Inflammatory bowel disease (IBD) comprises chronic inflammatory disorders of the gastrointestinal tract, primarily Crohn’s disease (CD) and ulcerative colitis (UC). Dysbiosis of the gut microbiota is now recognized as a critical factor in both the initiation and progression of IBD (1). The intestinal microbiome, which includes bacteria, viruses, fungi, and parasites, contains approximately 100 trillion microorganisms (2). Consequently, therapeutic strategies aimed at restoring microbial balance have emerged as promising approaches for IBD management (3).

5-Aminosalicylic acid (5-ASA) remains a cornerstone of IBD therapy (4, 5). However, its use is associated with a spectrum of adverse effects, including headaches, nausea, hepatotoxicity, pancreatitis, bone marrow suppression, and renal complications (6). Prolonged treatment may also result in diarrhea, alopecia, and myalgia. Similarly, corticosteroids, although effective, are linked to risks such as osteoporosis, hypertension, obesity, type 2 diabetes, and exacerbation of gastrointestinal ulcers (7–9). Some of these drug-induced adverse reactions may even be life-threatening (10). In addition, while antibiotics can temporarily reduce pathogenic bacteria, long-term use disrupts microbial homeostasis and promotes resistance (11).

Natural polysaccharides have demonstrated considerable benefits in IBD treatment, as they reduce drug-related side effects while enhancing therapeutic efficacy (12–14). This reduction in drug-related side effects is closely linked to their regulatory role in gut microbiota: Evidence suggests that polysaccharides stimulate the growth of beneficial bacteria, facilitate intestinal barrier repair, and regulate gut metabolism by promoting the production of SCFAs—for instance, SCFAs can alleviate 5-ASA-induced intestinal mucosal damage by enhancing epithelial barrier repair, and mitigate corticosteroid-associated oxidative stress via activating antioxidant pathways (15). Moreover, specific microbial enzymes degrade polysaccharides, converting them into SCFAs and other secondary metabolites with health-promoting properties (16). Such processes regulate microbial communities and support intestinal homeostasis. Recent findings further indicate that polysaccharides improve barrier integrity, modulate the gut microenvironment, and enhance metabolic functions in patients with IBD (17).

Additionally, polysaccharide-based nanoparticles have attracted attention for their ability to improve drug stability and sustain therapeutic activity (18, 19). Given their dual ability to regulate gut microbiota and reinforce intestinal barrier function, polysaccharides represent a highly promising strategy for IBD therapy (20). This review systematically discusses the mechanistic basis of polysaccharide interventions and highlights their potential in future therapeutic development.

Numerous studies have documented significant alterations in the intestinal microbiota of patients with IBD compared with healthy individuals (21–23). In healthy hosts, a dynamic balance is maintained among beneficial, potentially harmful, and commensal microbial populations (24). However, reductions in microbial diversity, shifts in metabolite profiles, disruption of the mucosal barrier, or immune dysregulation—often caused by disease, pharmacotherapy (e.g., antibiotics, laxatives), or unhealthy diets—can collectively drive the onset and progression of IBD (3, 25–29).

For example, one study reported markedly reduced levels of anti-inflammatory taxa such as Faecalibacterium prausnitzii, Bifidobacterium adolescentis, and other beneficial species in CD patients, alongside a significant increase in the pro-inflammatory species Ruminococcus gnavus (30). Similarly, murine models of colitis showed elevated levels of pathogenic genera including Shigella, Aeromonas, Clostridium, Sutterella, and Akkermansia muciniphila. These findings emphasize the contrasting roles of pathogenic and commensal bacteria in IBD pathophysiology (31, 32). Importantly, the impact of these bacteria is modulated by host immune status, environmental factors, and nutrient availability—conditions under which beneficial microbes may even exert neutral or deleterious effects, and vice versa.

