosarcina, Yaniella, and Jeotgalicicus	—	[91]
Tea mushroom	Water‐soluble polysaccharide	Hypolipidemic	Reduce the relative abundance of Firmicutes and Streptococcus, and increase the relative abundance of Bacteroides	Increase in butyric acid production	[92]
Ganoderma lucidum and Polyporus umbellatus	Water‐soluble polysaccharide	Anti‐colitis	Significant increase in lactic acid bacteria content, Desulfovibrio and Alistipes finegoldii content decreased significantly	Upregulation of SCFA metabolism	[80]
Jujube	Water‐soluble polysaccharide	Colon cancer	Increase the relative abundance of Bacteroides and Actinomycetes and significantly reduce the relative abundance of Firmicutes, Cyanophyta, Diasporobacteria, Spirochaeta, and Myxomycetes	—
Papyrus	Water‐soluble polysaccharide	Liver injury	The relative abundance of Desulfobacterota and Deferobacterota was reduced, and the relative abundance of Bdellovibrionota was significantly increased	Generate SCFA, including acetate and butyrate	[93]
Honeysuckle	Water‐soluble polysaccharide	Ulcerative colitis, regulating immunity	The relative abundance of Bifidobacteria and lactic acid bacteria was significantly increased, and the relative abundance of Bifidobacteria and lactic acid bacteria was significantly reduced	—	[85]
Grains insect	Homogeneous polysaccharide	Enteritis	Increase the relative abundance of Bacteroides and decrease the relative abundance of Firmicutes	Increased levels of total SCFAs, acetic acid and butyric acid
Garlic	Water‐soluble polysaccharide	Hypolipidemic	Significantly reduce the ratio of intestinal Firmicutes and Bacteroides, and increase the abundance of intestinal probiotics Akkermannsia	—	[94]
	Water‐soluble polysaccharide	Functional constipation	The relative abundance of Lactobacillus and Romboutsia increased, and the relative abundance of Lachnospiraceae_NK4A136_group and Roseburia decreased	—
Tibet Opuntia ficus‐indica	Water‐soluble polysaccharide	Regulate body immunity	It significantly regulates the relative abundance of Lactobacillus, Bacteroides, and Akkermania, and the newly added dominant bacteria in the intestine are Deferribacteres, Actinomycetes, Firmicutes, Tenericutes, Actinomycetes, and Pasteurella	—	Liu et al. [110]
Polygonatum odoratum	Water‐soluble polysaccharide	Anti‐obesity	Reduced the relative abundance of Clostridium, Enterococcus, Coprobacillus, Lactococcus, and Sutterella	Increased content of isobutyric acid, butyric acid, and valeric acid	[13]
	Water‐soluble polysaccharide	Anti‐obesity	Significantly increases the abundance of Parabacteroides, Bacteroides, and Lachnospiracea incertae sedis	—
Oysters	Water‐soluble polysaccharide	Anti‐obesity	It increases the relative abundance of beneficial bacteria (Bifidobacteria, Lactobacillus, Dobosiella, and fecal bacteria) and decreases the relative abundance of harmful bacteria (clostridium erysipelas, Helicobacter pylori, and mucus bacteria)	The output of acetic acid, propionic acid and butyric acid is significantly increased	[17]
Kelp	Water‐soluble polysaccharide	Anti‐obesity	The ratio of Firmicutes to Bacteroides was reduced, and the relative abundance of Verrucomycobia, Bacteroides, and Akkermansia was increased	Significantly increase the content of total SCFAs and propionic acid
Trichosporon sinensis	Water‐soluble polysaccharide	Anti‐obesity, type 2 diabetes	Significantly increased the relative abundance of Parabacteroides goldsteinii	—	Wu et al. [109]
Morel	Water‐soluble polysaccharide	Mediated immunity	Significantly increased the relative abundance of Bacteroides and Ruminococcaceae	Increased production of acetic acid, propionic acid, butyric acid, and valeric acid	[18]
	Water‐soluble polysaccharide	Functional constipation	Akkermansia, Lactobacillus, Butyricimonas, Candidatus arthromitus, and Prevotella, reducing the flora abundance of Clostridium and Dorea	—
	Water‐soluble polysaccharide	Functional constipation	Reduce the abundance of pathogenic bacteria (Desulfovibrio) and increase the relative abundance of beneficial bacteria (Lachnospiraceae_NK4A136_group)	Significant increase in SCFAs
Spirulina	Heteropolysaccharides	Lung cancer	Significantly increased the number of beneficial bacteria (such as Lactobacillus, Allobaculum, Alloprevotella, and Olsenella); decreased the abundance of conditional pathogens (such as Bacteroides and Acinetobacter); and increased the Firmicutes/Bacteroidetes (F/B) ratio.	—	Lu et al. [88]
Ganoderma lucidum	Heteropolysaccharides	Melanoma	Increase the population of Bacteroides and decrease the population of Christensenellaceae, Desulfovibrio, Odoribacter, and Parvibacter	—	[89]

