Mechanisms and therapeutic potential of traditional Chinese medicine for inflammatory bowel disease

Abstract

Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder of the intestine with a rising global incidence that significantly impairs patients’ quality of life. Although modern medical therapies can provide short-term symptom relief, they are often limited by dependence on medication and considerable adverse effects. Traditional Chinese medicine (TCM) has demonstrated longstanding clinical efficacy and preclinical advantages in IBD management, yet systematic summaries and in-depth mechanistic insights remain insufficient. This minireview explores recent advances in the mechanistic research of TCM for IBD to inform alternative therapeutic strategies. A systematic literature search was conducted using databases including PubMed, Science Citation Index Expanded, and China National Knowledge Infrastructure to synthesize current evidence, focusing on literature published between 2023 and 2025. Findings reveal that TCM exerts therapeutic effects through holistic, multicomponent, multi-target, and multi-pathway regulation. Key mechanisms involve modulation of inflammatory signaling pathways, immune homeostasis, gut microbiota composition, intestinal barrier integrity, autophagy, metabolic functions, gene expression, and synergistic multi-target therapy. Despite existing research limitations, the evolution from empirical herbal use toward modern scientific understanding promises to accelerate the modernization and global integration of TCM. This minireview provides foundational insights for future research and clinical practice, with the potential to benefit IBD patients worldwide.

Key Words: Traditional Chinese medicine; Inflammatory bowel disease; Mechanism; Inflammatory signalling pathways; Immune regulation; Gut microbiota; Intestinal barrier function; Multi-target therapy

Core Tip: Inflammatory bowel disease management faces limitations with conventional therapies. Traditional Chinese medicine (TCM) offers a holistic, multi-target therapeutic strategy. This minireview elucidates how TCM treats inflammatory bowel disease by synergistically modulating immunity, repairing the intestinal barrier, restoring gut microbiota, and regulating inflammatory pathways and autophagy, thereby accelerating the modernization and integration of TCM into global healthcare.

INTRODUCTION

Inflammatory bowel disease (IBD) is a chronic non-specific inflammatory disorder of the intestine, primarily comprising Crohn’s disease (CD) and ulcerative colitis (UC). Clinical manifestations include recurrent abdominal pain, diarrhoea, mucopurulent bloody stool, and extraintestinal features, such as arthritis and weight loss. The chronic and relapsing nature of IBD significantly impairs patients’ quality of life. Over recent decades, the incidence of IBD has been on the rise globally[1], posing a growing disease burden and emerging as a major public health concern[2]. For instance, in China, the reported incidence in 2013 was 0.46 per 100000 for CD and 1.33 per 100000 for UC, and the total number of IBD patients is estimated to exceed 1.5 million by 2025[3]. Conventional therapies, including aminosalicylates, corticosteroids, and biological agents, provide short-term symptom control but are limited by drug dependence and significant side effects[4]. Traditional Chinese medicine (TCM), with its millennia-old therapeutic legacy, has shown promising clinical efficacy in IBD management. In clinical practice, TCM diagnosis and treatment are based on syndrome differentiation, which identifies specific patterns of imbalance, including, for example, spleen-kidney yang deficiency, dampness-heat in the large intestine, and liver depression with spleen deficiency, through the analysis of symptoms, tongue appearance, and pulse manifestations. Treatment strategies and herbal formula modifications are tailored accordingly, a dynamic process aimed at restoring the balance of Qi, blood, Yin, and Yang. Modern research suggests that the mechanisms underlying such tailored interventions involve the modulation of inflammation, intestinal barrier repair, and gut microbiota regulation. Furthermore, scientific investigations into TCM syndrome-specific models are evolving. For example, studies have established disease-syndrome combined animal models of UC with dampness-heat pattern by simulating a “dampness-heat” state using factors like a high-fat/high-sugar diet and a hot-humid environment, followed by chemical induction with 2,4,6-trinitrobenzene sulfonic acid (TNBS)/ethanol or dextran sulfate sodium (DSS)[5]. Clinical evidence, including meta-analyses of randomized controlled trials, supports the efficacy of TCM interventions such as herbal enemas, demonstrating significant improvements in clinical response rates, elevation of anti-inflammatory cytokines like interleukin-10 (IL-10), and reduction of pro-inflammatory factors such as tumour necrosis factor-α (TNF-α) and IL-6, thereby contributing to mucosal healing[6]. Preclinical studies have substantiated the benefits of TCM in animal models, showing marked improvements in faecal consistency, rectal bleeding, colon shortening, and body weight loss. This minireview presents recent advances in the mechanistic investigations of TCM for IBD treatment with the aim of guiding future research and clinical practice.

THE MECHANISMS OF TCM FOR IBD

Modulation of inflammatory signalling pathways

As a central pathological mechanism of IBD, aberrant activation of inflammatory signalling pathways directly drives intestinal mucosal damage, immune dysregulation, and tissue fibrosis. In recent years, research has increasingly focused on understanding how TCM modulates inflammatory signalling pathways in the treatment of IBD.

Suppression of the nuclear factor-κB signalling pathway: The nuclear factor-κB (NF-κB) signalling pathway, a pivotal player in IBD pathogenesis, is characterised by dysregulated activation that perpetuates chronic intestinal inflammation and tissue injury. Functioning as a master transcriptional regulator of inflammation, NF-κB governs the expression of pro-inflammatory mediators including TNF-α and IL-6, thereby mediating excessive immune cell activation and intestinal epithelial barrier dysfunction. Furthermore, it forms a positive feedback loop with pattern recognition receptors, such as Toll-like receptor 4 (TLR4) and myeloid differentiation primary response 88 (MyD88), amplifying inflammatory cascades in a sustained manner. Administration of ginseng-derived exosome-like nanoparticles to Caco-2 cells and lipopolysaccharide (LPS)-induced RAW 264.7 macrophages demonstrated, via real-time polymerase chain reaction (PCR) analysis, that ginseng-derived exosome-like nanoparticles downregulate expression of IL-6 and TNF-α by inhibiting the NF-κB signalling pathway[6]. In a rat model of UC induced by TNBS and 75% ethanol, real-time quantitative PCR and western blot (WB) analyses demonstrated that treatment with Glycyrrhiza uralensis Fisch. aqueous extract significantly ameliorated colonic inflammation and immune damage by modulating the nucleotide-binding oligomerization domain-containing protein 2/receptor-interacting serine-threonine kinase 2/NF-κB signalling pathway[7]. In DSS-induced UC mice, tandem mass tag-based proteomic data revealed that Shaoyao decoction treatment restored lysosomal activity and glucose oxidative metabolism by activating the peroxisome proliferator-activated receptor (PPAR)/NF-κB signalling pathway, thereby inhibiting IL-17A-mediated M1 macrophage polarisation[8]. In C57BL/6 mice with DSS-induced UC models, WB, immunohistochemical (IHC) staining, and enzyme-linked immunosorbent assay (ELISA) confirmed that Suxin-Hugan-Fang attenuates inflammatory responses by inhibiting both Janus kinase 2/signal transducer and activator of transcription 3 (STAT3) and NF-κB signalling pathways. Simultaneously, Suxin-Hugan-Fang enhances antioxidant capacity and improves intestinal barrier function by upregulating the expression of tight junction proteins, zonula occludens-1 (ZO-1), occludin, claudin-1, and mucin 2 (MUC2)[9].

