Astragalus polysaccharide (APS) is a primary active component of Astragali Radix (AR). It has been reported to reduce oxidative stress and inflammatory response by downregulating pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) and myeloperoxidase (MPO) activity, decreasing malondialdehyde (MDA) level, and restoring superoxide dismutase (SOD) activity (20). Colonic cell infiltration in rats treated with AR was shown to be markedly reduced compared with that of the model group. In addition, the intestinal mucosa was repaired, suggesting that the AR therapeutic effect on colitis was associated with a reduction in intestinal inflammation, promotion of mucosal repair and improvement of the membrane barrier function (21).

The Scutellaria baicalensis Georgi polysaccharide is utilized in TCM theory to clear heat and dampness, purge fire and facilitate detoxification (22). Polysaccharides are notable components of Scutellaria baicalensis Georg, with a previous study having demonstrated that a polysaccharide derived from Scutellaria baicalensis Georgi alleviated UC by inhibiting NF-κB signaling and NLR family pyrin domain containing 3 inflammasome activation (23). An additional homogeneous polysaccharide, known as SP2-1, was also shown to reduce the levels of key pro-inflammatory cytokines, including IL-6, IL-1β and TNF-α (24).

Ginger polysaccharides have also been reported to alleviate UC symptoms by inhibiting the levels of key pro-inflammatory cytokines, including TNF-α, IL-6, IL-1β, IL-17A and IFN-γ, thereby regulating intestinal inflammation. In addition, they appear to aid in the repair of the intestinal barrier, as evidenced by occludin-1 and zonula occludens-1 (ZO-1) expression levels and gut microbiota modulation (25).

The Chinese yam polysaccharide (CYP) is derived from Dioscorea opposita L. and has been shown to alleviate colitis symptoms in dextran sulfate sodium (DSS)-treated mice. This effect was associated with enhanced IL-10 production, pro-inflammatory cytokine suppression (IL-1β and TNF-α) and reduced MPO activity. The CYP was also shown to have preserved intestinal barrier integrity by upregulating tight junction protein (ZO-1 and occludin) and mucin (MUC)-2 expression levels (26).

Polysaccharides derived from Dendrobium huoshanense (DHP) have been shown to alleviate UC symptoms and improve the colonic mucosal barrier function in mouse models (27). Previous studies have further indicated that DHP exerts anti-inflammatory effects by modulating the NF-κB signaling pathway, and the specific regulatory mechanism involves inhibiting the expression of NF-κB p65 in colon tissues, subsequently reducing the serum levels of key pro-inflammatory cytokines, including IL-1β, TNF-α, IL-17 and TGF-β, and ultimately blocking the inflammatory cascade in UC (28).

Turmeric polysaccharides (TPSs) are derived from ginger and have been shown to ameliorate pathological phenotypes, reinstate intestinal barrier integrity and suppress colonic inflammation. A 16S ribosomal RNA-based microbiota analysis further revealed that TPSs ameliorated DSS-induced gut microbiota dysbiosis by enriching tryptophan metabolism-associated probiotics (such as Lactobacillus and Clostridia-UCG-014) and promoting microbial tryptophan catabolism (29).

Atractylodes macrocephala Koidz. (AM), commonly known as Baizhu, is traditionally used in East Asian medicine for its spleen-invigoration, dampness-resolution and anti-inflammatory properties. Its polysaccharides (AMPs) have been identified as key bioactive components contributing to its therapeutic efficacy in treating UC treatment. A previous study evaluated the effects of AM and AMPs on DSS-induced UC in mice, with results demonstrating that AMP markedly ameliorated DSS-induced weight loss and mitigated colonic injury (30).

