Marine macroalgae (seaweeds), among the ocean’s most biologically valuable resources, are taxonomically classified into three groups—brown (Phaeophyceae), red (Rhodophyta), and green (Chlorophyta) algae—on the basis of pigmentation, monosaccharide profiles, molecular weight distributions, and structural polysaccharide composition (Xu et al., 2017). Fucoidan (FCD), a sulfated polysaccharide predominantly abundant in brown algae, coexists with other characteristic biopolymers, such as alginates and laminarin. FCD-producing species span diverse marine taxa, including Laminaria hyperborea, Sargassum stenophyllum, Hizikia fusiforme, Ascophyllum nodosum, Fucus spp. (F. evanescens, F. serratus, F. distichus, F. vesiculosus), Analipus japonicus, Caulerpa racemosa, Chorda filum, Padina gymnospora, Kjellmaniella crassifolia, and Dictyota menstrualis.

FCD, a sulfated polysaccharide with the molecular formula (C₆H₁₀O₇S)_n, contains sulfate groups as integral components of its structural composition. Predominantly isolated from brown algae, this biopolymer consists primarily of sulfated fucose residues (Koh et al., 2019), with minor constituents, including xylose, mannose, galactose, rhamnose, arabinose, glucose, glucuronic acid, and acetyl groups (Jin et al., 2019; Koh et al., 2019; Usoltseva et al., 2019). Located in the cell walls of brown algae, FCD contributes to structural integrity by preventing tissue dehydration and stabilizing cell membranes (Lakshmana Senthil, 2024).

Structurally, FCD exhibit species-specific variations. Two common α-L-fucopyranose backbone motifs are observed (1): a 1,3-linked framework and (2) alternating 1,3- and 1,4-linked residues. Sulfation typically occurs at the C-2 or C-4 positions of the fucose residues ( Figure 1 ) (Jia et al., 2025). While brown algal FCD share conserved backbone structures, they diverge in their sulfation patterns and glucuronic acid contents. For example, Fucus serratus (silky brown algae), Fucus distichus (pteridophyte brown algae), and Pelvetia canaliculata (tubular brown algae) exhibit similar core skeletons but differ in their branching complexity and monosaccharide diversity, which are correlated with functional distinctions (Ale et al., 2011; Wang et al., 2021; Obluchinskaya et al., 2023). Notably, certain FCD (e.g., from Bifurcaria and Himanthalia elongata) deviate from these canonical frameworks, suggesting additional structural heterogeneity (Sanjeewa et al., 2017).

The sulfate groups of FCD confer distinct biological activities. Studies have demonstrated its ability to mitigate intestinal barrier dysfunction through three mechanisms (1): enhancing tight junctions (TJs) and adherens junctions (AJs) protein interactions in epithelial cells (2), restoring the gut microbiota composition, and (3) suppressing proinflammatory cytokine production (Iraha et al., 2013; Shi et al., 2017; Luo et al., 2021). Both fucose-oligomeric polyphenol conjugates and desulfated FCD—structurally distinct precursors—alleviate dextran sulfate sodium (DSS)-induced acute colitis by suppressing inflammatory cytokine signaling (Lean et al., 2015). FCD has also been extensively studied for its antitumor, anticoagulant, and antioxidant activities; ability to modulate glucose and cholesterol metabolism; and potential hepatoprotective and nephroprotective effects.

The key bioactive properties of FCD are primarily attributed to its sulfated polysaccharide structure. Due to its complex structure, FCD cannot be predicted or classified. FCD exerts significant immunomodulatory, antitumor, and anti-inflammatory effects. Notably, FCD demonstrates pronounced impacts on intestinal function. An in vitro study by Chen et al. demonstrated that FCD modulates gut microbiota composition by altering SCFAs production (Chen et al., 2023). Furthermore, in a DSS-induced IBD model, Ye et al. showed that FCD intervention restructured gut microbial communities, enhanced colonic barrier integrity through upregulation of tight junction proteins (e.g., claudin-1, occludin), and suppressed colonic inflammation via the TLR4/NF-κB signaling pathway (Ye et al., 2024). Collectively, these findings highlight the therapeutic potential of FCD in IBD management.