Suppression of the mitogen-activated protein kinase signalling pathway: The mitogen-activated protein kinase (MAPK) pathway is a critical hub that mediates intestinal inflammation and drives disease progression through dysregulated activation, which modulates pro-inflammatory cytokine release, exacerbates intestinal epithelial barrier damage, and promotes immune dysregulation. Studies have revealed that TCM compounds and bioactive constituents exert therapeutic effects via multi-target strategies, such as inhibiting MAPK phosphorylation cascades and blocking downstream inflammatory mediator expression, while co-ordinately modulating intestinal mucosal repair and immune homeostasis. These findings provide critical insights into the molecular mechanisms underlying TCM-based interventions for IBD treatment. Sequential responses in both chronic colitis mice and bone marrow-derived macrophages, treated with the ethanolic fraction of modified Zhenwu decoction (CDD-2103-E), demonstrated that CDD-2103-E reduced C-C motif chemokine receptor 2-mediated macrophage infiltration into the colon by suppressing the Fyn kinase-mediated p38 MAPK signalling pathway in macrophages. This inhibition was evidenced by the reversal of CDD-2103-E’s suppressive effect on C-C motif chemokine receptor 2 mRNA expression following the pharmacological activation of Fyn kinase[10]. Network pharmacology revealed that Src kinase, MAPK, and protein kinase B (AKT) are crucial therapeutic targets for the Tongxie-Yaofang (TXYF) in UC. These targets primarily associate with IL-17, TNF, and hypoxia-inducible factor-1 (HIF-1) signalling pathways. Further experimental validation demonstrated that TXYF treatment suppressed phosphorylation of Src kinase, MAPK, and AKT1 in UC rat models, concurrently reducing myeloperoxidase activity and downregulating expression levels of the inflammatory cytokines IL-17, TNF-α, and HIF-1[11]. Qin et al[12] performed WB analysis of colon tissue homogenates from a murine UC model induced with 3% DSS. Their results demonstrated that panaxadiol alleviates colonic inflammation and promotes tissue repair by inhibiting the MAPK/NF-κB inflammatory pathway and activating the adenosine monophosphate-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (NRF2)/NAD(P)H quinone oxidoreductase 1 pathway. This dual regulation reduces pro-inflammatory cytokine and increases the production of mucins and tight junction proteins. The low molecular weight polysaccharide HEP10, derived from Hericium erinaceus, inhibited the NF-κB, AKT, and MAPK signalling pathways, as well as the activation of the nucleotide-binding oligomerisation domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. This resulted in reduced pro-inflammatory cytokine release in both LPS-stimulated murine macrophage RAW264.7 cells and DSS-induced colitis mice[13]. In DSS-induced UC mice, treatment with the Callicarpa nudiflora flavonoid extract (CNLF) suppressed the expression of key phosphorylated proteins, including p65 and p38, in the NF-κB and MAPK inflammatory signalling pathways, thereby reducing pro-inflammatory cytokine levels while elevating anti-inflammatory factors. Concurrently, CNLF treatment enhanced tight junction protein expression and decreased D-lactate, diamine oxidase, and LPS concentrations. Furthermore, 16S ribosomal RNA (16S rRNA) sequencing demonstrated CNLF-mediated modulation of gut microbiota composition[14].

Suppression of the TLR4 signalling pathway: The TLR4 signalling pathway demonstrates dual functionality in IBD. Regulated activation is crucial for preserving intestinal immune homeostasis, whereas excessive activation or dysregulation drives chronic inflammation and disease progression. Using a DSS-induced UC mouse model, Dai et al[15] demonstrated that Xianglian pill (XLP) ameliorates UC by suppressing the TLR4/MyD88/NF-κB signalling pathway. TLR4 gene knockout mouse experiments further confirmed that TLR4 is a critical therapeutic target for XLP-mediated improvement of DSS-induced UC. In both LPS-induced RAW264.7 cell inflammatory models and DSS-induced IBD mouse models, WB analysis demonstrated that ginseng-derived nanoparticles inhibited the TLR4/MAPK inflammatory pathway and activated the sequestosome 1 (p62)/NRF2/Kelch-like ECH-associated protein 1 antioxidant pathway[16]. In mice with DSS-induced UC, Clinopodium chinense Kuntze treatment significantly alleviated these pathological features. In vitro experiments using LPS-stimulated RAW 264.7 cells further demonstrated that Clinopodium chinense suppresses inflammation via the LPS-TLR4-NF-κB-inducible nitric oxide synthase/cyclooxygenase-2 (COX-2) signalling pathway[17]. Studies in UC mice orally administered Da-yuan-yin decoction for 7 days revealed that Da-yuan-yin decoction alleviates inflammation by suppressing complement system activation, blocking the LPS-TLR4/NF-κB inflammatory signalling pathway, and reducing neutrophil extracellular traps (NETs) formation[18].

Suppression of the phosphatidylinositol 3-kinase/AKT signalling pathway: The phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway exacerbates intestinal epithelial barrier damage and promotes pro-inflammatory cytokine release by mediating dysregulated cellular proliferation, apoptosis, and autophagy. Aberrant activation is associated with chronic inflammation and impaired mucosal repair in IBD patients. Mechanistic studies have demonstrated that the bioactive constituents of TCM synergistically modulate the intestinal immune microenvironment and tissue regeneration processes through multi-target strategies, including the suppression of PI3K phosphorylation and blockade of downstream effector molecules in the AKT cascade. Both in vivo and in vitro experiments have demonstrated that Astragaloside IV alleviates colitis-associated inflammation and restores intestinal barrier integrity by suppressing the PI3K/AKT signalling pathway[19]. By integrating network pharmacology prediction analysis with validation data from both the TNBS-induced murine model and TNF-α-induced colonic organoids, Huang et al[20] demonstrated that the natural compound cynaroside protects the intestinal barrier and ameliorates colitis by suppressing the PI3K/AKT signalling pathway and reducing intestinal epithelial cell (IEC) apoptosis. Following the oral administration of Xiangsha Liujunzi Wan to TNBS-induced CD model mice, WB revealed significantly reduced expression and phosphorylation of PI3K, AKT, c-Jun N-terminal kinase, and p38 kinase, along with upregulated expression of ZO-1 and occludin. This finding indicates that Xiangsha Liujunzi Wan ameliorates CD by suppressing the PI3K-AKT and MAPK signalling pathways, while enhancing intestinal barrier function[21]. Li et al[22] demonstrated at three levels, DSS-induced UC mice, mouse colon organoids, and cellular models, that Fuzi Lizhong pill reduces expression of pro-inflammatory factors, TNF-α and IL-6, by suppressing the PI3K/AKT/NF-κB signalling pathway, while concurrently repairing the mucosal barrier through upregulation of tight junction proteins ZO-1, occludin, and claudin-1.