6.1. Effects of Polysaccharides on Obesity and Related Metabolic Disorders Through the Intestinal Flora

Obesity is a disease that damages human health due to the excessive accumulation of fat, and obesity can develop for a wide range of reasons. The dramatic increase in the obese population has become a health challenge faced by countries around the world. Although people can control their body weight through surgery, diet control, or increased exercise, they are prone to rebound or even severe adverse effects. Recent studies have shown that polysaccharides extracted from plants such as Chinese hairy spores, plantain, and Grifola frondosa can exert beneficial effects on high‐fat diet‐induced metabolic disorders in obese mice by modulating bacterial diversity [77]. Yang et al. [16] reported that LBP‐W, a homogeneous polysaccharide isolated and purified from L. barbarum, can improve obesity by regulating the makeup of the intestinal flora and SCFA metabolism in mice fed a high‐fat diet without inhibiting appetite and energy extraction, suggesting that LBP‐W may be used as a prebiotic preparation to prevent obesity and related metabolic disorders. Ren et al. [19] reported that the abundances of Parabacteroides, Bacteroides, and Lachnospiracea incertae sedis in HFD‐fed mice increased in response to intervention with G. lucidum polysaccharide (GAP). These three genera play regulatory roles in promoting GAP decomposition, maintaining glucose homeostasis and anti‐inflammatory effects, and other key nodes of obesity. These findings indicate that GAP has great potential for development into a natural antiobesity drug.

6.2. Effects of Polysaccharides on IBD Through the Intestinal Flora

IBD is a disease characterized by disruption of the mucosal structure, intestinal microbial imbalance, and systemic biochemical abnormalities. UC and Crohn's disease (CD) are the two major disease subtypes of IBD [78]. According to statistics, more than 6.8 million people are affected worldwide, and it is expected that by 2030, more than 1% of the world's population will be affected. The specific pathogenesis of IBD is unknown, and the influencing factors include the environment, genes, and living habits [79, 80]. At present, glucocorticoids are commonly used in clinical treatment. However, these drugs have difficulty effectively inhibiting disease progression and have serious side effects on liver function and the nervous system [81]. Although the exact cause of IBD is unknown, NPs have been shown to improve IBD symptoms by regulating the gut microbiota, repairing the integrity of the intestinal barrier, activating inflammatory‐related pathways, and modulating the immune response [82, 83]. According to a study by Wang et al. [84], Rosa roxburghii Tratt fruit polysaccharide (RTFP) can be used as a natural anti‐inflammatory agent to improve chronic obese colitis. By regulating the intestinal flora, RTFP can reduce the ratio of Firmicutes and Bacteroidetes as well as the relative abundance of pathogenic bacteria, which can significantly promote the proliferation of beneficial bacteria. Therefore, it can improve metabolic disorders in the intestinal flora and reduce the inflammatory response. H.C. Zhou et al. [85] reported that, compared with those in normal mice, Lactobacillus, Bifidobacterium, and immunoglobulin A (SIgA, which are secreted by intestinal mucosal plasma cells and play important roles in immune regulation and anti‐inflammation) in the intestines of UC mice are significantly reduced, whereas Escherichia coli and Enterococcus are significantly increased. Ingestion of honeysuckle polysaccharide (LJP) significantly reversed the intestinal flora imbalance in UC model mice. L. Y. Li et al. [80] synthesized a complex polysaccharide called GPP, which consisted of 3 parts of GLP and 1 part of Polyporus umbellatus polysaccharide (PUP). Studies have shown that GPP can significantly reverse the decrease in Lactobacillus content in the mouse intestine and the increase in Alistipes finegoldii and Desulfovibrio contents caused by DSS and subsequently reduce DSS‐induced colon injury in model mice. A. finegoldii can be used as a microbial driver to induce colitis and tumors [86], and Desulfovibrio is a major sulfate‐reducing bacterium (Chen et al. 2019). It is closely associated with the onset of ulcerative enteritis [87].