Preclinical studies have characterized the absorption, distribution, metabolism, and excretion (ADME) properties of FCD. Absorption is quantified via enzyme-linked immunosorbent assay (ELISA) using FCD-specific antibodies (Torode et al., 2015; Pozharitskaya et al., 2018). In rats, oral administration of 737 kDa FCD resulted in peak serum concentrations at 4 hours postadministration, with renal deposition observed in nephrons (Nagamine et al., 2014). Systemic accumulation in extrarenal organs has also been documented (Nagamine et al., 2014). Notably, low-molecular-weight FCD (LMWF) has enhanced therapeutic potential; comparative pharmacokinetic analyses between LMWF and medium-molecular-weight FCD (MMWF) have shown superior bioavailability and tissue uptake of LMWF, supporting its clinical applicability. While FCD exhibits a favorable pharmacokinetic profile with minimal toxicity, inadequate data exist regarding its systemic redistribution.

A recent study by Kadena et al (Kadena et al., 2018). evaluated FCD absorption via oral administration. The authors proposed that dietary seaweed consumption influences FCD uptake. In their trial, 396 participants consumed up to 3 g of Cladosiphon okamuranus (Okinawan Mozuku), with urinary FCD detected in 385 individuals. In addition, Ikeda-Ohtsubo et al (Ikeda-Ohtsubo et al., 2020). investigated the in vitro modulation of the gut microbiota by FCD. High-purity (>95%) brown seaweed FCD (49.8 kDa), which was isolated from C. okamuranus cultivated in Japan, was administered to adult zebrafish at a 1:1 (w/w) feed ratio for 21 days. Pro- and anti-inflammatory cytokine levels were quantified via quantitative PCR (qPCR), while microbiota shifts were assessed by 16S rRNA sequencing. Compared with control zebrafish, FCD-supplemented zebrafish presented significantly reduced IL-1β (proinflammatory) expression. Additionally, FCD enhanced intestinal microbial diversity and altered community composition, favoring beneficial taxa.

While additional investigations are needed to elucidate the mechanisms of intestinal FCD absorption, multidisciplinary approaches remain critical to comprehensively characterize its pharmacokinetic behavior. The systematic accumulation of these data will establish a robust foundation for the translation of FCD into clinically viable therapeutics.

UC-associated pathogens include diverse Escherichia coli strains, such as diffuse adherent E. coli (DAEC) (Walczuk et al., 2019) and extraintestinal pathogenic E. coli (ExPEC) ( Figure 2 ). In 1987, Burke and Axon demonstrated that fecal isolates from UC patients predominantly comprised DAEC strains exhibiting enterotoxigenic and enteropathogenic traits, unlike those from healthy individuals. ExPEC strains harbor virulence genes encoding toxins (e.g., α-hemolysin) and adhesins (e.g., FimH) ( Figure 2 ) (Mirsepasi-Lauridsen et al., 2016; Mirsepasi-Lauridsen et al., 2019). Unlike pathogens that target small intestinal epithelia, these strains produce hemolysins that compromise intestinal epithelial cell (IEC) tight junction integrity, exacerbating colitis in murine models (Mirsepasi-Lauridsen et al., 2016; Mirsepasi-Lauridsen et al., 2020; Yang et al., 2020).

The genus Bacteroides, particularly Bacteroides vulgatus, is enriched in the colonic submucosal microbiota of UC patients. Notably, elevated serum titers of OmpA antibodies targeting Brucella outer membrane proteins are observed in a subset of individuals with UC ( Figure 2 ) (Sharma et al., 2022).

Candida albicans is a key fungal commensal in the human gut microbiota that contributes to immune system development through mechanisms such as systemic antifungal IgG production ( Figure 2 ) (Doron et al., 2021; Shao et al., 2022a). However, this fungus exacerbates intestinal inflammation via a self-reinforcing cycle: low-grade gut inflammation promotes fungal colonization, whereas C. albicans overgrowth amplifies inflammatory responses. Inflammation-driven C. albicans proliferation worsens colitis by lysing macrophages and secreting candidalysin, a hyphal exotoxin. Candidalysin directly induces intestinal inflammation, and in vitro studies have demonstrated that IL-1β production is correlated with UC severity (Doron et al., 2021; Shao et al., 2022a).