The Platycodon grandiflorus polysaccharide (PGP) derived from P. grandiflorus exhibits anti-inflammatory and antioxidant properties through colonic immune response modulation mediated by mesenteric lymphatic circulation (31). In addition, the pectic polysaccharide from Smilax china L. has been shown to mitigate colonic histological injury and reduce the production of key pro-inflammatory mediators, including MPO, IL-1β, IL-6 and TNF-α in DSS-induced UC mouse models. Galectin-3 has also been recognized for its role in inflammation promotion in UC (32).

Codonopsis Radix is a qi-tonifying and spleen-strengthening TCM herb that helps enhance physical strength, reduce fatigue, promote digestion and absorption and boost immunity (33). The Codonopsis Radix polysaccharide (CRP) has shown promise in UC treatment. CRP nanoparticles have exhibited enhanced colon adhesion and retention in DSS-induced colitis mice, thus alleviating disease severity, reducing pro-inflammatory cytokine levels and restoring the gut microbiota diversity, likely through inhibition of the toll-like receptor 4 (TLR4)/NF-κB pathway (34).

Bletilla striata has been demonstrated to quickly stop bleeding and promote wound healing (35). This makes it a viable therapeutic option for conditions such as hemoptysis in tuberculosis, gastrointestinal ulcers and skin ulcers. The Bletilla striata polysaccharide (BSP) has been formulated into a thermosensitive hydrogel using chitosan and loaded with puerarin-loaded thiolated hyaluronic acid nanoparticles. This composite hydrogel has been shown to adhere strongly to the colonic mucosa and provide sustained drug release at body temperature.

This therefore markedly ameliorated disease activity in murine UCmodels, accelerated colonic mucosal repair, downregulated pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) and upregulated the anti-inflammatory cytokine IL-10, thereby validating its efficacy as a localized therapeutic strategy for UC (36).

Amomum villosum Lour. is an edible plant that can alleviate symptoms such as diarrhea, gastric distension and abdominal bloating (37). The A. villosum polysaccharide (AVLP) has demonstrated potential antioxidant and glycosidase inhibitory activities. AVLP administration also helped maintain the intestinal barrier function by upregulating the ZO-1 protein expression. A gut microbiota analysis further indicated that AVLP protective effects against colitis were associated with intestinal bacteria regulation (38).

Lycium barbarum L. has also been found to have certain benefits in UC treatment. Lycium barbarum polysaccharides have been demonstrated to markedly reduce disease activity index scores and alleviate colon structural distortion. In addition, they have been shown to effectively decrease colonic pro-inflammatory cytokine levels (including IFN-γ, IL-17A and IL-22) and modulate colonic microbiota composition by reducing the relative abundance of colitis-enriched genera Turicibacter and Lachnospira, while elevating the relative abundance of Ruminiclostridium_9 (39,40).

Lonicera japonica Thunb. was first referenced during the Jin Dynasty in Ge Hong's ‘Zhouhou Beiji Fang’, a manual of first-aid medical prescriptions and aids in clearing heat and detoxification for bacterial dysentery, bronchitis and other infectious disease treatment in TCM (41). A previous study demonstrated that the Lonicera japonica Thunb. polysaccharide is an active ingredient that can ameliorate intestinal dysbiosis and enhance immune function in UC. Furthermore, it may elevate the activity of natural killer cells and cytotoxic T lymphocytes while promoting the proliferation of intestinal probiotics (Bifidobacterium and Lactobacillus) and suppressing pathogenic bacteria (Escherichia coli and Enterococcus) (42).

Yunnan pine pollen is the dried pollen of Pinus yunnanensis, a forest tree species native to southwestern China (43). The crude polysaccharide, PPM60, precipitated using 60% ethanol and its sulfated derivative (SPPM60) in the pollen of Yunnan pine, are the primary active components (44). This beneficial effect may be attained by restoration of the T helper (Th)-17/regulatory T cell (Treg) balance, reinforcement of colonic tight junctions, blocking of receptor interacting serine/threonine kinase 3-dependent necroptosis and stabilization of the gut microbiome and serum metabolome (45,46).