Suppression of the NLRP3 inflammasome: The NLRP3 inflammasome drives intestinal mucosal barrier damage and chronic inflammatory progression through its aberrant activation, which promotes the release of pro-inflammatory mediators such as IL-1β and IL-18. Studies have indicated that TCM exerts multi-target regulatory effects on inflammatory cascades and tissue repair by suppressing NLRP3 inflammasome assembly and inhibiting caspase-1 activation. Zhou et al[23] discovered that the compound DMD, isolated from the endophytic fungus Rhodiola tibetica, reduced the release of downstream inflammatory cytokines and restored intestinal barrier function by inhibiting NLRP3 inflammasome activation. This conclusion was further confirmed in NLRP3 knockout mice, where DMD lost its attenuating effect on DSS-induced UC. In mice with DSS-induced colitis, timosaponin B-II, an active component of the TCM Anemarrhena asphodeloides (Zhi Mu), alleviated intestinal permeability and inflammatory responses, potentially by inhibiting NLRP3 inflammasome signalling to block aberrant communication between IECs and macrophages. Conversely, in LPS + ATP-induced cell models, pharmacological inhibition of NLRP3 or NLRP3 overexpression significantly impaired the anti-inflammatory effects mediated by timosaponin B-II[24]. Wang et al[25] demonstrated, through a randomized controlled experiment in mice, that schisandrin, the primary active component of Schisandra chinensis, inhibits the serum/glucocorticoid regulated kinase 1/NLRP3 signalling pathway, thereby reducing the expression of inflammatory cytokines and associated proteins. Using a DSS-induced murine UC model, Feng et al[26] found that Aucklandiae Radix (Mu Xiang) inhibits NF-κB and NLRP3 inflammatory pathways by targeting pyruvate kinase isozyme type M2, thereby decreasing pro-inflammatory cytokine levels and modulating the regulatory T cell (Treg) to T helper 17 (Th17) cell ratio.

A substantial body of preclinical evidence demonstrates the modulation of inflammatory pathways such as NF-κB and MAPK by TCM, which is a compelling finding. However, a critical gap remains between these discoveries and their clinical translation. Most studies employ standardized chemically-induced or immune-mediated murine models. While suitable for preliminary screening, these models cannot fully recapitulate the chronic, relapsing nature and disease heterogeneity of human IBD. Figure 1 demonstrates the modulation of inflammatory signalling pathways by TCM.

Figure 1 Traditional Chinese medicine modulates inflammatory signalling pathways. LPS: Lipopolysaccharide; TLR4: Toll-like receptor 4; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; IκBα: Inhibitor of nuclear factor-kappa B alpha; NF-κB: Nuclear factor-kappa B; TNF-α: Tumour necrosis factor-alpha; IL-6: Interleukin-6; MyD88: Myeloid differentiation primary response 88; NLRP3: Nucleotide-binding oligomerisation domain-like receptor family pyrin domain containing 3; ROS: Reactive oxygen species; ERK: Extracellular regulated protein kinases; p38 MAPK: P38 mitogen-activated protein kinase; JNK: C-Jun N-terminal kinase; AP-1: Activator protein-1; IL-1β: Interleukin-1β.

Modulation of the immune system

Chronic inflammation and mucosal damage in IBD are closely linked to immune cell dysfunction and cytokine network imbalance, which directly drives intestinal barrier destruction and pathological progression. TCM can remodel immune homeostasis through the multi-target regulation of immune cell subset differentiation, signal transduction, and inflammatory mediator secretion.

Regulation of immune cells: IBD pathogenesis is strongly associated with a Th17/Treg imbalance, aberrant macrophage polarisation, and neutrophil infiltration. The functional dysregulation of these immune cells directly perpetuates chronic intestinal inflammation and barrier disruption. Overactivated effector T cells infiltrating intestinal tissues release large quantities of pro-inflammatory cytokines, directly attack IEC, disrupt barrier function, and trigger tissue damage. In a DSS-induced colitis mouse model, Shaoyao decoction reduced 5-hydroxytryptamine levels mainly by modulating intestinal flora and enhancing butyric acid production, thereby suppressing T lymphocyte activation and the secretion of inflammatory cytokines[27].

Th17/Treg imbalance represents a pivotal mechanism in IBD-related immune dysregulation; excessive activation of Th17 cells drives intestinal mucosal inflammation, whereas impaired Treg functionality results in insufficient immunosuppression. This disequilibrium amplifies the intestinal tissue injury. He et al[28] demonstrated that treatment of experimental colitis mice with Paris polyphylla extract restored the balance between Tregs and Th17 cells. This restoration occurred via activation of the PPAR-γ signalling pathway, inhibition of STAT3 phosphorylation, and suppression of HIF-1α expression. In DSS-induced colitis mice, intervention with Qingdai and its active components upregulated the expression of aryl hydrocarbon receptor (AHR), cytochrome P450 1A1, and forkhead box protein 3 while suppressing retinoic acid receptor-related orphan receptor gamma t in colonic tissues. This indicated that Qingdai promoted mucosal healing in UC by activating the AHR signalling pathway and enhancing the Treg/Th17 cell ratio[29]. In a UC mouse model established with 2.25% DSS in C57BL/6 mice, ELISA revealed that Huanglian Pingwei San enhanced antioxidant activity and reduced pro-inflammatory cytokine levels. Flow cytometry (FCM) analysis demonstrated that the Huanglian Pingwei San rebalanced the Th17/Treg cell equilibrium, thereby ameliorating UC[30]. In the TNBS-induced rat UC model, following treatment with Yiyi Fuzi Baijiang San, ELISA and IHC assays detected reduced levels of cytokines including IL-17A, IL-21, IL-22, TNF-α, and IL-6 in the serum and liver. Concurrently, WB analysis of the liver tissue revealed significant downregulation in the protein expression of NLRP3, NLR family CARD domain containing 4, apoptosis-associated speck-like protein containing a CARD, and Caspase-1. Additionally, metabolomics findings indicated that Yiyi Fuzi Baijiang San potentially restored the Th17/Treg cell balance by regulating metabolic pathways, such as glycerophospholipid metabolism[31].

If the number of regulatory memory B cells (MBCs) with anti-inflammatory potential decreases or if their function is impaired, they cannot effectively suppress inflammation, leading to the destruction of immune homeostasis. In a DSS-induced murine colitis model, intervention with Astragalus polysaccharide restored the number of MBCs and reestablished MBC subpopulation homeostasis. Concurrently, the expression of mitochondrial red fluorescent probes was significantly upregulated in MBCs and their subsets. Transcriptomic analysis further confirmed that Astragalus polysaccharide alleviated DSS-induced colitis by modulating mitochondrial metabolism in MBCs[32].

The phenotypic plasticity of macrophages (M1/M2 polarisation) dynamically regulates intestinal inflammation and repair. Excessive activation of M-type macrophages results in releasing pro-inflammatory factors that exacerbate mucosal damage. In contrast, M2 macrophages promote tissue regeneration via immunosuppression. Experiments in DSS-induced UC mice and LPS-induced RAW264.7 cells demonstrated that luteolin induces a shift in macrophage phenotype from classically activated (M1) to alternatively activated (M2) by suppressing M1 marker gene expression while enhancing M2 marker gene expression. Further investigation revealed that this effect was mediated through activation of the AMPK and PPAR-γ signalling pathway[33]. In RAW264.7 cells, gigantol, an active constituent of Dendrobium, demonstrated antagonistic effects on β2 integrin-mediated macrophage adhesion, migration, and chemotaxis, thereby reducing inflammatory infiltration in the colon[34]. Experiments in DSS-induced UC murine models and LPS-stimulated RAW264.7 cellular models demonstrated that Huangqin decoction ameliorates UC by activating the free fatty acid receptor 4-AMPK-PPARα pathway. This activation regulates the fatty acid metabolism-mediated polarisation of macrophages from the M1 to M2 phenotype[35].