6.3. Effects of Polysaccharides on Cancer Through the Intestinal Flora

Cancer (a malignant tumor) is a serious threat to human life and health worldwide. Polysaccharides might contribute to inhibiting tumor growth by regulating the intestinal flora, protecting the intestinal mucosal barrier, and reducing inflammatory damage. Ji et al. reported that in AOM/DSS‐induced colorectal cancer model mice after receiving jujube polysaccharide (JP) treatment, intestinal microorganisms were activated. At the genus level, Bacteroidetes and Actinobacteria increased, and Firmicutes, Cyanophyta, Diasporobacteria, Spirochetes, and Myxomycetes significantly decreased in relative abundance. These bacteria are involved in JP degradation and differential gene expression upregulation, produce an anti‐inflammatory factor pathway, and can improve colitis caused by intestinal flora disorders to prevent colon cancer. According to Lu et al. [88], Spirulina polysaccharide (PSP) can significantly reduce the tumor volume and weight of lung cancer‐bearing mice. Moreover, after PSP treatment, the gut microbiota structure of the lung cancer‐bearing mice significantly changed (increasing the abundance of Lactobacillus, Allobaculum, Alloprevotella, and Olsenella but decreasing the abundance of Bacteroides and Acinetobacter) and increasing the Firmicutes/Bacteroidetes (F/B) ratio. These findings indicate that PSP may maintain intestinal homeostasis by altering the abundance of probiotics and harmful bacteria in the gut microbiota, thereby achieving antitumor effects. A study by Xian et al. [89] revealed that G. lucidum polysaccharide peptide (GL‐pp) has antimetastatic activity against melanoma by alleviating gut microbiota dysbiosis. Specifically, GL‐pp altered the composition of the gut microbiota in melanoma‐bearing mice by increasing the abundance of Bacteroides and decreasing the numbers of Christensenellaceae, Desulfovibrio, Odoribacter, and Parvibacter.

6.4. Effects of Polysaccharides on Regulating Immunity Through the Intestinal Flora

Cyclophosphamide (Cyp) is a commonly used anticancer chemotherapeutic drug, but its use may cause damage to the body's immune cells. Therefore, the concomitant administration of drugs or dietary supplements with immunomodulatory properties has become a necessary option to mitigate side effects. The intestinal flora is closely linked to the immune system in that it produces beneficial metabolites and modulates the activity of immune cells, whereas polysaccharides, as nutrient sources for the intestinal flora, can promote the growth and reproduction of beneficial bacteria, thereby increasing the proportion of beneficial bacteria, which are frequently utilized as biological response modifiers (Table 2) [90]. Kan et al. [91] reported that Pseudostellaria polysaccharide (PF 40) regulates the intestinal flora by restoring the relative abundance of Odoribacter and Mucispirillum, reducing the relative abundance of Sporosarcina, Yaniella, and Jeotgalicoccus, and reducing the degree of immunosuppression caused by chemotherapy. Liu et al. [110] reported that the intake of Tibetan cactus polysaccharides (ODPs) significantly regulated the relative abundance of Akkermansia, Lactobacillus, and Bacteroides while increasing the presence of dominant flora such as Actinomycetes, Deferribacteres, Pasteurella, Tenericutes, and Firmicutes in the gut. This modulatory effect is achieved by regulating the intestinal flora and its metabolism and has an impact on the immune system.

7. Conclusions, Challenges, and Future Perspectives

With advances in research on the regulatory effects of polysaccharides on the gut microbiota and their influence on metabolic diseases, increasing attention has been given to their molecular mechanisms in disease treatment. Studies have demonstrated that polysaccharides can modulate the gut microbiota composition, increase probiotic populations, improve the intestinal microenvironment, strengthen intestinal barrier function, and thereby contribute to disease management and homeostasis. Despite these promising therapeutic benefits, significant challenges remain in the development of polysaccharide‐based therapies.

One major obstacle is the incomplete identification and characterization of certain polysaccharides, hindering the understanding of their structure–activity relationships. Innovative methods for the separation and purification of polysaccharides—such as ultrafiltration membrane extraction, molecularly imprinted polymers, and enzymatic technologies—are essential for accurate structural analysis, alongside emerging theories such as the “relatively ordered structure” (Wang et al. [111]).

Polysaccharide research has relied predominantly on animal studies, yet differences between rodent and human intestinal structure, gut microbiota composition, and nutrient metabolism limit translational accuracy. Zebrafish, whose gut genes closely resemble those of humans, present a valuable alternative model for studying the impact of polysaccharides on the gut microbiota and human health Furthermore, while some key pathways in the polysaccharide–gut microbiota–host health triad have been identified, the underlying molecular mechanisms remain poorly understood. Advanced technologies such as RNA sequencing (RNA‐seq) could reveal new biological processes and molecular mechanisms, offering deeper insights into the interactions among polysaccharides, the gut microbiota, and host health [95].

Author Contributions

Yigang Huang: resources, writing–review and editing. Yuchen Liu and Hongfei Guo: conceptualization, visualization, data acquisition. Jinjin Pei: acquisition, funding acquisition, resources, investigation, review and editing. Wengang Jin and Chella Perumal Palanisamy: supervision, resources, investigation, and formal analysis. Fatih Oz and A. M. Abd El‐Aty: conceptualization, formal analysis, validation, writing–review and editing.

Conflicts of Interest

The authors declare no conflicts of interests.

Huang Y., Guo H., Liu Y., Jin W., Palanisamy C. P., Pei J., Oz F., Abd El‐Aty A. M., Effects of Natural Polysaccharides on the Gut Microbiota Related to Human Metabolic Health. Mol. Nutr. Food Res. 2025, 69, e202400792. 10.1002/mnfr.202400792

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.