Poria polysaccharides are primary active ingredients in Poria cocos. Carboxymethylated Poria polysaccharides have been reported to exhibit therapeutic effects on UC by alleviating the infestation of inflammatory factors in colonic tissues and regulating gut microbiota dysbiosis (47,48). Poria cocos polysaccharides (PCPs) can enhance MUC-2, β-defensin and secretory IgA expression levels in intestinal tissues associated with the biochemical barrier. Furthermore, PCPs regulate the immunological barrier by enhancing TGF-β and IFN-γ production and increase short-chain fatty acid (SCFA) concentrations in the contents of the small intestine. PCPs influence the intestinal barrier function by modifying the microbial makeup of the gut. PCPs may also preserve the intestinal barrier integrity by enhancing the production of Wnt/β-catenin and low-density lipoprotein receptor-related protein 5(49).

Ganoderma atrum has been widely used as a functional food or dietary supplement for centuries (50-52). Its polysaccharide, PSG-1, is recognized as a major bioactive constituent and can alleviate DSS-induced UC by protecting the physical barrier regulated by apoptosis/autophagy and the immune barrier associated with dendritic cells (53). An additional active substance, known as the Ganoderma lucidum polysaccharide, is primarily composed of β-glucan and has been reported to alleviate DSS-induced colitis. This effect is mediated by increasing the abundance of SCFA-producing bacteria (such as Ruminococcus_1) and reducing enteric pathogens (including Escherichia-Shigella) in the rat small intestine and cecum (54).

Portulacae Oleracea L. (POL) is a plant with homologous medicinal and food sources. In TCM, POL is classified as a non-toxic herb characterized by its ability to clear heat, reduce swelling, detoxify the body and stop bleeding. In addition, it is utilized for removing dampness, treating diarrhea and eliminating parasites, with no marked side effects having been found (55,56). Polysaccharides derived from POL (POLPs) have been shown to elevate anti-inflammatory cytokine IL-10 levels while reducing the concentration of proinflammatory cytokines including IL-6 and TNF-α. In addition, POLPs may increase the abundance of intestinal probiotics, specifically Bifidobacterium and Lactobacillus. These findings indicate that POLPs contribute to UC treatment through their anti-inflammatory properties, the attenuation of hyperactive immune responses and intestinal dysbiosis modulation (57). Wang et al (58) also found that POLPs could alleviate UC symptoms through the NF-κB signal pathway by inhibiting IκBα degradation.

AL-I is an acidic polysaccharide fraction composed primarily of pectic polysaccharides. It was originally isolated from Aconitum carmichaelii leaves and has demonstrated immunomodulatory activity and attenuated intestinal inflammation in vitro (59). AL-I possesses numerous pharmacological effects that include anti-tumor, immune regulation, anti-depressive and cardiomyocyte protection. In addition, it has been associated with fewer adverse reactions and an increased safety profile. AL-I has also been demonstrated to ameliorate clinical symptoms and pathological damage in the colons of colitis mice. In addition, it modulates inflammatory markers in both the serum and colonic tissue, with AL-I administration having been shown to attenuate intestinal barrier impairment in mice by upregulating tight junction protein expression and restoring both colonic SCFA and branched-chain fatty acid production (59).

Crude polysaccharides from Schisandra chinensis (SCPs) are composed of eight monosaccharides dominated by galacturonic acid, galactose, arabinose and rhamnose. These are characteristic constituents of pectic polysaccharides. SCP administration has been shown to preserve the colonic mucus layer integrity and goblet cell abundance in DSS-challenged mice. Furthermore, SCP treatment has been shown to restore DSS-suppressed SCFA production, with butyrate levels exhibiting marked elevation (60).

