key: cord-0030346-064jleve
authors: Li, Qi; Li, Linyan; Li, Qiqiong; Wang, Junqiao; Nie, Shaoping; Xie, Mingyong
title: Influence of Natural Polysaccharides on Intestinal Microbiota in Inflammatory Bowel Diseases: An Overview
date: 2022-04-09
journal: Foods
DOI: 10.3390/foods11081084
sha: 72f65443200cd8895d186f4475478f4364f6941a
doc_id: 30346
cord_uid: 064jleve

The incidence of inflammatory bowel disease (IBD) has increased in recent years. Considering the potential side effects of conventional drugs, safe and efficient treatment methods for IBD are required urgently. Natural polysaccharides (NPs) have attracted considerable attention as potential therapeutic agents for IBD owing to their high efficiency, low toxicity, and wide range of biological activities. Intestinal microbiota and their fermentative products, mainly short-chain fatty acids (SCFAs), are thought to mediate the effect of NPs in IBDs. This review explores the beneficial effects of NPs on IBD, with a special focus on the role of intestinal microbes. Intestinal microbiota exert alleviation effects via various mechanisms, such as increasing the intestinal immunity, anti-inflammatory activities, and intestinal barrier protection via microbiota-dependent and microbiota-independent strategies. The aim of this paper was to document evidence of NP–intestinal microbiota-associated IBD prevention, which would be helpful for guidance in the treatment and management of IBD.

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a multifactorial disease characterized by immune system relapse and inflammation of the gastrointestinal tract. An epidemiological study in 2017 reported that more than 6.8 million people suffered from IBD globally [1] [2] [3] . Although the etiology and pathogenesis of IBD are currently unclear, studies have reported that IBD is linked to the environment, microorganisms, and immune mediators of genetically susceptible hosts [4] . Conventional drugs for IBD patients mainly include anti-inflammatory drugs such as 5aminosalicylic acid (sulfasalazine, olsalazine, and mesalazine), immunosuppressive drugs such as glucocorticoids (prednisolone and beclomethasone dipropionate), azathioprine, and 6-mercaptopurine, and biological products, such as infliximab, adalimumab, and golimumab [5] . Although those drugs are available for use in IBD treatment, they are associated with a range of side effects, such as weakened immunity. In addition, the major challenge encountered in IBD treatment is the limited initial reactivity and the high costs of biological products. Therefore, many IBD patients are still waiting for more effective and safer alternatives [6] .

Natural polysaccharides are long-chain polymers formed by more than 10-monosaccharide molecules joined together by a glycoside bond, which can be divided into lipopolysaccharides and heteropolysaccharides [7] . Based on compositional monosaccharide, they can also be classified into homopolysaccharides and heteropolysaccharides. Homopolysaccharides are a polymer composed of the same monosaccharide, such as starch, β-glucan, galactan, etc. Heteropolysaccharides are polymers composed of two or more monosaccharides, such as glucomannan, arabinogalactan, pectin, and so on [7] . They are widely distributed in natural resources, including plants, animals, fungi, bacteria, and algae. NPs are among the essential biological macromolecular substances required to maintain the everyday activities of organisms [8] . In recent decades, researchers have gradually recognized the biological roles of NPs, including hypoglycemic [9, 10] , hypolipidemic [11] , antitumor [12] , antioxidant [13] , immune modulatory [14] , and anti-inflammatory activities [15] . For example, β-glucans Lentinus, Cordyceps, and Ganoderma species were shown to have potent immunomodulatory, antitumor, and antivirus effects [16] . Arabinoxylan [17, 18] , glucomannan [19] , pectin [20] , galactomannan [21] , and other polysaccharides from plants were effective in controlling blood sugar balance and regulating intestinal microbiota. NPs also play an essential role in the treatment of colitis-related diseases [22] [23] [24] , and they are characterized by low toxicity, immunity enhancement, and prebiotic properties, in addition to facilitating IBD remission [25] . Although relatively few clinical trials have explored the use of NPs in IBD treatment, their effects under animal experiments, including in IL-10 deficient, dinitrobenzene sulfonic acid (DNBS), trinitrobenzene sulfonic acid (TNBS), and dextran sulfate sodium salt (DSS)-induced IBD mice models, have been investigated extensively [26] . According to the results of those pharmacological studies, NPs could ameliorate IBD symptoms through the activation of inflammation-related pathways, regulation of intestinal microbiota, modulation of the immune response, and repair of colon ulcer surfaces [27] .

Interactions among intestinal microbiota, intestinal mucosal barrier, and immune system systems are thought to drive the pathological process of IBD; in particular, microbiota dysbiosis is a crucial factor inducing IBD [28] . Host-microbe imbalance can lead to abnormal inflammatory responses, and thereafter, excessive and uncontrolled immune responses induce imbalance in intestinal immune function [27] . In addition, intestinal epithelial barrier dysfunction is also associated with intestinal dysbiosis and intestinal mucosa inflammation. Therefore, this review aimed to summarize the impacts of NPs on IBD prevention and treatment in view of the extensive relationships among intestinal microbiota and immune function, intestinal barrier, and inflammation. Conclusions would offer insights in facilitating innovation and research on the underlying mechanisms of IBD.