Excessive neutrophil infiltration releases reactive oxygen species (ROS), NETs, and matrix metalloproteinases, which directly degrade the intestinal epithelial tight junctions and exacerbate mucosal damage and chronic inflammation. Immunofluorescence and ROS staining of colonic tissues from mice with DSS-induced UC demonstrated that treatment with the n-butanol extract of Pulsatilla decoction, a TCM formulation, suppressed neutrophil infiltration and activation in the colon. WB and immunofluorescence co-localisation analyses further revealed that n-butanol extract of Pulsatilla decoction inhibited the expression of key NET-associated proteins and NET formation, thereby alleviating colonic mucosal damage[36].

AHR is expressed in multiple immune cell types, and the AHR signalling pathway plays a pivotal role in immune regulation. Studies in UC mice have revealed that Gegen Qinlian decoction (GQD) activates the AHR signalling pathway to promote IL-22 secretion, thereby restoring intestinal barrier function. Metabolomic and 16S ribosomal DNA (16S rDNA) analyses demonstrated that this effect was likely mediated through gut microbiota-associated tryptophan metabolism and the restoration of indole derivative production[37]. Using functional metabolomics and gut microbiota sequencing techniques, Jing et al[38] discovered that Wuji Wan enhanced the abundance of Lactobacillus. This promotes the microbial metabolism of tryptophan to indole-3-acetic acid and other metabolites, thereby activating the AHR signalling pathway. Consequently, this mechanism restores intestinal barrier function and alleviates colitis.

Restoration of cytokine network homeostasis: The imbalance between pro-inflammatory cytokines, such as IL-6 and TNF-α, and anti-inflammatory mediators, including IL-10, during IBD progression directly exacerbates chronic intestinal inflammation and barrier injury. Studies have demonstrated that TCM restores the dynamic equilibrium in the immune regulatory network by exerting multi-target regulatory effects on cytokine expression profiles. In DSS-induced UC murine model, administration of Zhenqi Granule reduced IL-1β, IL-6, and TNF-α. Network pharmacology analysis further identified inflammation-related signalling pathways, including the TNF-α signalling pathway and IL-17 signalling pathway, as critical underlying mechanisms[39]. Based on investigations of serum samples from UC patients and DSS-induced murine models, Jia et al[40] demonstrated that the QingChang-XiaoPi decoction ameliorated intestinal inflammation in UC by suppressing the IL-23/IL-17 axis and reducing phosphorylated STAT3 and IL-6, thereby decreasing serum inflammatory cytokine levels and altering the pathogenicity of Th17 cells. Based on a 4% DSS-induced UC model, Gao et al[41] demonstrated that oxymatrine, an active compound derived from Sophora flavescens, ameliorates UC through dual modulation of ferroptosis and inflammatory pathways. This effect is achieved by suppressing the key mediators including IL-6, IL-1β, indoleamine 2,3-dioxygenase 1, and nitric oxide synthase 2. Using DSS-induced Caco-2 cell experiments, Ren et al[42] demonstrated that yam polysaccharide CYP-3a suppressed IL-6 and TNF-α secretion, decreased glucose-regulated protein 78, C/EBP homologous protein, and NF-κB, and blocked the endoplasmic reticulum stress-mediated apoptotic pathway. In a chronic colitis mouse model established using 2% DSS, real-time quantitative PCR analysis demonstrated that Wumei Wan intervention markedly decreased pro-inflammatory cytokines, including TNF-α and IL-1a, as well as angiogenic mediators, such as serpin peptidase inhibitor, clade E, member 1, intercellular adhesion molecule-1, and matrix metalloproteinase 2[43]. Abelmoschus manihot ameliorated intestinal inflammation and gut microbial ecology in DSS-induced IBD mouse models. However, this effect is diminished in IL-10-deficient mice, suggesting that Abelmoschus manihot improves IBD and modulates gut microbiota by promoting IL-10 secretion[44]. Huang et al[45] established a DSS-induced UC mouse model. They demonstrated that isofraxidin alleviates inflammatory responses, an effect potentially mediated through sphingosine-1-phosphate receptor 1 regulation to suppress the IL-17 signalling pathway.

Research on TCM-mediated regulation of Th17/Treg balance and macrophage polarization is consistent with modern immunology. However, the therapeutic rebalancing of immune cells demonstrated in murine models requires validation in human patients, where genetic and environmental diversity results in varied individual responses. Figure 2 illustrates how TCM modulates immune system.

Figure 2 Traditional Chinese medicine modulates immune system. IL: Interleukin; IFN-γ: Interferon-γ; TGF-β: Transforming growth factor-β; TNF-α: Tumour necrosis factor-α; Treg: Regulatory T cell; Th17: T helper 17; CXCL8: C-X-C motif chemokine ligand 8.

Modulation of gut microbiota

Normal human gut microbiota performs essential physiological functions, including metabolic support, immune regulation, and pathogen resistance. Intestinal dysbiosis, a pathological microbial imbalance, is a key pathogenic mechanism of IBD. This imbalance directly contributes to the initiation and maintenance of chronic intestinal inflammation by disrupting the microbiota-host interaction equilibrium, activating aberrant immune responses, and inducing metabolic disturbances. The characteristic hallmarks of dysbiosis in IBD include three interconnected pathological dimensions: Compositional imbalance of microbial communities, dysfunctional metabolic activity, and impaired microbiota-host crosstalk. Wang et al[46] utilised an acetic acid-induced rat model of IBD to show that ginsenosides alleviated intestinal inflammation by modulating the gut microbiota and microbiota-host co-metabolites. Li et al[47] discovered that MIR2911, a plant-derived microRNA from honeysuckle, enables direct modulation of gut microbiota structure, reducing the abundance of Escherichia-Shigella and thereby ameliorating colitis symptoms. In mice with colitis treated with humic acids, beneficial bacterial communities, such as Lactobacillus and Bifidobacterium, increased. This modulation reduced LPS levels, thereby suppressing pro-inflammatory cytokine through the TLR4-NF-κB pathway[48]. Using 16S rRNA gene analysis, Liu et al[49] revealed that Sishen pill and TXYF ameliorated the gut microbiota structure. This modulation may increase propionate and butyrate levels, thereby activating the HIF-1α acetylation pathway and ultimately alleviating UC. Using 16S rRNA sequencing, faecal microbiota transplantation (FMT), and metabolomic techniques, Luo et al[50] demonstrated that Banxia Xiexin decoction alleviated UC through multiple mechanisms. Specifically, Banxia Xiexin decoction promotes the proliferation of beneficial bacteria, including Muribaculaceae and Akkermansia, inhibits pathogenic bacteria, such as Faecalibaculum, and regulates amino acid, purine, and lipid metabolic pathways. Song et al[51] discovered that sea buckthorn extract significantly increased the abundance of Faecalibaculum rodentium and its metabolite butyrate, thereby alleviating UC via the butyrate-G protein-coupled receptor 109A (GPR109A) axis. Conversely, the therapeutic effects were diminished upon vancomycin administration or GPR109A blockade, demonstrating the critical roles of Faecalibaculum rodentium and the butyrate-GPR109A axis. Through 16S rRNA sequencing, molecular biological analysis, and FMT, Cai et al[52] elucidated that Si-Ni-San alleviates murine colitis by modulating the gut microbiota. Furthermore, Si-Ni-San combined with Akkermansia muciniphila enhanced MUC2 production. Broad-spectrum antibiotic-mediated microbiota depletion experiments and non-oral administration studies collectively demonstrated that the therapeutic effect of polysaccharides from Pericarpium Citri Reticulatae ‘Chachiensis’ on DSS-treated rats was linked to its modulation of gut microbiota. Furthermore, Pericarpium Citri Reticulatae ‘Chachiensis’ enriches the gut commensal bacterium Parabacteroides goldsteinii and alleviates colitis by suppressing the PI3K-AKT signalling pathway[53]. In 3% DSS solution-induced colitis mice, treatment with Shenling Baizhu San restored intestinal homeostasis by remodelling the gut microbiota structure, inhibiting the NLRP3 inflammasome, and enhancing intestinal barrier function. Antibiotic-mediated microbiota depletion experiments further confirmed that the efficacy of Shenling Baizhu San depends on the presence of gut microbiota[54]. In DSS-induced colitis mice, continuous administration of Codonopsis pilosula polysaccharide for 7 days revealed gut microbiota remodelling and facilitated short-chain fatty acid binding to GPRs, thereby inhibiting the activation of NLRP3 inflammasome. The FMT experiments further validated that gut microbiota modulation is the key mechanism by which Codonopsis pilosula polysaccharide ameliorates colitis[55]. In a damp-heat UC model established in BALB/c mice, 16S rRNA gene sequencing revealed that aqueous extracts of Reynoutria japonica modulated gut microbiota composition. Non-targeted metabolomic analysis of faeces demonstrated that aqueous extracts of Reynoutria japonica regulates amino acid metabolism and short-chain fatty acid content, thereby collectively ameliorating UC symptoms[56]. In UC mice, Zhili decoction increased beneficial bacteria including Bacteroidota, reduced the Firmicutes/Bacteroidota ratio, promoted the butyrate acid metabolic pathway, inhibited the arachidonic acid metabolic pathway, and suppressed the TLR4/NF-κB/NLRP3 inflammatory pathway[57].