Scutellaria barbata is an established perennial herb used in TCM and valued for its ability to clear heat and toxins, promote blood circulation, remove blood stasis and induce diuresis to reduce edema (61). Recent pharmacological studies have substantiated its properties, including its anticancer effects, bacteriostatic action, antiviral capabilities, anti-inflammatory benefits, antioxidative properties and ability to enhance immunity (61-63). S. barbata polysaccharides (PSBs) attenuate colonic inflammatory cytokine levels, including those of TNF-α, IFN-γ, IL-1β, IL-6 and IL-18. PSB administration has been shown to inhibit DSS-induced activation of the NF-κB and STAT3 signaling pathways. In addition, enrichment of beneficial bacterial genera (Lachnospiraceae_NK4A136_group, Ruminococcus, Bacteroides, Parasutterella and Eisenbergiella) following PSB treatment has been associated with reduced intestinal inflammation. These findings demonstrate the therapeutic potential of PSBs in UC and other dysbiosis-associated conditions (64).

Euphorbia humifusa is a medicinal and edible plant traditionally used to treat diarrhea and intestinal disorders. It exhibits anti-inflammatory, hemostatic and hepatoprotective properties. Its polysaccharides (EHPs) are primarily composed of galactose, glucose and glucuronic acid. In DSS-induced UC mice, EHP administration has been shown to alter gut microbiota composition by increasing the relative abundances of Bifidobacterium and Holdemanella while reducing Escherichia-Shigella, Tyzzerella and Parasutterella. Furthermore, EHP administration has been shown to downregulate pro-inflammatory cytokine levels (IL-6 and IL-17) and upregulate anti-inflammatory IL-10 levels to markedly attenuate colon tissue damage (65).

Herbal polysaccharides have garnered attention for their potential to protect the intestinal mucosal barrier, which is important in maintaining overall health. Recent studies have highlighted the multifaceted role these natural compounds serve in enhancing the gut barrier function (66-68). A previous study showed that APSs may increase the number of goblet cells and promote MUC secretion, thereby enhancing the stability of the intestinal mucosal barrier and reducing the intestinal inflammatory response. These polysaccharides may also upregulate the expression of tight junction proteins, such as ZO-1 and occludin, further strengthening intestinal barrier function (69).

Cui et al (24) also found that a homogenous polysaccharide isolated from Scutellaria baicalensis Georgi exhibited the ability to repair the intestinal barrier. This was achieved by increasing ZO-1, occludin and claudin-5 expression levels, all of which are important in maintaining intestinal epithelium structural integrity. Xiao et al (70) found that Tremella fuciformis polysaccharides markedly alleviated symptoms in a DSS-induced UC mouse model. This treatment notably reduced the infiltration of inflammatory cells and restored the integrity of the intestinal epithelial barrier by enhancing the expression of intestinal barrier-related genes and proteins (TJP1/ZO-1 and OCLN/occludin) and mucus barrier-associated molecules (Muc-2 and Clca1). The Eucommia ulmoides polysaccharide, modified with nano-selenium particles, has also been shown to improve DSS-induced intestinal barrier function by notably increasing the expression of tight junction proteins occludin, claudin-1, claudin-3 and ZO-1(13).

In a DSS-induced colitis model, polysaccharides were shown to restore the reduced thickness of the mucus layer due to inflammation. In addition Astragalus membranaceus polysaccharides have been shown to markedly increase MUC-2 secretion to form a protective mucus layer (71). MUC-2 is secreted by intestinal goblet cells to form a major constituent of the mucus layer. This layer serves a key role in segregating the epithelial surface from the contents within the intestinal lumen. Patients with UC often experience pathological changes such as thinning of the mucus layer and interruption of its continuity (72).

Oxidative stress constitutes a key pathological element in UC, arising from an overabundance of ROS and dysfunction of the antioxidant system. SOD1 deficiency exacerbates oxidative stress in the DSS-induced acute colitis mouse model, resulting in significant body weight loss, intestinal epithelial barrier disruption and reduced activities of core antioxidant enzymes, including total SOD, glutathione peroxidase (GPx), catalase and glutathione (GSH) (73). A previous study also demonstrated a marked increase in colonic MDA concentrations in patients with UC, in contrast to a marked decline in the activity of antioxidant enzymes such as GPX, catalase and SOD (74).