Dynamic fluctuations in microbial populations critically influence gut diversity and ecosystem stability. In IBD, chronic inflammation disrupts this stability—pathogenic bacteria (e.g., Ruminococcus gnavus) proliferate rapidly, while beneficial taxa (e.g., Faecalibacterium prausnitzii) decline, leading to chaotic microbial fluctuations and reduced diversity (30, 32). Probiotic intervention can counteract such disruptive fluctuations: In a study of DSS-induced colitis, administration of Lactobacillus rhamnosus GG (LGG, 10⁹ CFU/day) markedly improved microbiota diversity, reversing dysbiosis by enriching beneficial taxa such as Bifidobacterium, Olsenella, Paenibacillus, and butyrate-producing bacteria (33). Moreover, a 14-day LGG intervention suppressed pathogenic clusters, including Escherichia coli, Zhiphyllobacterium, Osteobacillus, and Desulphurobacteria, thereby alleviating colonic inflammation in UC mouse models (34).

Under physiological conditions, the mucus layer segregates luminal bacteria from intestinal epithelial cells (IECs), and the immune system maintains tolerance toward luminal antigens (26, 35). In IBD, barrier disruption increases permeability, enabling bacteria to contact IECs directly (36) and translocate into systemic circulation (37). This translocation triggers inflammatory cytokine expression and immune activation (38, 39). Barrier dysfunction is further characterized by reduced mucin content (40), diminished glucose-derived metabolites (41), impaired lipid-associated protective factors (42), and decreased secretion of pancreatic-derived defense molecules (43).

Metabolic studies further link microbial composition to functional pathways. Dysbiotic states are associated with reduced polysaccharide-degrading capacity and upregulated oxidative stress-related genes (44). Excess bacterial metabolites elevate ROS, thereby exacerbating epithelial injury and inflammation (45). Elevated Desulfovibrio spp. in IBD patients promote hydrogen sulfide overproduction, inducing oxidative stress, damaging IECs, and aggravating mucosal inflammation (46).

Additionally, dysbiosis frequently results in SCFA depletion, which worsens intestinal inflammation (47–49). As major products of polysaccharide fermentation, SCFAs suppress pathogen proliferation, enhance nutrient absorption, regulate immune responses, and reinforce the mucus barrier (50–53). They lower intestinal pH, facilitating the colonization of beneficial bacteria such as Lactobacillus and Bifidobacterium. These bacteria further ferment carbohydrates into SCFAs, strengthening mucosal immunity (54). Probiotics such as Bifidobacterium and Lactobacillus mitigate inflammation by modulating NF-κB signaling, enhancing epithelial adhesion, and inhibiting pathogens (55, 56). The dominant gut phyla, Bacteroidetes and Firmicutes, produce acetate and propionate (mainly Bacteroidetes) and butyrate (predominantly Firmicutes) (57). Butyrate, in particular, serves as the primary energy source for IECs and promotes epithelial proliferation, which is essential for mucosal repair (58).

The inflammatory response in IBD originates from the activation of innate immune cells—including macrophages, dendritic cells, neutrophils, natural killer cells, and innate lymphoid cells—which release cytokines, chemokines, and antimicrobial peptides. This innate activation subsequently triggers adaptive immunity, with T and B lymphocytes serving as central mediators of intestinal inflammation in IBD (84) ( Figure 1 ).

Accumulating evidence indicates that distinct microbial communities differentially regulate T cell-mediated immunity. For instance, Faecalibacterium prausnitzii alleviates chemically induced colitis in mice by enhancing regulatory T cell (Treg) activity (85). Similarly, Clostridium butyricum promotes the expansion of CD4⁺Foxp3⁺ Tregs in the intestinal lamina propria, thereby preventing colitis and attenuating hypersensitivity reactions (86).

Invariant natural killer T (iNKT) cells, which share features of both NK and T cell lineages, also contribute to intestinal immunoregulation. Germ-free mice display heightened susceptibility to iNKT-mediated colitis and asthma following oxazolone or ovalbumin challenge. This susceptibility arises because germ-free conditions lack microbial metabolites (e.g., SCFAs, bile acid derivatives) that suppress iNKT cell overactivation—neonatal exposure to commensal microbes promotes the production of these metabolites, thereby limiting iNKT-mediated inflammatory responses. Remarkably, neonatal exposure to commensal microbes is required to mitigate this susceptibility (87).