The role of the gut microbiota represents a major area of research interest, yet current findings remain largely correlative. A key limitation stems from the vast differences in composition and function between the murine and human gut microbiomes, which complicates the direct translation of findings. Although TCM compounds can induce reproducible shifts in the gut microbiota in mouse models, establishing a causal relationship in humans remains challenging.

Restoration of intestinal barrier function

The intestinal barrier, which comprises mechanical, chemical, and immunological barriers, collectively maintains intestinal homeostasis by preventing the translocation of pathogens, toxins, and undigested antigens into the submucosal layer. Intestinal barrier dysfunction is a core pathological mechanism in the development of IBD, in which barrier breakdown triggers a vicious cycle of bacterial translocation, immune activation, and chronic inflammation. In IBD, barrier defects primarily manifest as four interrelated pathological alterations: Disruption of epithelial intercellular junctions, deficiencies in the mucosal layer, aberrant epithelial cell death, and Paneth cell dysfunction. Analyses of UC patients, UC mouse models, and cellular intestinal barrier models revealed that Qingchang Wenzhong decoction (QCWZD) repaired intestinal mucus-mechanical barrier damage. Guanylyl cyclase-C plasmid overexpression and knockdown experiments further clarified that the guanylyl cyclase-C signalling pathway is pivotal for QCWZD-mediated amelioration of intestinal inflammation and barrier dysfunction[58]. Indigo and indirubin synergistically reinforce intestinal barrier function in colitis mice, which is associated with the increase of tight junction proteins and MUC2, modulation of inflammatory cytokines, reduction of immune cell infiltration, production of ROS/reactive nitrogen species, and regulation of intestinal microbiota[59]. The transient receptor potential vanilloid 4 (TRPV4) small interfering RNA knockdown experiment confirmed that TRPV4 is a critical target for honokiol in regulating endothelial permeability. Further investigation indicated that honokiol targets the Q239 residue within the ankyrin repeat domain of TRPV4 and competitively binds with ATP to prevent channel opening[60]. In DSS-induced mouse models and the NCM460 cell injury model, phillygenin enhanced tight junction protein expression, while suppressing fibrosis and apoptosis. Cellular experiments further confirmed that these effects were achieved by Takeda GPR5 activation to inhibit the protein kinase R-like endoplasmic reticulum kinase-eukaryotic initiation factor 2α-Ca²⁺ pathway[61]. In mice with DSS-induced colitis, supplementation with Smilax glabra polysaccharides increased goblet cell numbers, gut tight junction proteins and mucin while reducing the proportion of apoptotic cells[62].

HIF-1α mitigates mucosal damage and promotes repair by enhancing intestinal epithelial barrier function and suppressing the formation of NETs. Both LPS-induced IEC-6 cells and in vivo TNBS-induced UC models confirmed that angelicin, the core active component of the TCM compound Sishen pill-TXYF, alleviated UC. This effect is associated with activation of the GPR/extracellular signal-regulated kinase/specificity protein 1/histone deacetylase 1/HIF-1α signalling pathway[63]. In a DSS-induced UC mouse model, QCWZD protected the intestinal barrier by activating the HIF pathway. Further studies in LPS-induced HT29 and RAW264.7 cell models revealed that HIF-targeted suppression reduced ROS generation and mRNA levels of pro-inflammatory cytokines[64].

The Notch signalling pathway exerts dual regulatory effects in IBD by modulating intestinal epithelial differentiation, immune responses, and energy metabolism. While physiological activation promotes mucosal repair, its dysregulation exacerbates intestinal injury through mechanisms such as the suppression of goblet cell differentiation, amplification of Th17-driven inflammation, and disruption of barrier homeostasis. Zhang et al[65] revealed that the aqueous extract of Sarcandra glabra effectively alleviates DSS-induced UC through regulation of the IL-17/Notch1/forkhead box protein 3 signalling pathway and balancing the M1/M2 macrophage ratio. Additionally, evaluation of human colonic epithelial cells demonstrated that the extract promoted intestinal cell proliferation and restitution. Alcian blue periodic acid-Schiff and Ulex europaeus agglutinin-1 staining revealed that Shaoyao decoction restored the mucus layer in colitis mice. This effect occurred through inhibition of the Notch signalling pathway in LPS-stimulated LS174T cell models[66]. Research using DSS-induced UC mouse models revealed that Periplaneta americana extract (PAE) alleviates colonic inflammation and intestinal barrier damage. In Notch1-activated Jurkat T cells, PAE intervention ameliorated the Th17/Treg imbalance. This suggests that PAE modulates the Th17/Treg immune balance by suppressing the Notch1 signalling pathway[67].

Physiological activation of the Wnt/β-catenin signalling pathway enhances intestinal epithelial repair and facilitates stem cell differentiation. Yu et al[68] demonstrated that the Wnt signalling pathway and its core genes were significantly upregulated in DSS + notoginsenoside R1 (NGR1)-treated mice and that NGR1 effectively alleviated the DSS-induced decline in Lgr5 expression in organoids. Co-treatment experiments with the Wnt inhibitor ICG-001 further confirmed that NGR1 promotes intestinal Lgr5+ stem cell proliferation and differentiation by potentiating the Wnt/β-catenin signalling pathway. In DSS-induced UC mice, Qinghua Quyu Jianpi decoction treatment activated the Wnt signalling pathway. In vitro studies using a cellular inflammatory model further confirmed that Qinghua Quyu Jianpi decoction promotes Caco-2 cell proliferation and accelerates cell cycle progression via the Wnt/β-catenin axis[69]. In the UC mouse model established with 3% DSS, transcriptome sequencing revealed that Shengjiang Xiexin decoction intervention activated the Wnt/β-catenin signalling pathway, subsequently elevating intestinal stem cell-associated genes and intestinal regeneration markers. Further analysis demonstrated that Shengjiang Xiexin decoction modulated gut microbiota structure, which was also correlated with the Wnt/β-catenin signalling pathway[70].