There is a clear structure-activity association between the antioxidant activity of polysaccharides and their structural characteristics. Studies on longan polysaccharides have shown that purified acidic polysaccharide components exhibit stronger free radical scavenging and metal ion chelating activities, which are associated with their uronic acid content and molecular weight distribution (75-77).

Dictyophora indusiata polysaccharides exhibit notable antioxidant activity through their unique structural characteristics, including direct free radical scavenging and enhancing the endogenous antioxidant enzyme system (78). APS is derived from Astragalus mongholicus Bunge and suppresses DSS-induced colitis by suppressing the Nrf2/HO-1 axis, thereby upregulating GPX4, ferritin heavy chain-1 and GSH-Px4 activity. Consequently, Fe²⁺ accumulation and lipid ROS are reduced, leading to ferroptosis inhibition in intestinal epithelial cells (79). Huaier polysaccharide (HP), extracted from Trametes robiniophila Murr., has been shown to notably attenuate DSS-induced weight loss, the elevated disease activity index and colonic shortening. Mechanistically, HP decreases colonic MDA levels, restores GSH and SOD activity and preserves epithelial barrier integrity by enhancing MUC-2 expression. Metabolomics has further revealed that HP remodels the gut microbiota and promotes antioxidant phospholipid metabolites (80). Network pharmacology coupled with in vivo validation in trinitrobenzene sulfonic acid-ethanol colitis rats has demonstrated that the Dang Shen polysaccharide downregulated PI3K/Akt signaling, decreased pro-inflammatory cytokine production (IL-6 and TNF-α) and concurrently reduced Fe²⁺, MDA and MPO levels while enhancing GPX4, GSH activity and SOD (81).

TCM polysaccharides have multi-target and bidirectional balance characteristics that regulate the differentiation and function of numerous immune cells. The immune imbalance of UC causes an abnormal increase in the ratio of Th17 to Tregs, which is a core pathological feature. Th17 cells are differentiated and developed from CD4⁺ T cells and their cell membranes express high levels of C-C motif chemokine receptor 6 that can migrate to the intestinal mucosa (82). IL-17 can stimulate macrophages, epithelial cells and fibroblasts to produce a variety of cytokines, such as IL-1β, IL-6 and TNF-α. This leads to inflammatory response amplification, with IL-17 triggering the release of IL-6, thus further activating the STAT3 pathway. The NF-κB pathway is then activated and implicated in the occurrence and development of the immune response (79). This pathway helps maintain this response when the host needs to fight off infection, as often an abundance of inflammatory cytokines causes colonic damage (83).

Eomesodermin and forkhead box P3 are two key nuclear transcription factors implicated in modulating Treg cell development and promoting the secretion of anti-inflammatory cytokines, including IL-10, IL-35 and TGF-β1 (84,85). IL-10 enhances Treg cell differentiation and function through STAT3 signaling, further inhibiting Th17 cell differentiation. IL-35 can also inhibit RAR-related orphan receptor γ-t activation, restrict IL-17 expression and reduce Th17 cell activity, which is conducive to inducing the proliferation of Treg cells (86,87). In the intestinal mucosa of patients with UC, the positive chemotaxis of IL-10, IL-35 and TGF-β on Treg cell proliferation and the inhibition of the Th17-type immune response has been shown to jointly maintain the Th17/Treg immune balance (88,89).

An in vivo study demonstrated that PGPs effectively lower Th17-associated cytokines and transcription factors, as well as enhance Treg-associated cytokines and transcription factors by modulating the Th17/Treg balance (31). APS markedly upregulated peripheral blood Treg cells in mice with DSS-induced colitis, reshaping the Th17/Treg homeostasis to treat UC (21). In addition, according to an additional study, SCFA levels were elevated in UC mice following APS treatment and this was mediated by reorganization of the intestinal microbiota structure and enrichment of SCFA-producing microbes. These changes support the gut barrier, mitigate inflammation and sustain the balance between Th17 and Treg cells (86,90).