Systemic antifungal IgG production depends on the CARD9 signaling pathway ( Figure 2 ) (Doron et al., 2021). The DSS-induced murine colitis model recapitulates the clinical and histopathological features of human UC (Yang and Merlin, 2024). Card9-deficient mice exhibit impaired immune responses, including reduced expression of IL-6, IL-17A, and IL-22 and regenerating islet-derived protein 3γ (RegIIIγ) after DSS challenge (Sokol et al., 2013).

Candida albicans, a pathobiont of the gut microbiota, exacerbates UC via mycelium-associated hemolysin production (Moyes et al., 2016; Li et al., 2022). Strain-dependent variations in C. albicans macrophage lytic activity further modulate disease progression ( Figure 2 ) (Li et al., 2022). While C. albicans has been implicated in the severity of Crohn’s disease, recent studies have associated its abundance with chronic prostatitis progression, with increased colonization in advanced cases (Li et al., 2022; Hidalgo-Vico et al., 2024).

Studies have demonstrated the critical role of yeast morphology in Candida albicans adaptation (1): Deletion of EFG1 (Enhanced Filamentous Growth Protein 1) (Park et al., 2020) or FLO8 (Flocculation Protein 8, key regulators of filamentation) (Hidalgo-Vico et al., 2024) enhances fungal colonization in the antibiotic-treated murine gut (2). Heterologous expression of UME6 (Transcriptional Repressor UME6, a hyphal transition driver) (Shao et al., 2022b) reduces colonization capacity (3). ZCF8 (Zinc Finger Transcription Factor UME6-interacting Protein 2), TRY4 (Trypsin-4), and ZFU2 (Zinc Finger Transcription Factor UME6-interacting Protein 2) —negative regulators of filamentation—are essential for fungal survival in abiotic environments (Böhm et al., 2017) (4). Null mutations in HMS1 (Hyphal Morphology and Stress Response Protein 1) (Wakade et al., 2023) and CPH2 (cAMP-dependent Protein Kinase Homolog 2, yeast morphology promoters under anaerobic conditions) impair colonization (5). Yeast morphology is dominant in murine gut symbionts, suggesting fitness for intestinal niches (Zhang et al., 2025).

While yeast forms thrive in the gut, filamentous morphotypes may colonize other mucosae. For example, hyphal structures are prevalent in the oral mucosa (Jin et al., 2019), although their presence does not inherently indicate pathogenicity.

Probiotic efficacy requires survival in the gastrointestinal (GI) tract, gastric acid tolerance, the absence of antibiotic resistance genes, and demonstrable host benefits (Nya, 2022). Among probiotic candidates, Lactobacillus spp. remain the most widely utilized and studied ( Figure 2 ).

Lactobacilli modulate GI immune responses by enhancing intestinal barrier integrity and inhibiting pathogen colonization (Kong et al., 2020). These effects are mediated through interactions with innate and adaptive immune cells via microbe-associated molecular patterns (MAMPs), which engage pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), nucleotide-binding oligomerization domain (NOD)-like receptors, and C-type lectins (Veiga et al., 2010). Additionally, Lactobacillus species secrete immunoregulatory proteins. For example, Lactobacillus rhamnosus GG (ATCC 53103) secretes p40 and p75 proteins, which activate the Akt signaling pathway and inhibit TNF-α-induced epithelial cell apoptosis in human and murine colonic epithelial cells ( Figure 2 ).

Synbiotic approaches combining Bifidobacterium lactis with lactobacilli reduce colitis severity and Enterobacteriaceae levels—a family associated with colitogenic potential—during early disease stages (Veiga et al., 2010). Many Lactobacillus species negatively correlate with UC severity. DeMarco et al (De Marco et al., 2018). demonstrated that the probiotic strains Lactobacillus acidophilus, L. casei, Lactococcus lactis, L. reuteri, and Saccharomyces boulardii exert anti-inflammatory effects by selectively modulating the production of cytokines—including IL-10, IL-1β, TNF-α, PGE-2, and IL-8—in HT-29 intestinal epithelial cells. Jia et al. alleviated colitis by increasing intestinal macrophage proportions and IL-10 secretion via Lactobacillus johnsonii (Jia et al., 2022). Sun et al. attenuated DSS-induced UC through L. plantarum-12 administration, enhancing barrier function by upregulating Mucin 2 (MUC2) protein expression (Sun et al., 2020).