During programmed cell death, neutrophils release neutrophil extracellular traps (NETs)—web-like structures composed of chromatin, histones, proteases, granule proteins, and enzymes such as myeloperoxidase and neutrophil elastase. NETs restrict pathogen dissemination and exhibit bactericidal activity through associated proteases. However, their components can also disrupt immune homeostasis (88). NETs have been shown to influence B cell differentiation and function. In rheumatoid arthritis, for example, NET-immune cell interactions promote B cell proliferation and autoantibody production via B cell-activating factor, while synovial NETs provide citrullinated proteins that fuel anti-citrullinated protein antibody (ACPA) responses (89).

In IBD, depletion of SCFA-producing bacteria—particularly butyrate producers—correlates with increased neutrophil infiltration and NET formation, thereby accelerating disease progression (90). Microbial metabolites, especially SCFAs, also shape macrophage function: SCFAs suppress pro-inflammatory cytokine production by inhibiting histone deacetylases, while upregulating anti-inflammatory IL-10 (91). Butyrate, in particular, inhibits HDAC3, reduces mTOR activation and glycolysis, enhances macrophage bactericidal activity, and promotes an anti-inflammatory phenotype (92).

Considerable evidence supports a role for SCFAs in regulating CD4⁺ T cell subsets, particularly Tregs, which are critical for immune tolerance. SCFAs promote Treg differentiation by inhibiting HDAC activity; however, under strong anti-CD3 stimulation favoring Th1/Th17 polarization, this induction is attenuated (93). Although less studied, SCFAs also affect CD8⁺ T cells, which are essential for intracellular pathogen clearance and tumor surveillance. For example, systemic acetate elevation during bacterial infection enhances glycolysis and boosts memory CD8⁺ T cell recall responses (94).

Beneficial microbes such as Bifidobacterium and Lactobacillus further modulate intestinal Treg populations, highlighting their role in IBD pathogenesis (95). Treg-deficient mice spontaneously develop colitis, underscoring the indispensable role of Tregs in intestinal homeostasis (96). Moreover, LGG promotes B cell differentiation and IgA secretion in the intestinal lamina propria of piglets, thereby strengthening mucosal immunity (97).

Additional mechanisms involve microbial regulation of innate sensors and inflammatory pathways. For instance, Bacteroides fragilis suppresses NLRP3 inflammasome activation via SCFA production, thereby inhibiting M1 macrophage polarization and reducing pro-inflammatory cytokines such as IL-18 and IL-1β (98). Faecalibacterium prausnitzii exerts anti-inflammatory effects by downregulating IL-12 and IFN-α, while enhancing IL-10 secretion and inhibiting NF-κB signaling (85, 99).

In IBD, excessive production of ROS—including superoxide anions, peroxynitrite, hypochlorite, and hydrogen peroxide—has been strongly implicated in disease progression. ROS directly damage IECs, activate mucosal immune responses, and trigger oxidative stress-related signaling pathways such as NF-κB and nuclear factor erythroid 2-related factor 2 (Nrf2), thereby aggravating barrier dysfunction and chronic inflammation (100, 101).

Metagenomic analyses of IBD patients have revealed downregulation of genes involved in carbohydrate and amino acid metabolism, coupled with upregulation of genes associated with oxidative stress responses. These findings suggest that altered microbial metabolic capacity may exacerbate IBD by enhancing oxidative stress and impairing epithelial integrity.

LGG exhibits potent antioxidant activity and supports intestinal barrier function. LGG reduces oxidative stress-induced damage by enhancing endogenous antioxidant enzyme production, including superoxide dismutase (SOD) and glutathione (GSH), while simultaneously suppressing ROS generation. These protective effects are mediated through activation of the Keap1/Nrf2 pathway and inhibition of ERK1/2 and NF-κB signaling (102). Further studies demonstrate that LGG reduces Giardia-induced colonization, enhances antioxidant defenses, and lowers lipid peroxidation, thereby maintaining epithelial integrity (103).

In a hydrogen peroxide-induced oxidative stress model using porcine IECs, extracellular polysaccharides from LGG accelerated ROS clearance by upregulating antioxidant enzyme expression and downregulating oxidative stress-related proteins. These effects collectively facilitated the repair of epithelial barrier damage (104).