Intestinal microbiota are complex microbial communities composed of trillions of fungi, viruses, archaea, microeukaryotes, and especially bacteria. Although most of them are beneficial microorganisms, some are pathogens. Intestinal microbiota significantly affect human and animal health [29, 30] . The mechanisms involved in intestinal microbiota alleviation IBD are summarized in Figure 1 . In IBD patients, increased populations of pathogenic bacteria in the intestine lead to imbalance in intestinal microbiota composition. The pathogenic bacteria migrating through damaged thin mucus layers cannot be protected by the impaired intestinal immune system. In addition, short-chain fatty acid (SCFA) and lactic acid production could be affected the gut environments. Consequently, the microbiota lose the essential source of energy for intestinal epithelial cells. Activated mucosal macrophages generate high levels of reactive oxygen species and inflammatory cytokines and thus exacerbate inflammatory responses. Conversely, in healthy intestine, intestinal microorganisms are distributed throughout the mucosal layer, and the intestinal epithelium is intact, so they are resistant to bacterial invasion. Intestinal microbiota and their metabolites, such as SCFAs, secreted proteins, indoles, organic acids, extracellular vesicles, and bacteriocins, have positive effects on the structural and functional integrity of the intestinal barrier, tight junctions, and mucosal immune response, which inhibits the growth of pathogenic microbes and facilitates homeostasis in the intestine. 

Intestinal microbiota play essential roles in various physiological processes, such as inflammatory responses, immune system function, and energy homeostasis [31] . Over the past few decades, the impact of intestinal microbiota on host intestinal health has increasingly attracted the attention of researchers [32] . The human intestinal microbiota contains about 10 14 bacterial cells; among them, Firmicutes are the most abundant, followed by Bacteroidetes [33, 34] . Compared to healthy individuals, IBD patients have intestinal dysbiosis [35] . Dysbacteriosis, i.e., a decrease in microbial diversity, has been demonstrated in IBD diseases: for example, a decreased abundance of some beneficial bacteria, such as Erysipelotrichales, Bactereroidales, Clostridial, Bifidobacterium, and Lachnospiraceae, and increased abundance of some pathogenic bacteria, such as Enterobacteriaceae, Pasteurellcaea, Veillonellaceae, Fusobacteriaceae, Proteobacteria, Ruminococcus gnavus, and Desulfovibrio [25, 27] . Specifically, Enterorhabdus spp., Desulfovibrio spp., Alistipes spp., and Bacteroides spp. are closely associated with protective effects against colitis [36] . Changes in such bacteria result in minimal resistance to the growth and colonization of pathogenic bacteria in the gut. Although pathogenic bacteria are relatively abundant in the intestines of IBD patients [37, 38] , there is no direct evidence of a specific pathogen that causes IBD.

NPs have been demonstrated to modulate the richness and diversity of intestinal microbiota and restore the structure of intestinal microbiota, resulting in significant alleviation of IBD symptoms [25, 39] . As summarized in Table 1 , polysaccharides from plants, fungi, animals, bacteria, and algae significantly regulated intestinal microbiota composition. For example, Ziziphus jujuba Mill var. polysaccharides significantly increased Firmicutes abundance and decreased Bacteroidetes abundance [40] . Hericium erinaceus polysaccharides can significantly increase microbial diversity in the gut of UC rats, with Verrucomicrobia, Firmicutes, Bacteroidetes, and Proteobacteria richness being close to levels in healthy rats [41] . In addition, Glycyrrhiza polysaccharides can regulate intestinal microbiota composition, with Enterorhabdus spp., Odoribacter spp., Ruminococcaceae_UCG_014, and Ruminiclostridium 5 as the potential targets [42] . Fucoidan could inhibit 1,2-dimethylhydrazine-induced Prevotella proliferation in rat colorectal cancerous intestine and increase Alloprevotella abundance [43] . Sporisorium reilianum polysaccharides significantly improved intestinal microbial diversity and microbiota composition in DSS-induced coli- 

Intestinal microbiota play essential roles in various physiological processes, such as inflammatory responses, immune system function, and energy homeostasis [31] . Over the past few decades, the impact of intestinal microbiota on host intestinal health has increasingly attracted the attention of researchers [32] . The human intestinal microbiota contains about 10 14 bacterial cells; among them, Firmicutes are the most abundant, followed by Bacteroidetes [33, 34] . Compared to healthy individuals, IBD patients have intestinal dysbiosis [35] . Dysbacteriosis, i.e., a decrease in microbial diversity, has been demonstrated in IBD diseases: for example, a decreased abundance of some beneficial bacteria, such as Erysipelotrichales, Bactereroidales, Clostridial, Bifidobacterium, and Lachnospiraceae, and increased abundance of some pathogenic bacteria, such as Enterobacteriaceae, Pasteurellcaea, Veillonellaceae, Fusobacteriaceae, Proteobacteria, Ruminococcus gnavus, and Desulfovibrio [25, 27] . Specifically, Enterorhabdus spp., Desulfovibrio spp., Alistipes spp., and Bacteroides spp. are closely associated with protective effects against colitis [36] . Changes in such bacteria result in minimal resistance to the growth and colonization of pathogenic bacteria in the gut. Although pathogenic bacteria are relatively abundant in the intestines of IBD patients [37, 38] , there is no direct evidence of a specific pathogen that causes IBD.