As a key target, the TLR4/NF-κB signaling pathway is a mechanism through which polysaccharides (derived from TCM) exert their immunomodulatory effects (91). As a pattern recognition receptor, TLR4 detects pathogens in the gut and activates the NF-κB pathway. This triggers the release of IL-1β, IL-6 and TNF-α, which further contribute to chronic intestinal mucosal inflammation (92). In UC animal models, TCM polysaccharide treatments have been shown to notably reduce the expression levels of the key proteins p50 and p100 in the NF-κB pathway (84). An additional in vivo experiment demonstrated that POLPs markedly downregulated TLR4, myeloid differentiation primary response 88 and NF-κB protein expression levels in the colonic tissues of mice with DSS-induced colitis. This suggested that the effect of POLP on UC may be associated with the suppression of TLR4 activation and its subsequent downstream signaling proteins (93).

NF-κB serves an important role in the pathological mechanism of UC. Through a number of pathways, it participates in the regulation of the inflammatory response, the maintenance of the intestinal barrier function and the balance of intestinal microecology. In vitro, NF-κB inhibitors have been shown to reduce apoptosis of intestinal epithelial cells and enhance their barrier function (94). In addition, studies on macrophages and T cells have shown that NF-κB activity inhibition reduces pro-inflammatory cytokine secretion and decreases immune response strength (95). Following a stimulus signal, NF-κB signaling is activated through a series of signaling cascades (classical and non-classical NF-κB signaling pathways). Thus, two independent in vivo experiments have shown that DHP and the Scutellaria baicalensis Georgi polysaccharide SP1-1, notably reduced NF-кB p65 expression, suggesting that DHP and SP1-1 can inhibit the NF-кB signaling pathway and reduce pro-inflammatory factor expression to treat UC (23,28). The pectin polysaccharide from the fruit of Prunus salicina has also been shown to markedly reduce the expression of Cemip, a cancer-promoting gene associated with colorectal cancer, by inhibiting the NF-κB pathway (96).

Regulation of the inflammatory factor network by TCM polysaccharides is particularly important. Herbal polysaccharides have been shown to mitigate inflammatory responses and oxidative stress (66,95), both of which can compromise the mucosal barrier (97). Numerous bioactive polysaccharides, including those derived from Plantago asiatica, Lycium barbarum, Spirulina spp. and Coix lacryma-jobi, can suppress pro-inflammatory cytokine expression levels (including those of IL-6, IL-8, IL-12 and TNF-α). These actions collectively enhance epithelial barrier integrity by reducing inflammation and stabilizing paracellular permeability (98-101). Wang et al (102) demonstrated that polysaccharides derived from astragalus and ginseng mitigated lipopolysaccharide-induced intestinal barrier damage in weaned piglets. In a murine sepsis model generated by cecal ligation and puncture, polysaccharides derived from Zizyphus jujuba cv. Muzao were also found to ameliorate impairment of the intestinal epithelial barrier. This protection was achieved through the downregulation of pro-inflammatory cytokines and TLR4/NF-κB signaling pathway inhibition (103). Rhodiola rosea polysaccharides have been shown to exert therapeutic effects by reducing pro-inflammatory factors, such as IL-6, TNF-α and IL-1β, in the intestines of mice with colitis (104) and according to the findings of this research, polysaccharides exhibit the ability to regulate a number of signaling pathways, allowing them to limit the release of pro-inflammatory cytokines and preserve a damaged intestinal barrier. Therefore, the chronic inflammatory state of UC has been associated with the abnormal activation of numerous signaling pathways, including the TLR4/NF-κB signaling pathway, which mediates the excessive secretion of pro-inflammatory cytokines and further compromises intestinal mucosal barrier function.