Additional studies have investigated synergistic effects of natural polysaccharides with bioactive plant-derived compounds. For example, Lycium barbarum polysaccharides (LBPs), known for immunomodulatory properties, and capsaicin, an anti-inflammatory and antioxidant agent, were tested in a DSS-induced colitis rat model. LBPs alone decreased serum IL-6 and malondialdehyde (MDA, a lipid peroxidation marker), while enhancing catalase activity. Co-administration of LBPs and capsaicin further reduced IL-6 and colonic tumor necrosis factor-α (TNF-α), and significantly increased SOD activity. These results underscore the synergistic antioxidant and anti-inflammatory potential of combining natural polysaccharides with plant bioactives in ulcerative colitis therapy (105).

Natural polysaccharides are widespread biological macromolecules that function as structural components, energy reserves, and protective agents in diverse organisms. They are complex carbohydrates formed by the condensation of multiple monosaccharide units through glycosidic bonds, generally represented by the formula (C₆H₁₀O₅)_n (106). Polysaccharides can be derived from plants, algae, animals, or microorganisms (107, 108). Their physicochemical properties—including monosaccharide composition, chain length, branching degree, and substituents—profoundly influence their bioactivities. Hydrophilic groups such as hydroxyl, carboxyl, and amino groups confer high solubility and dispersibility, while additional functional groups permit chemical modification, enabling the formation of functionalized supramolecular structures (109) ( Figure 2 ).

However, due to variations in monosaccharide composition, degree of polymerization, and linkage patterns, extraction and purification of polysaccharides are inherently complex. For example, polysaccharides with high branching degrees require more precise ethanol concentration adjustments to avoid co-precipitation with impurities; high-molecular-weight polysaccharides (due to high polymerization degrees) easily clog membrane pores during separation, necessitating stricter pressure control; and different monosaccharide linkages affect the binding affinity to macroporous resins, complicating elution gradient design. In plant polysaccharide extraction, ethanol precipitation is commonly applied to remove proteins, lipids, nucleic acids, pigments, and other small molecules from crude extracts, followed by fractionation to obtain homogeneous polysaccharides. Frequently used purification strategies include macroporous adsorption resins for initial separation, ion-exchange chromatography for selective fractionation, and membrane separation techniques exploiting molecular weight cut-offs under controlled pressure (110, 111).

Polysaccharides are generally classified by source into animal-, plant-, microbial-, and marine-derived types (112). Animal polysaccharides—often early pharmaceutical candidates—are typically mucopolysaccharides with high water solubility (113, 114). Plant-derived polysaccharides, such as pectin, Angelica, LBP, rhubarb, and Bupleurum polysaccharides, are usually water-soluble and low in toxicity, making them suitable for precise dosing in experimental settings (115). In contrast, starch and cellulose are insoluble plant polysaccharides. Microbial polysaccharides are produced by bacteria and fungi, while marine polysaccharides, isolated from aquatic organisms, often possess unique biological activities (116, 117).

Functionally, polysaccharides act as fermentable carbon sources for probiotics, promoting their growth, reshaping microbial community structure, and suppressing pathogenic bacteria (118). For example, polysaccharides extracted from Polygonum multiflorum increase populations of Bifidobacterium and Lactobacillus while decreasing Helicobacter, thereby alleviating gut dysbiosis and contributing to IBD management (119). In juvenile Hucho taimen, dietary supplementation with lentinan enhanced beneficial genera such as Lactobacillus, Trichinella, and Ruminococcus, while reducing harmful taxa including Enterobacteriaceae, Fusobacteriaceae, and Flavobacteriaceae, thus improving microbial balance (120).

The structural features of polysaccharides also determine preferential fermentation by specific microbes (121). For instance, oat β-glucans selectively promote Bifidobacterium and Lactobacillus (122), while Bacteroides efficiently degrade fructans (123), and Prevotella bryantii utilizes xylan (124). In vitro fermentation studies with Fuzhuan brick tea polysaccharides (FBTPS-3) showed modulation of IBD patient microbiota toward a profile resembling that of healthy individuals, specifically by increasing Bacteroides and decreasing Escherichia/Shigella (125).

Beyond shaping microbial composition, polysaccharides reinforce the mucus barrier by enhancing thickness, adhesiveness, and protective capacity, thereby preventing pathogen invasion (126). Dietary polysaccharides also directly upregulate tight junction proteins such as occludin and ZO-1, strengthening epithelial barrier integrity. For example, interventions significantly enhanced occludin and claudin-1 expression while reducing pro-inflammatory cytokines including TNF-α and IL-1β (127).