Collectively, these findings demonstrate that probiotics attenuate inflammation by suppressing proinflammatory cytokines (e.g., IL-1β and TNF-α) and enhancing anti-inflammatory mediators (e.g., IL-10) through PRR- and Akt-dependent pathways.

The NF-κB transcription factor exists as homo or heterodimeric complexes (e.g., p50/p65) bound to the inhibitory protein IκBα under basal conditions. Upon stimulation, IκBα is phosphorylated and ubiquitinated, leading to proteasomal degradation and subsequent release of NF-κB subunits (e.g., p65), which translocate to the nucleus to activate proinflammatory target genes ( Figure 4 ) (Hu et al., 2018). In a murine chronic colitis model, Cladosiphon okamuranus Tokida-derived FCD inhibited NF-κB pathway activation, reducing IL-6 and IFN-γ levels and ameliorating disease severity (Matsumoto et al., 2004). This compound also suppressed LPS-induced secretion of nitric oxide (NO), prostaglandin E2 (PGE2), TNF-α, and IL-1β in macrophages without inducing cytotoxicity. Notably, low-dose FCD enhanced the production of NO, inducible nitric oxide synthase (iNOS), ROS, and cytokines (IL-1β, IL-6, IL-12, and TNF-α) by macrophages, whereas high-dose FCD attenuated these mediators, revealing a concentration-dependent biphasic anti-inflammatory response.

NF-κB signaling is central to inflammatory pathogenesis (Zahan et al., 2022). FCD attenuated the LPS-induced nuclear translocation of NF-κB p65 and the accumulation of intracellular ROS in RAW 264.7 macrophages ( Figure 4 ). Furthermore, it reversed CPA-induced immunosuppression by reducing ROS levels and downregulating proinflammatory cytokines (IL-6, IL-1β, and IL-12) via NF-κB pathway inhibition, thereby restoring intestinal immune homeostasis (Zahan et al., 2022).

Mounting evidence demonstrates FCD ‘s inhibitory effects on NF-κB signaling. K.K. Asanka Sanjeewa et al. isolated FCD from Padina commersonii and stimulated RAW264.7 cells, revealing that FCD significantly downregulates mRNA and protein expression of TLR2, TLR4, and MyD88 in LPS-induced inflammation, thereby suppressing inflammatory responses (Asanka Sanjeewa et al., 2019). In an in vivo model of UC induced by a fiber-deficient diet, Weiyun Zheng et al. found that FCD inhibits NF-κB pathway activation, reduces intestinal LPS levels, ameliorates inflammatory cell infiltration, and preserves gut barrier integrity, collectively mitigating UC pathology (Zheng et al., 2024).

The MAPK family comprises phosphotransferases that regulate cytosolic signaling cascades via the phosphorylation of serine/threonine residues (Braicu et al., 2019). Researchers have quantified the expression of three MAPK isoforms: extracellular signal-regulated kinase 1/2 (ERK1/2), phosphorylated c-Jun N-terminal kinase (JNK), and phosphorylated p38. In IBD, colonic macrophages predominantly exhibit the proinflammatory M1 phenotype, which drives disease progression through the secretion of mediators such as IL-1β, IL-6, IL-12α, IL-23, and TNF (Zhao et al., 2022). Classically activated macrophage (M1 macrophages) are polarized by Th1 cytokines (e.g., interferon-γ) and Toll-like receptor (TLR) ligands (e.g., LPS). In DSS-induced colitis, ERK signaling is activated, which is correlated with increased M1 macrophage infiltration ( Figure 4 ).

LPS binds to TLR4, triggering MAPK pathway activation and upregulating proinflammatory mediators, including TNF-α, NO, inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2) ( Figure 4 ). FCD dose-dependently suppressed ERK1/2 and p38 phosphorylation, reduced iNOS and COX-2 protein levels, and attenuated TNF-α and IL-1β production, demonstrating potent MAPK pathway inhibition.

FCD in the MAPK pathway remains relatively unexplored, particularly in UC. However, FCD’s anti-inflammatory effects via MAPK inhibition are established. Junhan Cao et al. investigated sea cucumber-derived FCD, demonstrating its suppression of Helicobacter pylori-induced gastritis through MAPK/NF-κB signaling and gut microbiota modulation. Specifically, FCD significantly enhanced biosynthesis of microbial metabolites including butyrate, isobutyrate, hexanoate, and phospholipids, thereby attenuating gastric inflammation (Cao et al., 2025).