Intestinal dysbiosis is an important part of UC pathogenesis. Harmful bacteria penetrate the damaged intestinal epithelial barrier and activate the intestinal immune system. This leads to the release of pro-inflammatory factors that form part of the harmful ‘microbiota-immune axis’ cycle (105). Beneficial gut microbiota growth is also positively influenced by polysaccharides. Furthermore, they can enhance the proliferation and metabolism of immune cells within the gut, contributing to the wider defense mechanisms against pathogens (106). However, the mechanisms that underlie their protective effects are not fully understood and warrant further investigation.

The gut microbiota includes the phyla Firmicutes (such as Lactobacillus, Enterococcus, Clostridium and Bacillus) and Bacteroidetes (including Bacteroides and Prevotella), as well as the phyla Actinobacteria (such as Bifidobacterium) and Ascomycetes (including Escherichia coli) (107). Gut microbiota imbalances have been shown to be associated with digestive system inflammatory diseases, including inflammatory bowel disease, non-alcoholic steatohepatitis and metabolic dysfunction-associated steatohepatitis, and with the application of macro-genomic analyses, an association between the gut microbiota and UC is gradually emerging (108-112).

Herbal polysaccharides derived from TCM are macromolecular compounds that generally cannot be absorbed into the blood through intestinal mucosa; hence, their pharmacological effect is perhaps associated with a change in the gut microbiota composition and metabolites (113). Arabinogalactan from Lycium barbarum (114), AMPs (30) and polysaccharides from Chrysanthemum morifolium Ramat (115) have been shown to increase both Chao1 and Abundance-based Coverage Estimator indices, two critical metrics that quantify the community richness of gut microbiota (30), as well as increase the abundance and diversity of gut microbiota in UC rats/mice. In addition, DHP has been shown to restore gut microbiota β diversity (27).

At the phylum level, SP2-1 and EHPs markedly elevate the total abundance of Firmicutes, a dominant polysaccharide-fermenting phylum in the gut that can efficiently degrade indigestible polysaccharides and convert them into SCFAs. This phylum is negatively associated with intestinal inflammation and the reduced abundance of Firmicutes is a key feature of intestinal dysbiosis in patients with UC (24). In addition, SP2-1 and EHPs reduce the relative abundance of Proteobacteria, a phylum enriched with opportunistic pathogens whose growth can disrupt the intestinal barrier and activate inflammatory responses (24,61). At the genus level, Chrysanthemum polysaccharides, SP2-1 and EHPs restore the abundance of Bifidobacterium and Lactobacillus that exert anti-UC effects by inhibiting pro-inflammatory cytokine secretion and enhancing the epithelial barrier function (61,88,115). SP2-1 notably upregulates Roseburia, which directly alleviates colonic inflammation by promoting Treg differentiation, enhancing the secretion of anti-inflammatory cytokines (such as IL-10 and TGF-β) and suppressing pro-inflammatory cytokines, including IL-1β, IL-6 and TNF-α. In addition, SP2-1 notably inhibits the proliferation of the genera Bacteroides and Staphylococcus, both of which are capable of disrupting the intestinal immune homeostasis and aggravating epithelial injury (24). By contrast, EHPs reduce the abundances of Escherichia-Shigella, Tyzzerella and Parasutterella, thereby decreasing endotoxin release and pro-inflammatory signaling activation (61).