NPs have been demonstrated to modulate the richness and diversity of intestinal microbiota and restore the structure of intestinal microbiota, resulting in significant alleviation of IBD symptoms [25, 39] . As summarized in Table 1 , polysaccharides from plants, fungi, animals, bacteria, and algae significantly regulated intestinal microbiota composition. For example, Ziziphus jujuba Mill var. polysaccharides significantly increased Firmicutes abundance and decreased Bacteroidetes abundance [40] . Hericium erinaceus polysaccharides can significantly increase microbial diversity in the gut of UC rats, with Verrucomicrobia, Firmicutes, Bacteroidetes, and Proteobacteria richness being close to levels in healthy rats [41] . In addition, Glycyrrhiza polysaccharides can regulate intestinal microbiota composition, with Enterorhabdus spp., Odoribacter spp., Ruminococcaceae_UCG_014, and Ruminiclostridium 5 as the potential targets [42] . Fucoidan could inhibit 1,2-dimethylhydrazine-induced Prevotella proliferation in rat colorectal cancerous intestine and increase Alloprevotella abundance [43] . Sporisorium reilianum polysaccharides significantly improved intestinal microbial diversity and microbiota composition in DSS-induced colitis. The abundances of Bacteroidota and Proteobacteria at the phylum level, and Bacteroides, Coprobacillus, Streptococcus, and Lac-tobacillus, at the genus level, returned to healthy levels as compared with normal control mice [44] . Water-soluble garlic polysaccharides alleviated DSS-induced colitis by modulating gut microbiota, and the key bacterial groups included Muribaculaceae, Lachnospiraceae, Lachnospiraceae_NK4A136_group, Mucispirillum, Helicobacter, Ruminococcus_1, and Rumini-clostridium_5 [45] . Sargassum fusiforme - [83] Porphyra haitanensis ↑Bacteroides thetaiotaomicron, ↑Bacteroides ovatus, ↑Defluviitalea saccharophila, ↑Faecalibacterium prausnitzii ↑AA> PA> BA [84] Note: AA (acetic acid), PA (propionic acid), BA (butyrate acid), IBA (isobutyric acid), IVA (isovaleric acid), VA (valeric acid), and LA (lactic acid); "-" means not mentioned in the reference; "↑" means "significantly increased the relative abundance of bacteria or productions of SCFAs"; "↓" means "significantly decreased the relative abundance of bacteria or productions of SCFAs".

The metabolism of complex carbohydrates is mainly mediated by carbohydrate-active enzymes (CAZymes) in the digestive tract. Intestinal microbiota encode a majority of CAZymes that are arranged in the polysaccharide utilization site gene cluster and are capable of degrading polysaccharides [34] . The degradation produces several functional metabolites, such as SCFAs, lactic acid, pyruvic acid, and ethanol, and gases, such as H 2 , CO 2 , CH 4 , and H 2 S [46, 85] . Among them, SCFAs are the main fermentation products of NPs with biological activity that inhibit inflammation [50] . Specifically, the potential mechanisms of NPs that maintain intestinal homeostasis include a reduction in the secretion of pro-inflammatory factors and increase in functional metabolites through promoting the production of SCFAs, especially butyric acid. Butyric acid is an agonist of GPR41, GPR43, and GPR109a [86, 87] , and it can induce the differentiation of Treg cells and T cells by activating G-protein-coupled receptor signals in intestinal epithelial cells [88] . In addition, butyric acid could regulate the growth and function of dendritic cells and macrophages [89] as well as reduce the secretion of inflammatory cytokines [90, 91] (Figure 2 ). In a previous study, Tremella fuciformis polysaccharides improved dysbiosis in DSS-induced UC mice and increased the concentrations of butyric acid, which stimulated FOXP3 + T cells [78] and upregulated the expression of GPR41 and GPR43 [53] . Gracilaria lemaneiformis polysaccharides could also promote the expression of SCFA receptors, GPR43 and GPR109a, and increase the concentrations of butyric acid as well as inhibit the secretion of pro-inflammatory factors, including IL-1β, IL-6, and TNF-α [92] . Scutellaria baicalensis polysaccharides also improved colitis by regulating Firmicutes and Roseburia abundance, enhancing the concentration of butyric acid, and reducing the levels of IL-6, IL-1β, and TNF-α [65] . In an IL-10-deficient mouse model, Goji berry polysaccharides have been demonstrated to alleviate inflammation through increasing the abundance of butyric acid-producing Lachnospiraceae and Ruminococcaceae [93] . Acetic acid also exhibits anti-inflammatory effects. Polysaccharides from Crataegus pinnatifida could alleviate colitis by modulating intestinal microbiota, increasing acetic acid contents, and reducing inflammatory cytokine secretion [50] . Flammulina velutipes polysaccharides could restore the structure and abundance of intestinal microbiota and promote the growth of lactic acid-producing Lactobacillus and butyric acid-producing Ruminococaceae while reducing the abundance of Enterococcus and Bacteroidetes [80] . In addition, tryptophan-metabolizing Lactobacillus strains can reduce intestinal inflammation by activating aromatic hydrocarbon receptors, especially Lactobacillus reuteri, which regulate the transformation of intraepithelial CD4 + T helper cells into immunoregulatory T cells by activating the aromatic hydrocarbon receptors through indole derivatives [94] [95] [96] . T. fuciformis polysaccharides have been reported to protect the colon from inflammation by increasing the level of the tryptophan metabolite [78] .