Ferroptosis exacerbates IEC injury and barrier disruption through mechanisms such as iron overload, lipid peroxidation, and glutathione peroxidase 4 (GPX4) inactivation, while simultaneously activating inflammatory signalling pathways to amplify immune responses. GQD significantly increased levels of ferroptosis markers and associated proteins in mouse models and partially reversed mitochondrial ROS, malondialdehyde, and ferrous ion (Fe²⁺) levels in RAS-selective lethal 3 (RSL3)-induced intestinal organoids, collectively demonstrating that GQD alleviates inflammatory injury in UC by inhibiting the ferroptosis pathway[71]. In vivo studies showed that cynaroside mitigated intestinal damage induced by RSL3 (a GPX4-targeting ferroptosis inducer), while in vitro experiments confirmed its protective effect against RSL3-triggered ferroptosis. These results demonstrate that Changyanning tablet alleviates CD by suppressing the GPX4-mediated ferroptosis pathway[72].

Research on intestinal barrier restoration remains crucial, but experimental models often induce severe acute injury, which contrasts with the more subtle, chronic barrier dysfunction characteristic of human IBD. Most in vitro studies utilize monocultures of cell lines exposed to a single injurious factor, which fails to recapitulate the complex mucosal microenvironment in vivo. Although TCM components can increase the expression of tight junction proteins in these models, definitive clinical evidence demonstrating barrier repair in patients is still limited. Figure 3 shows that TCM modulates gut microbiota and intestinal barrier function.

Figure 3 Traditional Chinese medicine modulates gut microbiota and intestinal barrier function. SCFAs: Short-chain fatty acids; HIF-α: Hypoxia inducible factor-α; GPX4: Glutathione peroxidase 4; MUC2: Mucin 2.

Modulation of autophagic function

Autophagy, a critical homeostatic mechanism through which cells degrade damaged intracellular components or pathogens via lysosomal pathways, has essential functions including pathogen clearance, cellular homeostasis maintenance, and immune response regulation. Dysfunctional autophagy plays a pivotal role in the pathogenesis of IBD, particularly CD, and drives the progression of chronic intestinal inflammation through impaired clearance mechanisms, dysregulated immune modulation, and intestinal barrier defects. The core pathological manifestations of autophagic dysfunction in IBD involve three interconnected mechanisms: Autophagy-related gene mutations that predispose patients to IBD susceptibility, autophagic deficiency that exacerbates immune dysregulation, and epithelial barrier impairment. Following treatment with Baitouweng decoction, the DSS-induced colitis mouse model exhibited elevated autophagy levels, increased proportions of colonic goblet cells, and enhanced expression of tight junction proteins. This protective effect was further demonstrated to be mediated through the activation of the AMPK/mammalian target of rapamycin signalling pathway[73]. Experiments using small interfering RNA to silence NRF2 gene expression in Caco-2 cells, combined with WB blotting, revealed that drug-containing serum of liquorice promotes autophagy and reduces inflammatory damage by activating the NRF2/phosphatase and tensin homolog-induced putative kinase 1 signalling pathway[74]. FCM analysis revealed that Modified Jiaoqi powder dose-dependently reduced the apoptotic rate of LPS-stimulated cells in a dose-dependent manner. Further investigations demonstrated that Modified Jiaoqi powder reconstructs the intestinal epithelial barrier by enhancing IEC autophagy to inhibit TNF-mediated apoptosis[75]. Autophagy, a fundamental cellular process, has well-established links to impaired function in IBD. Evidence for its modulation by TCM is encouraging but remains largely preliminary. A key methodological limitation lies in the reliance on indirect markers of autophagy measured in whole-tissue homogenates, which are insufficient to delineate cell type-specific effects within the complex intestinal mucosa.

Modulation of metabolic regulation

Metabolic dysregulation is a critical factor in the pathogenesis of IBD, driving chronic inflammatory progression through the reprogramming of energy metabolism and disturbances in lipid and amino acid metabolism. These alterations collectively impair immune cell functionality, disrupt intestinal barrier homeostasis, and compromise microbiota-host interactions, thereby perpetuating a pro-inflammatory microenvironment. Studies in mice and RAW264.7 cells revealed that XLP significantly increased itaconate levels in colonic tissue, thereby inhibiting macrophage polarisation from M0 to M1 phenotype and reducing levels of TNF-α, IL-6, and inducible nitric oxide synthase, ultimately alleviating UC[76]. The spleen-kidney yang deficiency-associated UC rat model was established and treated with Fuzi Lizhong pill. Combined serum metabolomics and 16S rRNA sequencing for microbial community analysis revealed that Fuzi Lizhong pill ameliorated UC by modulating gut microbiota composition and regulating amino acid and energy metabolism[77]. In the 4% DSS-induced UC mouse model, Evodia rutaecarpa-processed Coptidis Rhizoma significantly increased α-ketoglutarate levels. Subsequent α-ketoglutarate intervention elevated Lactobacillus reuteri abundance and alleviated mucosal damage in UC mice[78]. 16S rRNA gene sequencing and untargeted metabolomics demonstrated that Shenlin Baizhu decoction modulates the gut microbiota structure and galactose metabolism pathway[79]. In DSS-induced UC mouse models, treatment with the Causonis japonica extract significantly attenuated the inflammatory response. Analyses of untargeted metabolomics, pseudo-targeted lipidomics, and 16S rRNA sequencing revealed that the modulation of glycerophospholipids, arachidonic acid, and energy metabolism are critical factors for this therapeutic effect[80]. In mice with UC induced by 2.5% DSS, treatment with Jasminum elongatum significantly reduced the expression of inhibitor of NF-κB, NF-κB p65, and COX-2, as demonstrated by IHC analysis of colon tissues. Both metabolomic and network pharmacology approaches have highlighted the critical involvement of the arachidonic acid metabolic pathway. These findings collectively indicate that Jasminum elongatum ameliorates UC in mice by modulating the inhibitor of NF-κB/p65/COX-2/arachidonic acid signalling axis[81].

Metabolic reprogramming is an emerging frontier. Current studies are predominantly descriptive, identifying changes in metabolites such as itaconate, α-ketoglutarate, or the arachidonic acid pathway. A major critique is the difficulty in distinguishing whether observed metabolic shifts are drivers of the therapeutic effect or merely consequences of reduced inflammation. The intricate interplay between host cellular metabolism and gut microbial metabolism adds another layer of complexity.