Chinese herbal polysaccharides markedly promote the proliferation of SCFA-producing bacteria by regulating the gut microbiota composition. SCFAs (such as butyric acid, propionic acid and acetic acid) are primary metabolites of dietary fiber fermented by the gut microbiota, possessing marked anti-inflammatory properties and being regarded as key protective factors against inflammatory bowel disease (116). SCFAs are the primary energy substrate in colonic tissue and they directly affect the gastrointestinal tract of the host by altering the colonic epithelial cell phenotype. In particular, butyric acid can activate the energy metabolism regulator, adenosine monophosphate-activated protein kinase, which can regulate both cellular energy homeostasis and metabolic stress to improve the function of the UC intestinal mucosal barrier (117). Ginseng polysaccharides, such as A. senegalensis, increase the tryptophan metabolic level of the host and promote indole derivative generation (66). These findings are important to consider as microbiota remodeling is associated with metabolite changes. Overall, TCM polysaccharides regulate the microbiota composition and affect its metabolic functions, thereby generating beneficial metabolites.

Tryptophan metabolism is an additional important avenue through which TCM polysaccharides regulate the gut-immune axis. Tryptophan is converted into indole and its derivatives under the action of the bacterial community, activating the AhR signaling pathway. Ginseng neutral polysaccharides have been shown to markedly increased the content of indole derivatives in the intestines of aged mice and activate the AhR pathway (66). After activation, AhR can promote IL-22 secretion, stimulate the proliferation of intestinal epithelial cells and mucus production, enhance tight junction protein expression, reduce intestinal permeability, inhibit the NF-κB signaling pathway, alleviate intestinal inflammation and promote intestinal stem cell self-renewal and differentiation (66). These metabolites act as ligands for AhRs and serve a key role in the regulation of the intestinal immune balance, forming a complete functional chain of ‘polysaccharide-microbiota-metabolite-host’.

A number of preclinical studies have shown that TCM polysaccharides have a notable therapeutic effect on UC (118,119). Huangqin Decoction (HQD) and Gegen Qinlian Decoction (GQD) are classic TCM formulas recorded in Shang Han Lun, which have been extensively applied in gastrointestinal diseases and show marked efficacy against UC. HQD, consisting of four herbal ingredients, alleviates UC by regulating gut microbiota, amino acid metabolism, mTOR signaling and the intestinal epithelial barrier. GQD and its modified preparation ameliorate chronic UC through repairing intestinal mucus barriers, inhibiting NLRP3 inflammasome activation and reducing pro-inflammatory γδT17 cell responses. However, the majority of recent studies remain at the animal experimental stage, lacking large-scale randomized controlled clinical trial data to verify the exact efficacy and safety of these polysaccharide components.

Therapeutic application of TCM polysaccharides in UC remains largely confined to animal models and preclinical studies. This limited progress may be attributed to a number of key factors (120), such as their large molecular size and high hydrophilicity, which notably reduce their transmembrane efficiency. In addition, structural damage and activity loss caused by exposure to gastric acid, bile salts and digestive enzymes, may lead to diminished efficacy. Lastly, a lack of colon-targeting specificity hinders their enrichment at inflammatory sites to achieve effective therapeutic concentrations.

With regard to the oral route, polysaccharides can be engineered into charge-targeted nanoparticles. A representative approach may involve the development of amphiphilic prodrug nanoparticles from the Codonopsis polysaccharide (34). This design exploits the positively charged, protein-rich microenvironment of the inflamed colonic mucosa to markedly enhance nanoparticle adhesion and retention. With a typical diameter of ~180 nm, these nanoparticles readily penetrate the mucus layer and accumulate in diseased tissues through the enhanced permeability and retention effect. Consequently, systemic circulation is markedly prolonged. This is evidenced by an extended half-life of ~25 h. In addition, bioavailability is notably improved, with this being reflected by an increase in the area under the curve value. In parallel, rectal administration uses in situ thermosensitive gelling systems such as hydrogels composed of BSP, chitosan and β-glycerophosphate (35). These systems undergo a reversible sol-to-gel transition at body temperature, completely avoiding upper gastrointestinal degradation and hepatic first-pass metabolism. In addition, the incorporation of mucoadhesive components, such as thiolated hyaluronic acid, enables the formation of disulfide bonds with the colonic mucus layer. This interaction extends local retention beyond 48 h and ensures controlled drug release.