tivating G-protein-coupled receptor signals in intestinal epithelial cells [88] . In addition, butyric acid could regulate the growth and function of dendritic cells and macrophages [89] as well as reduce the secretion of inflammatory cytokines [90, 91] (Figure 2) . In a previous study, Tremella fuciformis polysaccharides improved dysbiosis in DSS-induced UC mice and increased the concentrations of butyric acid, which stimulated FOXP3 + T cells [78] and upregulated the expression of GPR41 and GPR43 [53] . Gracilaria lemaneiformis polysaccharides could also promote the expression of SCFA receptors, GPR43 and GPR109a, and increase the concentrations of butyric acid as well as inhibit the secretion of pro-inflammatory factors, including IL-1β, IL-6, and TNF-α [92] . Scutellaria baicalensis polysaccharides also improved colitis by regulating Firmicutes and Roseburia abundance, enhancing the concentration of butyric acid, and reducing the levels of IL-6, IL-1β, and TNF-α [65] . In an IL-10-deficient mouse model, Goji berry polysaccharides have been demonstrated to alleviate inflammation through increasing the abundance of butyric acidproducing Lachnospiraceae and Ruminococcaceae [93] . Acetic acid also exhibits anti-inflammatory effects. Polysaccharides from Crataegus pinnatifida could alleviate colitis by modulating intestinal microbiota, increasing acetic acid contents, and reducing inflammatory cytokine secretion [50] . Flammulina velutipes polysaccharides could restore the structure and abundance of intestinal microbiota and promote the growth of lactic acid-producing Lactobacillus and butyric acid-producing Ruminococaceae while reducing the abundance of Enterococcus and Bacteroidetes [80] . In addition, tryptophan-metabolizing Lactobacillus strains can reduce intestinal inflammation by activating aromatic hydrocarbon receptors, especially Lactobacillus reuteri, which regulate the transformation of intraepithelial CD4 + T helper cells into immunoregulatory T cells by activating the aromatic hydrocarbon receptors through indole derivatives [94] [95] [96] . T. fuciformis polysaccharides have been reported to protect the colon from inflammation by increasing the level of the tryptophan metabolite [78] . 

The intestinal barrier, including mechanical, immune, chemical, and biological barriers [25] , constitute the "first line of defense" against pathogen invasion in the human body. Figure 3 summarizes the composition and function of the intestinal barrier. Repairing damaged intestinal barriers has become the primary goal of IBD treatment [97] . Intestinal dysbiosis influences the integrity of the intestinal barrier and induces IBD [98] . Under normal circumstances, the mechanical, chemical, and immune barriers can all be regulated by microbial metabolism [99] . However, intestinal microbiota dysbiosis, i.e., a decrease in beneficial microbes and an increase in harmful microbes, would destroy the intestinal barrier [100] . The growth of bacteria with strong mucus degradation ability, for example, Ruminococcus torques, would be increased. In contrast, the proportion of bacteria with weak mucus degradation ability, such as Akkermansia muciniphila (A. muciniphila), decreases significantly. The abundance of some probiotics, such as Lactobacillus, Bifidobacterium, and Prevotella, would reduce when the bacterial membrane barrier is destroyed. In healthy individuals, beneficial bacteria that can inhibit the adhesion and colonization of pathogenic bacteria to protect against damage to the intestinal barrier are distributed in the mucus layer [85, 101] .

The intestinal barrier, including mechanical, immune, chemical, and biological barriers [25] , constitute the "first line of defense" against pathogen invasion in the human body. Figure 3 summarizes the composition and function of the intestinal barrier. Repairing damaged intestinal barriers has become the primary goal of IBD treatment [97] . Intestinal dysbiosis influences the integrity of the intestinal barrier and induces IBD [98] . Under normal circumstances, the mechanical, chemical, and immune barriers can all be regulated by microbial metabolism [99] . However, intestinal microbiota dysbiosis, i.e., a decrease in beneficial microbes and an increase in harmful microbes, would destroy the intestinal barrier [100] . The growth of bacteria with strong mucus degradation ability, for example, Ruminococcus torques, would be increased. In contrast, the proportion of bacteria with weak mucus degradation ability, such as Akkermansia muciniphila (A. muciniphila), decreases significantly. The abundance of some probiotics, such as Lactobacillus, Bifidobacterium, and Prevotella, would reduce when the bacterial membrane barrier is destroyed. In healthy individuals, beneficial bacteria that can inhibit the adhesion and colonization of pathogenic bacteria to protect against damage to the intestinal barrier are distributed in the mucus layer [85, 101] . NPs as prebiotics could repair the IBD-induced damage to intestinal barrier by regulating intestinal microbiota [102] and re-establish a suitable growth environment for probiotics in the intestine and simultaneously inhibit the growth of potential pathogenic bacteria [102] [103] [104] . H. erinaceus polysaccharides can increase the relative abundance of key microbiota, including Clostridium spp., A. muciniphila, and Desulfovibrio spp., and improve the intestinal microbiota imbalance triggered by colitis [105] . In an αIL-10R-induced colitis mouse model, NP could upregulate the relative abundance of Firmicutes and downregulate the relative abundance of A. muciniphila [106] . Treatment of DSS-induced colitis mice with water-soluble polysaccharides from burdock increased the abundance of Firmicutes, Ruminococcaceae, and Lacetospiraceae, and it reduced the abundance of Proteobacteria, A. muciniphila, Staphylococcus, and Bacteroides [46] .