Polysaccharides from natural sources have demonstrated protective effects against colitis. Gloiopeltis furcata polysaccharides safeguard colonic mucosa by modulating mucin-microbe interactions, promoting probiotic growth, and reducing epithelial injury (128). Dendrobium huoshanense polysaccharides increase goblet cell numbers and stimulate mucin secretion in both small and large intestines, reinforcing mucosal defenses (129). Functionalized fucoidan restores microbial balance and mucosal integrity after injury (130). In vitro studies reveal that glucomannan from Aloe vera gel maintains barrier function via the Nrf2-mitochondrial axis and alleviates anoikis induced by mitochondrial dysfunction (131).

Marine polysaccharides such as fucoidan exhibit strong anti-inflammatory and immunomodulatory activity by inhibiting NF-κB signaling and downregulating TNF-α, IL-6, and IL-8 (132). Fucoidan also promotes Treg differentiation, enhances tight junction proteins and IgA secretion, and reduces intestinal permeability (133). In murine models, fucoidan mitigates colitis by lowering nitric oxide, myeloperoxidase, and malondialdehyde levels, reducing immune cell infiltration, and preserving colon length (134, 135). Additionally, fucoidan may stimulate dendritic cell maturation via TNF-dependent pathways, strengthening host immunity.

Other plant polysaccharides also improve IEC structure. Yam polysaccharides maintain epithelial morphology, increase goblet cell density, and decrease inflammatory infiltration (136). High-molecular-weight fucoidan from Undaria pinnatifida and Sargassum fusiforme protects Caco-2 cells against ROS-induced injury, likely via antioxidant activity (137). Composite polysaccharides (e.g., yam plus inulin) modulate microbiota by reducing Proteus, Bacteroides, and Firmicutes, enhancing metabolism, and relieving oxidative stress, ultimately improving ulcerative colitis (138).

Polysaccharide-mediated modulation of SCFA production represents another therapeutic mechanism (139). Ganoderma lucidum polysaccharides significantly increase acetate, propionate, and butyrate levels (140, 141). Similarly, LBPs undergo fermentation to generate SCFAs while enriching Bifidobacterium and Lactobacillus (142). Longan polysaccharides enrich SCFA-producing taxa such as Bifidobacterium, Bacillus, and Bacteroides fragilis, boosting acetate, propionate, and butyrate synthesis (143). Seaweed polysaccharides also act as fermentation substrates, indirectly supporting probiotic growth (144–147).

Importantly, the structural features of polysaccharides dictate fermentation kinetics and SCFA profiles, with identical fermentation conditions producing variable SCFA yields (148). Thus, targeted research on specific polysaccharides is required to define their optimal application in colitis therapy ( Table 1 ). Taken together, natural polysaccharides reshape gut ecology (beneficial taxa↑, SCFAs↑), reinforce the epithelial barrier (mucus/TJ proteins↑), rebalance mucosal immunity (Tregs↑, NF-κB↓), and mitigate oxidative stress (Nrf2 axis↑). However, these biological benefits are highly contingent on local concentration and residence time at inflamed colonic sites. Oral administration faces substantial hurdles—acidic gastric milieu, digestive enzymes, rapid mucus clearance, and heterogeneous lesion distribution—leading to suboptimal on-target exposure. This translational gap motivates an engineering solution: polysaccharide-based nanomedicines that exploit the inflammatory microenvironment (pH↓, ROS↑, bacterial glycosidases↑, receptor overexpression) to achieve spatiotemporally controlled delivery and thereby amplify the very mechanisms delineated above.

We therefore conceptualize polysaccharide nanomedicines as mechanism amplifiers: mucoadhesion and receptor targeting extend residence (boosting barrier repair); pH/ROS/enzyme responsiveness gates on-site release (boosting anti-inflammatory and antioxidant actions); and co-delivery strategies align metabolic support (SCFAs) with immune reprogramming (Tregs↑, M1→M2). The following subsections organize the evidence not by polymer name, but by pathophysiological lever addressed, creating a one-to-one mapping between IBD axes and nanodesign features. Natural polysaccharides are attractive candidates for nanocarrier development in IBD therapy due to their inherent bioactivity, pH responsiveness, gastric stability, susceptibility to colonic microbial degradation, and strong mucoadhesive properties (172–176). By modifying functional groups on their surfaces, polysaccharide-based nanocarriers can be engineered to encapsulate drugs, achieve sustained release, and selectively target specific gut microbial populations (177).