Regulation of gene expression

TCM can precisely regulate the expression spectrum of genes related to inflammation, immunity, and barrier repair by affecting the activity of transcription factors, epigenetics, and the expression of non-coding RNA, which is an important molecular basis for TCM to achieve multi-target and multi-level regulatory effects. Epigenetic dysregulation modulates gene expression through mechanisms such as DNA methylation, histone modification, and non-coding RNA regulation without altering DNA sequences, thereby contributing to pathological processes including immune dysregulation, intestinal barrier disruption, and dysregulated microbiota-host interactions. Based on transcriptome profiling revealing a distinct genetic profile in colonic tissues from n-butanol extract of Shen Ling Bai Zhu San-treated mice compared with DSS-induced colitis models, Qu et al[82] proposed that this therapeutic effect might be attributed to ginsenosides and other bioactive constituents, potentially mediated through the regulation of pivotal gene expression and biological functions. Based on the therapeutic outcomes observed in a DSS-induced colitis mouse model, treatment with Zanthoxyli Pericarpium significantly suppressed inflammatory response and oxidative stress, thereby mitigating colonic injury. This protective mechanism may involve modulation of key genes such as prostaglandin-endoperoxide synthase 2[83]. Following treatment with the ethanol extract of Limonium bicolor, LPS-stimulated RAW 264.7 macrophages exhibited reduced cytokine secretion, DSS-induced UC damage was alleviated, and gut microbiota dysbiosis in UC mice was reversed. These mechanisms may involve the modulation of inflammation-associated genes, including prostaglandin-endoperoxide synthase 2, plasminogen, and PPAR-γ, by major bioactive compounds[84]. Research on gene expression regulation often represents the final, integrative step in elucidating mechanistic pathways. While transcriptomic analyses reveal broad changes, they often stop at identifying enriched pathways and lack deeper functional validation. A significant gap is the scarcity of research on epigenetic mechanisms, a hypothesized, durable mode of action for TCM that remains critically understudied.

Synergistic multi-target therapeutic strategy

Chronic inflammation and tissue damage in IBD involve the interplay of multiple pathological components, including aberrant activation of inflammatory signalling, immune homeostasis disruption, intestinal barrier breakdown, and microbial dysbiosis. The multi-target therapeutic strategy of TCM in IBD treatment serves as a paradigm for addressing complex pathological networks, thereby highlighting the unique advantage of simultaneously modulating interconnected disease-driving mechanisms. Murine experiments demonstrated that Valeriana jatamansi extract (VJE) significantly ameliorated UC symptoms and reduced inflammatory cytokine levels. Untargeted colon metabolomics and 16S rDNA sequencing revealed that VJE reversed the perturbed colonic metabolic profiles and gut microbiome composition in mice with UC, representing a pivotal mechanism underlying VJE’s therapeutic efficacy against UC[85]. Based on a DSS-induced colitis mouse model, studies have revealed that velvet antler water extracts, derived from Formosan sambar deer and red deer, alleviate colitis by suppressing pro-inflammatory cytokines, restoring intestinal barrier integrity, and modulating gut microbiota homeostasis. Untargeted metabolomic analysis further identified key components within velvet antler water extract, such as L-carnitine and hypoxanthine, which may contribute to the amelioration of colitis symptoms[86]. Zhong et al[87] established a murine model of obesity-complicated colitis and administered ginsenoside Rg1. The results demonstrated that ginsenoside Rg1 alleviates colitis symptoms by modulating the gut microbiota composition, improving lipid metabolism in colonic contents, and regulating Th1/Th2/Th17 cell differentiation. Both Caco-2 cells and UC mice experiments demonstrated that Yinhua Miyanling tablets intervention significantly alleviated pathological colonic damage. Subsequent metabolomics and network pharmacology studies identified seven key targets, IL-6, TNF-α, myeloperoxidase, COX-2, hexokinase 2, tryptophan hydroxylase, and CYP1A2, along with four core metabolic pathways: Arachidonic acid metabolism, linoleic acid metabolism, glycolysis/gluconeogenesis, and tyrosine biosynthesis[88]. In murine models of UC, integrated analyses through 16S rDNA sequencing, bile acid-targeted metabolomics, transcriptomics, reverse transcription PCR, and WB demonstrated that baicalin magnesium effectively regulates bile acid metabolism, maintains intestinal microecological balance, and suppresses activation of the NF-κB and PPARα signalling pathways, thereby exerting therapeutic effects[89]. Based on experimental findings in murine models of UC, Sijunzi decoction effectively ameliorated UC symptoms by modulating the gut microbiota composition, suppressing pro-inflammatory cytokine production, and upregulating intestinal epithelial barrier protein expression. Multivariate statistical analysis demonstrated a close correlation between these mechanisms, collectively contributing to therapeutic efficacy[90]. Based on experimental findings in murine models of UC, Saussurea costus (SC) administration reversed the DSS-induced downregulation of tight junction proteins ZO-1 and occludin in colonic tissues, as confirmed by immunofluorescence and WB analyses. Concurrently, 16S rRNA gene sequencing revealed that SC reduced pathogenic bacterial populations while enhancing beneficial bacteria such as Lactobacillus spp. These results collectively demonstrate that SC may alleviate UC by modulating the gut microbiota composition and restoring intestinal barrier integrity[91]. Administration of berberine-evoadiamine (BBR-EVO), the active component derived from the TCM compound Yulian decoction, to colitis mouse models has revealed its therapeutic effects. BBR-EVO enhances the expression of tight junction proteins, reduces pro-inflammatory cytokine levels, and restores gut microbiota homeostasis, thereby ameliorating colitis. Moreover, BBR-EVO attenuates secondary liver injury in colitic mice, suggesting that modulation of the gut-liver axis may represent an additional mechanism underlying its efficacy[92]. A mouse model of UC was established in C57BL/6N mice using 1% DSS solution. WB analysis revealed that Xianglian Zhixie tablet (XLZXT) upregulated the expression of MUC2, occludin, and ZO-1. XLZXT also modulates the TLR4/MyD88/NF-κB p65 signalling pathway. Additionally, high-throughput sequencing of 16S rRNA in mouse faeces demonstrated that XLZXT regulates the gut microbiota[93]. Following the establishment of a chronic colitis model using 2% DSS, intragastric administration of Qing Hua Chang Yin (QHCY) ameliorated DSS-induced tissue injury, as observed by haematoxylin-eosin and periodic acid-Schiff staining. IHC further revealed that QHCY reduced the levels of pro-inflammatory cytokines, while enhancing the expression of tight junction proteins and MUC2. Additionally, 16S rRNA sequencing demonstrated that QHCY restructured microbiota composition[94]. Administration of Li-Hong Tang to mice with 2.5% DSS-induced UC reduced the levels of inflammatory markers and oxidative stress. IHC and 16S rDNA sequencing further demonstrated that this effect might be mediated through increased levels of NRF2 and heme oxygenase-1, along with the amelioration of gut microbiota dysbiosis[95]. Following treatment with carbon dots derived from scrambled Coptidis Rhizoma (SCR-CDs), UC mice exhibited an alleviation of clinical symptoms. Studies on hygroscopic curves and bleeding times suggested that this therapeutic effect may be closely associated with the inherent hygroscopic capability and haemostatic bioactivity of SCR-CDs. Furthermore, SCR-CDs exerted protective effects against IBD by repairing the intestinal mucosal barrier and ameliorating gut microbial dysbiosis[96]. With concurrent administration of Kuijie decoction (KJD) in a DSS-induced UC model, 16S rRNA sequencing and untargeted metabolomics revealed that KJD ameliorated the gut microbiota structure and metabolic profile. FCM further demonstrated that KJD restored the Th17/Treg balance. Additionally, KJD modulated the intestinal barrier function by upregulating ZO-1 and occludin expression and downregulating claudin-2 levels[97]. When administered orally to C57BL/6 mice with DSS-induced IBD, Cajanus cajan leaf extract, an AHR agonist, was found to influence M1/macrophage polarisation via FCM and correct the Th17/Treg cell balance. Furthermore, Cajanus cajan leaf extract modulates gut microbiota composition, regulates inflammatory cytokine profiles, and protects the intestinal epithelial barrier[98].