An imbalance in intestinal microbiota can cause intestinal mucosal barrier dysfunction, increase intestinal cell permeability [107] , and inhibit tight junction (TJs) and adherent junction synthesis [108] [109] [110] . NPs could obviously upregulate the expression levels of NPs as prebiotics could repair the IBD-induced damage to intestinal barrier by regulating intestinal microbiota [102] and re-establish a suitable growth environment for probiotics in the intestine and simultaneously inhibit the growth of potential pathogenic bacteria [102] [103] [104] . H. erinaceus polysaccharides can increase the relative abundance of key microbiota, including Clostridium spp., A. muciniphila, and Desulfovibrio spp., and improve the intestinal microbiota imbalance triggered by colitis [105] . In an αIL-10R-induced colitis mouse model, NP could upregulate the relative abundance of Firmicutes and downregulate the relative abundance of A. muciniphila [106] . Treatment of DSS-induced colitis mice with water-soluble polysaccharides from burdock increased the abundance of Firmicutes, Ruminococcaceae, and Lacetospiraceae, and it reduced the abundance of Proteobacteria, A. muciniphila, Staphylococcus, and Bacteroides [46] .

An imbalance in intestinal microbiota can cause intestinal mucosal barrier dysfunction, increase intestinal cell permeability [107] , and inhibit tight junction (TJs) and adherent junction synthesis [108] [109] [110] . NPs could obviously upregulate the expression levels of TJs, including occludin, claudin, JAMs 1-3, cingulin, and connexins from the (zonula occludens (ZOs). For example, α-glucan from a marine fungus, Phoma herbarum YS4108, directly repaired DSS-induced intestinal mucosal damage by upregulating the expression of ZO-1 and claudin-1 in the colon while restoring the populations of associated intestinal microbiota, i.e., increasing the abundance of Bacteroidetes, and decreasing the abundance of Firmicutes, Proteobacteria, Clostridiales, and Lachnospiraceae [73] . Chitosan can promote the expression of TJ proteins such as claudin-1, occludin, and ZO-1, and increase Blautia and Lactobacillus populations, in turn enhancing intestinal barrier function [111] . Fuzhuan Brick Tea polysaccharides promoted the expression of occludin and ZO-1 [112] . Dictyophora indusiata polysaccharides could enhance mucin, claudin-1, occludin, and ZO-1 expression to improve tissue structure and intestinal integrity by increasing the abundance of beneficial bacteria such as Lactobacillus spp [79] . Similarly, Chinese Yam polysaccharides can enhance the expression of ZO-1, claudin-1, occludin, and connexin-43, and reduce the relative abundance of Firmicutes, Alistipes, and Helicobacter, while increasing the relative abundance of Bacteroidetes, Muribaculum, Roseburia, and Dubosiella [49] .

Reduced MUC2 mRNA levels in the inflammatory bowel are also associated with increased intestinal permeability in IBD mice models [113] . G. lemaneiformis polysaccharides can alleviate DSS-induced colitis through regulation of the expression of MUC2, with a reduction in the relative abundance of norank_f_Erysipelotrichaceae, nclassified_f_Family_XIII, Acetatifactor, and Defluviitaleaceae_UCG-011, and increasing the relative abundance of Actinobacteria, Corynebacterium_1, Enterorhabdus, and Yaniella.