TLRs constitute an essential class of PRRs that orchestrate innate immune responses against microbial pathogens (Yang et al., 2015). TLR4, the principal receptor for LPS signaling, regulates cytokine cascades and caspase activation while pathogen-associated molecular patterns (PAMPs) are detected, thereby bridging pathogen detection and inflammatory signaling in innate immunity (Kawasaki and Kawai, 2014). Upon ligand binding, TLR activation initiates intracellular signaling via recruitment of the adaptor protein myeloid differentiation primary response 88 (MyD88), enabling IRAK-4 association with the receptor–ligand complex. This cascade activates the IκB kinase (IKK) complex, triggering IκB phosphorylation and proteasomal degradation, which enables NF-κB nuclear translocation and subsequent transcription of proinflammatory genes ( Figure 4 ) (Kawasaki and Kawai, 2014; Vaamonde-García et al., 2021). FCD derived from Ascophyllum nodosum suppresses LPS-induced macrophage inflammation by inhibiting TLR4/NF-κB signaling ( Figure 4 ). Specifically, FCD attenuated LPS-stimulated NO production (IC50: 27.82 μg/mL), iNOS, and COX-2 expression in RAW 264.7 macrophages in a dose-dependent manner (Fernando et al., 2017).

ROS, including superoxide, hydroxyl radicals, hydroperoxyl radicals, NO, and singlet oxygen, are key mediators of oxidative damage in inflamed tissues (Bassoy et al., 2021). ROS amplify inflammation by upregulating factors linked to innate and adaptive immune responses, exacerbating mucosal injury (Tian et al., 2017). Sustained ROS release in inflammatory microenvironments induces cytosolic and metabolic dysfunction, driving tissue damage through lipid peroxidation (LPx), enzyme inactivation, and DNA oxidation (Schieber and Chandel, 2014; Esmaeeli et al., 2023; Liu et al., 2023). In IBD, oxidative stress (OS) arises from an imbalance between oxidant production and antioxidant defenses (Bourgonje et al., 2020). ROS directly activate proinflammatory signaling pathways, including the NF-κB, MAPK, and signal transducer and activator of transcription 3 (STAT3) pathways. Leukocyte infiltration in inflamed mucosa further amplifies ROS generation, perpetuating cellular and tissue injury (Wang et al., 2016).

Excessive ROS production induces compensatory antioxidant responses to counteract oxidative damage. The NADPH oxidase (NOX) family serves as the primary enzymatic generator of ROS in mammalian cells, with NF-κB activation driven by ROS-dependent activation of the IκB kinase α/β (IKKα/β) complex ( Figure 4 ). Cyclophosphamide (CPA), an immunosuppressant employed in cancer therapy, paradoxically exacerbates oxidative stress through ROS overproduction and the downregulation of antioxidant enzymes—including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px)—in the spleen and thyroid tissues (Xu and Zhang, 2015; Li et al., 2017). ROS disrupt intestinal epithelial barrier integrity by redistributing TJs and AJs proteins through PKC-, MAPK-, JNK-, and ERK-dependent mechanisms ( Figure 4 ). FCD counteracts these effects by inhibiting ROS-driven lipid peroxidation. For example, polysaccharide fractions from the seaweed Solieria filiformis exhibit dose-dependent antioxidant activity, scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals with an IC50 of 1.77 mg/mL (Sousa et al., 2016).

FCD ameliorates intestinal disorders by restoring intestinal barrier integrity, attenuating lipid peroxidation, and suppressing proinflammatory mediators. FCD modulates the gut microbiota composition, enhances SCFAs production by commensal bacteria, and reverses dysbiosis in UC patients, thereby mitigating disease progression. Through synergistic interactions with the gut microbiota, FCD inhibits the NF-κB and MAPK signaling pathways, downregulates proinflammatory cytokines (e.g., IL-12, IL-23, IL-6, IL-36γ, and IL-13), and counteracts oxidative stress-induced intestinal damage by reducing ROS accumulation. Concurrently, FCD upregulates TJs proteins, MUC2, and sIgA, collectively enhancing mucosal protection in UC.