The multi-target strategy constitutes both a central strength of TCM and a major challenge for modern scientific validation. It remains unclear which combinations of constituents are critical for efficacy and whether their actions are merely additive or truly synergistic. Furthermore, the identification of primary, non-redundant therapeutic targets is hindered by numerous simultaneous actions, posing challenges for quality control and rational optimization. Table 1 summarises key TCM interventions, their molecular targets, and the level of supporting evidence.

Table 1 Key traditional Chinese medicine interventions, their primary targets, and level of evidence in inflammatory bowel disease.

Key TCM intervention	Primary targets/pathways	Level of evidence
Xianglian pill	TLR4/MyD88/NF-κB	B
Abelmoschus manihot extract	IL-10	B
Glycyrrhiza uralensis aqueous extract	NOD2/RIP2/NF-κB	B
Luteolin	AMPK/PPAR-γ	B, C
Shaoyao decoction	PPAR/NF-κB	B
Phillygenin	TLR4/Src/MAPK, NF-κB	B
Si-Ni-San	Gut microbiota (Akkermansia muciniphila)	B
Ginsenoside-derived exosome-like nanoparticles	NF-κB	C
Gegen Qinlian decoction	AHR/ferroptosis pathway	B
Astragaloside IV	PI3K/AKT	B, C
Baitouweng decoction	AMPK/mTOR	B
Schisandrin	SGK1/NLRP3	B
Qingchang Wenzhong decoction	Guanylyl cyclase-C/HIF-α	B, C (patient cells)
Saussurea costus	Gut microbiota/tight junctions	B
Citropten	NF-κB, JAK/STAT3	B

TCM: Traditional Chinese medicine; TLR4: Toll-like receptor 4; MyD88: Myeloid differentiation primary response 88; NF-κB: Nuclear factor-kappa B; IL: Interleukin; NOD2: Nucleotide-binding oligomerization domain-containing protein 2; RIP2: Receptor-interacting serine-threonine kinase 2; AMPK: Adenosine monophosphate-activated protein kinase; PPAR-γ: Peroxisome proliferator-activated receptor-γ; MAPK: Mitogen-activated protein kinase; AHR: Aryl hydrocarbon receptor; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; mTOR: Mammalian target of rapamycin; SGK1: Serum/glucocorticoid regulated kinase 1; NLRP3: Nucleotide-binding oligomerisation domain-like receptor family pyrin domain containing 3; HIF-α: Hypoxia inducible factor-α; JAK: Janus kinase; STAT3: Signal transducer and activator of transcription 3.

IBD is a complex chronic intestinal disorder involving multifaceted pathological mechanisms, including dysregulated signalling pathways, immune dysfunction, gut microbiota dysbiosis, and impaired epithelial barrier function. This minireview systematically summarises and synthesises recent mechanistic research on TCM for IBD treatment, highlighting that herbal medicines exert unique, holistic regulatory effects through their multicomponent, multi-target, and multi-pathway therapeutic profile.

Conventional therapies offer the advantages of rapid, potent, and targeted suppression of specific inflammatory pathways, supported by a robust hierarchy of evidence from large-scale randomised controlled trials (RCTs). However, their limitations include significant side effects, high cost, primary or secondary non-response, and a predominant focus on managing overt inflammation and symptoms. In contrast, the core strength of TCM lies in its holistic approach aimed at restoring the body’s internal balance, and its principle of individualised treatment is well-suited to the heterogeneous nature of IBD. However, major weaknesses of TCM include a lack of standardised treatment protocols, variability in the quality and chemical composition of herbal products, and a paucity of high-quality clinical evidence by contemporary standards. This contrast defines a clear potential for synergy. An integrative strategy could leverage TCM’s regulatory effects to improve long-term disease control, reduce relapse rates, and enhance patient quality of life, while utilising conventional drugs to rapidly induce remission during severe acute flares. Such an approach may also allow for dose reduction of conventional agents, thereby minimising their adverse effects.

Current mechanistic research on TCM for IBD faces several limitations and challenges. Most preclinical studies have employed DSS- or TNBS-induced murine colitis models[8,21,31]; however, insufficient attention has been paid to the pathological disparities between these models and human IBD. For example, DSS models primarily induce acute epithelial damage, whereas human UC is a chronic relapsing disease. A further limitation is the lack of syndrome-specific models. TCM therapy emphasises “syndrome differentiation and treatment”, but existing research predominantly focuses on the “disease” level, neglecting mechanistic exploration of TCM syndromes. For instance, the syndromes of “dampness-heat in the large intestine” and “spleen-kidney yang deficiency” may involve fundamentally different immune microenvironments and microbiota profiles. However, current animal models lack the capability to establish stable models that correspond to specific syndromes, hindering research into the individualised therapeutic features of TCM.

Additional critical challenges impede translational research. These include: A lack of standardization in herbal extracts, where batch-to-batch variability compromises experimental reproducibility and clinical consistency; potential herb-drug interactions, the safety profiles of which require further investigation when herbs are co-administered with conventional immunomodulators; and the generally low translatability of findings from animal models to human clinical efficacy.

In the clinical domain, despite millennia of application and recognition among TCM practitioners of its efficacy in IBD management, most reported studies are small-scale observational investigations or animal experiments[36]. There is a paucity of large-scale RCTs and long-term follow-up data, resulting in a low level of clinical evidence. Enhancing the evidence base for TCM in IBD is imperative, necessitating multicentre, large-sample RCTs. Real-world studies are also needed, including the establishment of dedicated IBD-TCM cohorts to collect long-term data on medication use, recurrence rates, and safety. The gap between widely accepted TCM practice and high-level evidence stems from significant methodological and practical hurdles. The individualised approach of TCM conflicts with the fixed protocols of standard RCTs, complicating trial design. Moreover, positive results in homogeneous animal models do not guarantee success in a heterogeneous human population, underscoring the translational gap. Concerns regarding herbal standardization and safety further increase the complexity and cost of large-scale trials.

CONCLUSION

Mechanistic research on TCM for IBD has achieved significant progress, evolving from the empirical use of herbs for “heat-clearing and detoxifying” to a modern scientific understanding based on immune microenvironment modulation, microbiota-immune axis regulation, and signalling pathway control. To advance this progress and address existing challenges, future research priorities should include: (1) Conducting rigorous pragmatic RCTs and real-world studies to generate high-grade clinical evidence; (2) Applying multi-omics approaches (e.g., transcriptomics, metabolomics, proteomics) to elucidate the complex network effects of TCM; and (3) Developing advanced “disease-syndrome combined” models to bridge TCM theory with biomedical mechanisms. TCM research for IBD is now in a pivotal transition from empirical to precision medicine. A deeper understanding of the biological basis underlying the “disease-pattern-prescription” framework, along with a clearer elucidation of TCM’s multi-target regulatory mechanisms, is essential to advance the modernisation and global integration of TCM in IBD treatment, ultimately benefiting patients worldwide.