Intestinal dysbiosis could increase bacterial translocation, which stimulates the activation of antigen-presenting cells, such as dendritic cells and macrophages, subsequently inducing changes in T cell subsets. Among them, Th1 cells produce IFN-γ/TNF-α, and Th2 cells produce IL-6; Th17 cells secrete IL-17, and Treg cells reduce IL-10, causing proinflammatory responses and exacerbating colon tissue damage [114, 115] . Treg cells, another subgroup of CD4 + T cells, participate in host immune responses by secreting cytokines, such as IL-4 and IL-10, to facilitate immune balance (Figure 1 ) [116] . Interactions between Th17 and Treg cells maintain intestinal immune balance, and IBD is induced when changes in specific intestinal microbiota lead to Th17/Treg imbalance [117] , and such pro-inflammatory cytokines would certainly enhance intestinal inflammation. Current findings indicated the role of immune-regulatory effects of NPs by targeting intestinal microbiota [115] . Schisandra chinensis polysaccharides restore intestinal microbiota and reduce the secretion of pro-inflammatory factors (TNF-α, IL-6, and IL-17), in addition to decreasing the relative abundance of Firmicutes, Verrucomicrobia, Lactobacillus, and Turicibacter, and increasing the relative abundance of Bacteroidetes, Actinobacteria, Desulfovibrio, and Alistipes [64] . Morus atropurpurea polysaccharides could alleviate inflammation in DSS-induced colitis mice and reduce the abundance of Proteobacteria, Prevotellaceae, and Staphylococcus, while increasing the abundance of Lactobacillaceae, Lachnospiraceae, Ruminococcaceae, and Lactobacillus significantly [46] . In addition, Chrysanthemum morifolium Ramat polysaccharides could reduce the abundance of opportunistic pathogens, Escherichia and Enterococcus, and inhibit the secretion of pro-inflammatory factors (IFN-γ, IL-6, IL-1β, and IL-17), while increasing Clostridium, Butyricicoccus, Lactobacillus, and Bifidobacterium abundance [118] . Exopolysaccharides from Lactobacillus plantarum NCU116 significantly reduced the amounts of CD11b + , CD45 + , and CD3 + in DSS-induced colitis C57BL/6 mice. Meanwhile, the levels of Lactobacillaceae and Bifidobacteriaceae were increased significantly [119] . Similarly, Ipomoea batatas polysaccharides alleviated colonic inflammation by reducing the relative abundance of Proteobacteria, Bacteroides, and Staphylococcus, and increasing the relative abundance of Lactobacillus, Roseburia, and Bifidobacterium, when the secretion of pro-inflammatory factors (IL-1β, IL-6, and TNF-α) was inhibited [120] . D. indusiata polysaccharides reduced the production of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IFN-γ) in DSSinduced mice and the relative abundance of pathogenic bacteria (Proteus, Enterobacteriaceae, Bacteroides), and increased the relative abundance of Lactobacillus [121] . Ramulus mori polysaccharides inhibited the secretion of inflammatory cytokines IFN-γ and IL-6 and regulated intestinal microbiota abundance, including that of Firmicutes, Bacteroides, Myxospirillum, and Paraprevotella, and therefore, alleviated DSS-induced colitis in a mouse model [63] .

The activation of inflammatory signaling pathways induces the production of pro-inflammatory cytokines, leading to the aggravation of IBD. NPs can improve intestinal inflammation by modulating TLR4, MyD88, and NF-κB signaling pathways ( Figure 2) [122, 123] . Polysaccharides from Dendrobium officinum prevented UC by decreasing the expression of TLR4 [124] , restoring intestinal microbiota diversity, and increasing the abundance of Bacteroides, Lactobacillus and Ruminococcus while decreasing the abundance of Proteobacteria [53] . Radix pseudostellaria polysaccharides restored intestinal microbiota, upregulated TLR4 expression, increased the abundance of Bacteroides and Pseudomonas, and decreased the abundance of Verrucomicrobia and Akkermansia [39] . MyD88 is involved in protective inflammatory responses that regulate intestinal bacteria and the homeostasis of intestinal epithelial cells [125] . Ganoderma lucidum polysaccharides reduced the abundance of Lachnoclostridium, Oscillibacter, Desulfovibrio, Alipipes, and Parasutterella, and they inhibited the expression of MyD88, thereby alleviating DSS-induced colitis in mice [75] . Astragalus polysaccharides established intestinal microbiota balance by regulating the relative abundance of Lactobacillus, Bifidobacteria, and Enterobacteriaceae, and they inhibited the activation of the MyD88 signaling pathway so as to alleviate intestinal inflammation [126] . The NF-κB signaling pathway was activated by inhibiting the phosphorylation of NF-κB inhibitors, thereby promoting intestinal immune tolerance [127] . Polysaccharides from Chinese yams could inhibit the activation of the NF-κB signaling pathway and ameliorate DSS-induced microbiota imbalance by reducing Alistipes and Helicobacter abundance [49] . Polysaccharides from S. baicalensis Georgi ameliorated colitis via suppression of the NF-κB signaling pathway [128] while increasing the levels of Firmicutes, Bifidobacterium, Lactobacillus, and Roseburia and reducing the levels of Bacteroides, Proteobacteria, and Staphylococcus [65] . Similarly, Pacific abalone polysaccharides could inhibit the activation of the NF-κB signaling pathway, increase Muribaculaceae and Lachnospiraceae abundance, and decrease Bacteroidaceae, Prevotellaceae, and Rickenellaceae abundance [129] .

Obviously, NPs were effective in IBD diseases, and their mechanisms were possibly related to the following three aspects: (1) repairing the damaged intestinal barrier, including mucosa, microbiota, intestinal permeability, etc.; (2) maintaining the intestinal microenvironment by modulating the diversity and richness of the intestinal microbiota community, for example, increasing the beneficial intestinal bacteria, improving bacterial translocation, and production of SCFAs; (3) ameliorating the severe immune responses of the host mucosa, such as promoting the secretion of anti-inflammatory cytokines and reducing the production of pro-inflammatory cytokines, activating epithelial lymphocytes and mucosal lamina propria immune cells, etc. In that way, they improve intestinal immunity and inflammatory responses in various IBD mice models.

Although NPs have been demonstrated to inhibit the activation of several inflammatory signaling pathways, no direct evidence of SCFAs produced by NPs fermentation with inflammatory responses or expression of peroxisome proliferator-activated receptor has been presented. In addition, glycan chain length and linkage type have been found to influence the immunogenicity and efficacy of glycoconjugate vaccines [130] ; however, their structure-activity relationship in terms of IBD remains poorly understood. Furthermore, the bioavailability of NPs should be investigated to better understand their utilization in human body. Lastly, further large-scale clinical trials are required to facilitate the rigorous evaluation of their medical use.