Nanomedicine delivery systems, owing to their nanoscale dimensions and unique structural properties, enhance drug accumulation and retention at target sites, thereby supporting localized therapy (178). The viscosity and intrinsic charge of polysaccharides further enable intimate interactions with the intestinal barrier, prolonging retention within the colon (13, 179). For instance, positively charged nanoparticles adhere to or penetrate negatively charged mucosal surfaces via electrostatic interactions, whereas negatively charged nanoparticles preferentially accumulate in positively charged inflamed tissues, thereby improving lesion targeting. Moreover, polysaccharide-based nanocarriers promote cellular uptake by IECs and immune cells through endocytosis and exocytosis (180). Collectively, these systems improve solubility, intestinal retention, and site-specific drug accumulation, resulting in enhanced therapeutic efficacy and reduced systemic side effects (172, 181).

Currently, chitosan (CS), alginate (ALG), hyaluronic acid (HA), and Angelica sinensis polysaccharide (ASP) are among the most widely studied polysaccharide-based nanocarriers for IBD treatment, owing to their favorable biocompatibility and functionality (18, 19) ( Figure 3 ). However, some polysaccharides exhibit high solubility and poor film-forming ability, leading to premature drug release and reduced colonic targeting. To address these limitations, composite nanocarrier systems combining multiple polysaccharides have been developed, effectively overcoming the weaknesses of single-component carriers (182, 183). Despite these advances, challenges remain, including instability in gastric acid and limited colon-targeting efficiency. Moreover, clinical data on dose-response relationships of polysaccharides in IBD remain scarce (131).

This review has systematically analyzed the core pathological mechanisms underlying IBD, including gut microbiota dysbiosis, impaired intestinal barrier function, immune dysregulation, and oxidative stress. Natural polysaccharides, derived from diverse sources and exhibiting distinct structural characteristics, demonstrate strong therapeutic potential in modulating these pathways. Their dual mechanisms—microbiota regulation and barrier enhancement—include stimulation of beneficial bacteria such as Lactobacillus and Bifidobacterium, elevation of SCFA production (e.g., butyrate as an epithelial energy source, acetate for Treg differentiation), inhibition of TLR4/NF-κB inflammatory signaling, and activation of the Nrf2/HO-1 antioxidant pathway. Moreover, the context-dependent roles of key microbes, such as Akkermansia muciniphila, highlight their ability to maintain barrier integrity in health but exacerbate inflammation under pathological conditions.

Polysaccharide-based nanocarriers—including CS, ALG, HA, and ASP—further enhance therapeutic efficacy by enabling targeted, responsive, and sustained drug delivery. Smart designs, such as pH/ROS dual-sensitive RH-F/C-NPs and composite carriers like CS-PIPP, combine prebiotic activity, controlled release, and mucoadhesion, achieving superior probiotic enrichment and pathogen suppression compared with single-component systems. Recent advances have also underscored the importance of polysaccharide structure-activity relationships. For instance, low-molecular-weight fucoidan (2.56 kDa) and konjac glucomannan (KGM2, 7413 Da) exhibit enhanced anti-inflammatory activity due to improved microbial fermentation into SCFAs, while branched polysaccharides such as SHPS-1 exert effects via specific glycosidic linkages (257).

Despite these promising developments, challenges remain. Structural complexity, variability in extraction and purification, and difficulties in achieving reproducible formulations hinder translational application. Furthermore, polysaccharide bioactivity is strongly influenced by molecular weight, branching degree, and monosaccharide composition (258, 259). Although low-molecular-weight fractions often show superior bioactivity (260–262), results remain inconsistent. Future efforts should focus on clarifying structure-activity relationships, designing multi-responsive nanocarriers for precise release, and extending applications to biomacromolecule delivery systems such as vaccines and nucleic acids. In conclusion, polysaccharides and their nanoformulations represent highly promising therapeutic strategies for restoring microbial homeostasis, reinforcing mucosal barriers, and attenuating intestinal inflammation in IBD.