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Inhibition effect of glycyrrhiza polysaccharide (GCP) on tumor growth through regulation of the gut microbiota composition

Effects of fucoidan on gut flora and tumor prevention in 1,2-dimethylhydrazine-induced colorectal carcinogenesis

Whole and polysaccharide powdered Sporisorium reilianum improves DSS-induced colitis in BALB/c mice by modulating gut microbiota

Anti-inflammatory and intestinal microbiota modulation properties of Jinxiang garlic (Allium sativum L.) polysaccharides toward dextran sodium sulfate-induced colitis

Edible fungal polysaccharides, the gut microbiota, and host health

Polysaccharides from Atractylodes macrocephala Koidz. Ameliorate ulcerative colitis via extensive modification of gut microbiota and host metabolism

Polysaccharides from the flowers of tea (Camellia sinensis L.) modulate gut health and ameliorate cyclophosphamide-induced immunosuppression

Structural characteristics of a mannoglucan isolated from Chinese yam and its treatment effects against gut microbiota dysbiosis and DSS-induced colitis in mice

Crataegus pinnatifida polysaccharide alleviates colitis via modulation of gut microbiota and SCFAs metabolism

Cyclocarya paliurus polysaccharide improves metabolic function of gut microbiota by regulating short-chain fatty acids and gut microbiota composition

Dendrobium fimbriatum Hook polysaccharide ameliorates dextran-sodium-sulfate-induced colitis in mice via improving intestinal barrier function, modulating intestinal microbiota, and reducing oxidative stress and inflammatory responses

Identification of the core active structure of a Dendrobium officinale polysaccharide and its protective effect against dextran sulfate sodium-induced colitis via alleviating gut microbiota dysbiosis

Phosphorylation of polysaccharides: A review on the synthesis and bioactivities

Effect of Durio zibethinus rind polysaccharide on functional constipation and intestinal microbiota in rats

Ficus carica polysaccharide attenuates DSS-induced ulcerative colitis in C57BL/6 mice

Ameliorating effects of short-chain inulin-like fructans on the healing stage of Trinitrobenzene Sulfonic Acid-induced colitis in rats

Anti-inflammatory and gut microbiota modulatory effects of polysaccharides from Fuzhuan brick tea on colitis in mice induced by dextran sulfate sodium

Protective role of a new polysaccharide extracted from Lonicera japonica Thunb in mice with ulcerative colitis induced by Dextran Sulphate Sodium

Lycium barbarum polysaccharide combined with aerobic exercise ameliorated nonalcoholic fatty liver disease through restoring gut microbiota, intestinal barrier and inhibiting hepatic inflammation

Morinda citrifolia L.) fruit polysaccharides regulated IBD mice via targeting gut microbiota: Association of JNK/ERK/NF-kappa B signaling pathways

Structural characterization of a water-soluble purple sweet potato polysaccharide and its effect on intestinal inflammation in mice

Ramulus mori polysaccharide-loaded PLGA nanoparticles and their anti-inflammatory effects in vivo

The anti-colitis effect of Schisandra chinensis polysaccharide is associated with the regulation of the composition and metabolism of gut microbiota

Scutellaria baicalensis Georgi polysaccharide ameliorates DSS-induced ulcerative colitis by improving intestinal barrier function and modulating gut microbiota

The bioavailability of soybean polysaccharides and their metabolites on gut microbiota in the simulator of the human intestinal microbial ecosystem (SHIME)

An orally administered butyrate-releasing xylan derivative reduces inflammation in dextran sulphate sodium-induced murine colitis

Microbiome-metabolomic analysis of the impact of Zizyphus jujuba cv. Muzao polysaccharides consumption on colorectal cancer mice fecal microbiota and metabolites

Metagenomic analysis of gut microbiota modulatory effects of jujube (Ziziphus jujuba Mill.) polysaccharides in a colorectal cancer mouse model

Chain conformation, physicochemical properties of fucosylated chondroitin sulfate from sea cucumber Stichopus chloronotus and its in vitro fermentation by human gut microbiota

Gut microbiota response to sulfated sea cucumber polysaccharides in a differential manner using an in vitro fermentation model

Oyster polysaccharides ameliorate intestinal mucositis and improve metabolism in 5-fluorouracil-treated S180 tumour-bearing mice

The α-D-glucan from marine fungus Phoma herbarum YS4108 ameliorated mice colitis by repairing mucosal barrier and maintaining intestinal homeostasis

Polysaccharide isolated from Auricularia auricular-judae (Bull.) prevents dextran sulfate sodium-induced colitis in mice through modulating the composition of the gut microbiota

Ganoderma lucidum polysaccharide modulates gut microbiota and immune cell function to inhibit inflammation and tumorigenesis in colon

Ganoderma lucidum polysaccharide improves rat DSS-induced colitis by altering cecal microbiota and gene expression of colonic epithelial cells

Suppression of obesity and inflammation by polysaccharide from sporoderm-broken spore of Ganoderma lucidum via gut microbiota regulation

Tremella fuciformis polysaccharides inhibited colonic inflammation in Dextran Sulfate Sodium-treated mice via Foxp3+ T cells, gut microbiota, and bacterial metabolites

Attenuation of DSS induced colitis by Dictyophora indusiata polysaccharide (DIP) via modulation of gut microbiota and inflammatory related signaling pathways

Polysaccharide from Flammuliana velutipes improves colitis via regulation of colonic microbial dysbiosis and inflammatory responses

Exopolysaccharides from Lactobacillus plantarum NCU116 induce c-Jun dependent Fas/Fasl-mediated apoptosis via TLR2 in mouse intestinal epithelial cancer cells

Polysaccharide extracted from Enteromorpha ameliorates cisplastin-induced small intestine injury in mice

A fucoidan from Sargassum fusiforme with novel structure and its regulatory effects on intestinal microbiota in high-fat diet-fed mice

Microbial catabolism of Porphyra haitanensis polysaccharides by human gut microbiota

Effects of non-starch polysaccharides on inflammatory bowel disease

A cross-talk between microbiota-derived short-chain fatty acids and the host mucosal immune system regulates intestinal homeostasis and inflammatory bowel disease

GPR109A is a G-protein-coupled receptor for the bacterial fermentation product butyrate and functions as a tumor suppressor in colon

Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells

Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis

The epigenetic effects of butyrate: Potential therapeutic implications for clinical practice

The role of short-chain fatty acids in health and disease

Gracilaria lemaneiformis polysaccharides alleviate colitis by modulating the gut microbiota and intestinal barrier in mice

Goji berry modulates gut microbiota and alleviates colitis in IL-10-deficient mice

Gut microbiota-derived metabolites as key actors in inflammatory bowel disease

Circulating levels of the anti-oxidant indoleproprionic acid are associated with higher gut microbiome diversity

Trp) modulates gut homeostasis via aryl hydrocarbon receptor (AhR)

Transcriptional regulation of macrophage polarization: Enabling diversity with identity

Inflammatory Bowel Diseases (IBD) and the microbiome-Searching the crime scene for clues. Gastroenterology 2021

Dietary nutrients shape gut microbes and intestinal mucosa via epigenetic modifications

Carcinogenesis and therapeutics: The microbiota perspective

Proximal colon-derived O-glycosylated mucus encapsulates and modulates the microbiota

Protective effects of natural polysaccharides on intestinal barrier injury: A review

Potential benefits of dietary fibre intervention in inflammatory bowel disease

Probiotics and prebiotics: Effects on diarrhea

Polysaccharide of Hericium erinaceus attenuates colitis in C57BL/6 mice via regulation of oxidative stress, inflammation-related signaling pathways and modulating the composition of the gut microbiota

Microbiota fermentation-NLRP3 axis shapes the impact of dietary fibres on intestinal inflammation

Tight junctions in inflammatory bowel diseases and inflammatory bowel disease associated colorectal cancer

lnjury of intestinal mucosaI barrier function and its restitution

Role of the microbiota in immunity and inflammation

Role of the gut microbiota in the development and function of lymphoid cells

Chitosan ameliorates DSS-induced ulcerative colitis mice by enhancing intestinal barrier function and improving microflora

Fuzhuan brick tea polysaccharide improved ulcerative colitis in association with gut microbiota-derived tryptophan metabolism

New developments in goblet cell mucus secretion and function

Microbiomarkers in inflammatory bowel diseases: Caveats come with caviar

The mpacts of natural polysaccharides on intestinal microbiota and immune responses-A review

Review of the relationships among polysaccharides, gut microbiota, and human health

Specific microbiota direct the differentiation of IL-17-producing T-Helper cells in the mucosa of the small intestine

Polysaccharides from Chrysanthemum morifolium Ramat ameliorate colitis rats via regulation of the metabolic profiling and NF-κ B/TLR4 and IL-6/JAK2/STAT3 signaling pathways

Exopolysaccharides from Lactobacillus plantarum NCU116 facilitate intestinal homeostasis by modulating intestinal epithelial regeneration and microbiota

Anti-inflammatory properties and gut microbiota modulation of an alkali-soluble polysaccharide from purple sweet potato in DSS-induced colitis mice

Protective effect and mechanism of polysaccharide from Dictyophora indusiata on dextran sodium sulfate-induced colitis in C57BL/6 mice

The microbiome in inflammatory bowel disease: Current status and the future ahead

Astragalus polysaccharides protect against dextran sulfate sodium-induced colitis by inhibiting NF-κB activation

Protective effect of three glucomannans from different plants against DSS induced colitis in female BALB/c mice

MyD88 signalling plays a critical role in host defence by controlling pathogen burden and promoting epithelial cell homeostasis during Citrobacter rodentium-induced colitis

Astragalus polysaccharides attenuated inflammation and balanced the gut microflora in mice challenged with Salmonella typhimurium

Engineering release kinetics with polyelectrolyte multilayers to modulate TLR signaling and promote immune tolerance

Polysaccharide from Scutellaria baicalensis Georgi ameliorates colitis via suppressing NF-κB signaling and NLRP3 inflammasome activation

Sulfated polysaccharides from pacific abalone attenuated DSS-induced acute and chronic ulcerative colitis in mice via regulating intestinal micro-ecology and the NF-kappa B pathway

Combined effects of glycan chain length and linkage type on the immunogenicity of glycoconjugate vaccines