Key Takeaways & Executive Findings
- •• • Global UC prevalence reached approximately 5 million cases in 2023, with North America and Northern Europe maintaining the highest incidence rates, while emerging industrialized nations—particularly China—exhibit the most rapid growth; this epidemiological shift underscores the urgent clinical need for cost-effective, multi-target therapeutic alternatives to biologics, which currently suffer from high non-response rates and prohibitive costs. • • The 'gut microbiota dysbiosis–barrier injury' vicious cycle is mechanistically driven by reduced microbial diversity, decreased beneficial bacteria, and increased pathogenic taxa, leading to SCFA and tryptophan metabolic disturbances, downregulation of tight junction proteins, and increased intestinal mucosal permeability; this cycle constitutes the core pathological basis for UC's chronicity and refractoriness, making it a prime target for intervention. • • TCM formulas such as Baitouweng Decoction, Lizhong Decoction, Banxia Xiexin Decoction, Gegen Qinlian Decoction, and Sishen Pill demonstrate efficacy in DSS-induced colitis models by modulating gut microbiota-SCFAs-Th17/Treg axis, activating AhR/IL-22 signaling to repair the intestinal barrier via microbiota-related tryptophan metabolism, and regulating the TLR4/NF-κB/NLRP3 signaling pathway; these multi-target mechanisms offer advantages over single-target biologics in addressing the complex pathophysiology of UC. • • The 'turbidity-toxin' theory provides a coherent TCM framework linking gut microbiota dysbiosis and cell pyroptosis to UC pathogenesis, with clinical studies showing that Huazhuo Jiedu formulas reduce serum NLRP3 inflammasome, IL-18, and IL-1β levels while improving gut microbiota and mucosal barrier function; this integration of traditional theory with modern molecular targets facilitates the development of evidence-based TCM therapies for UC.
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Abstract
Ulcerative colitis (UC) is a chronic, non-specific inflammatory bowel disease with a continuously rising global incidence; an estimated 5 million cases were recorded worldwide in 2023, with emerging industrialized nations such as China showing the most pronounced increases. The core pathophysiological driver of UC's recurrent and refractory nature is a self-reinforcing vicious cycle between gut microbiota dysbiosis and intestinal barrier dysfunction. Reduced microbial diversity, depletion of beneficial taxa, and expansion of pathogenic bacteria disrupt short-chain fatty acid (SCFA) and tryptophan metabolism, impair the mucus layer, downregulate tight junction (TJ) proteins, and compromise immune barrier integrity, thereby exacerbating mucosal inflammation. Conventional therapies—aminosalicylates, glucocorticoids, immunosuppressants, and biologics—frequently fail to achieve durable remission and impose substantial economic burden. Traditional Chinese medicine (TCM), guided by the 'turbidity-toxin' theory, intervenes through multi-component, multi-target mechanisms: reshaping gut microbial composition, enhancing beneficial metabolite production, and upregulating TJ protein expression. This review systematically synthesizes the gut microbiota–barrier interaction in UC and the theoretical and modern biological mechanisms of TCM intervention, providing a theoretical reference for optimizing clinical strategies and highlighting the potential of TCM in UC management.
1. Introduction
Ulcerative colitis (UC) is a chronic, idiopathic inflammatory bowel disease characterized by continuous mucosal inflammation, predominantly affecting the rectum and extending proximally. The global disease burden has escalated sharply, with an estimated 5 million prevalent cases in 2023 and the most rapid incidence increases occurring in newly industrialized countries such as China. Current pharmacological management relies on aminosalicylates, corticosteroids, immunosuppressants, and biologics; however, a substantial proportion of patients experience inadequate response, steroid dependence, therapeutic resistance, and severe financial toxicity. These limitations stem from the complex, multifactorial pathogenesis of UC, which involves genetic susceptibility, environmental triggers, immune dysregulation, epithelial barrier defects, and aberrant cytokine production. Among these, the vicious cycle between gut microbiota dysbiosis and intestinal barrier dysfunction has emerged as a central mechanism driving disease chronicity and relapse.
The gut microbiota, the largest microecosystem in the human body, and the intestinal barrier—comprising physical, chemical, immunological, and biological components—maintain a homeostatic balance essential for intestinal health. Disruption of this balance, characterized by reduced microbial diversity, depletion of anti-inflammatory commensals, and expansion of pro-inflammatory pathobionts, leads to metabolic disturbances in bile acids and short-chain fatty acids (SCFAs). These metabolic shifts activate excessive immune responses, downregulate tight junction proteins, and increase mucosal permeability, further aggravating inflammation and reinforcing the dysbiosis–barrier injury cycle. Conventional therapies targeting single inflammatory mediators have largely failed to break this cycle. Traditional Chinese medicine (TCM), guided by the 'turbidity-toxin' theory, offers a multi-component, multi-target strategy that simultaneously reshapes gut microbial composition, promotes beneficial metabolite production, and upregulates tight junction protein expression. This review systematically examines the gut microbiota–barrier interaction in UC and the theoretical and modern biological mechanisms of TCM intervention, aiming to provide a robust theoretical foundation for optimizing clinical management strategies.
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ZHANG Xinran, WANG Yixuan, CHEN Jiayu (2026). Research Progress on the Role of Gut Microbiota–Intestinal Barrier Interaction in Ulcerative Colitis and Traditional Chinese Medicine Intervention. Chinese Traditional and Herbal Drugs. https://doi.org/10.7501/j.issn.0253-2670.2026.16.20261633
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Frequently Asked Questions
What specific molecular mechanisms link gut microbiota dysbiosis to tight junction protein downregulation in UC, and how do TCM interventions reverse this?
Dysbiosis reduces SCFA-producing bacteria, lowering colonic butyrate levels, which impairs AMPK activation and leads to decreased expression of tight junction proteins such as occludin and ZO-1. Additionally, tryptophan metabolism shifts away from indole-3-propionic acid (IPA) production, reducing AhR/IL-22 signaling that is essential for epithelial barrier repair. TCM formulas such as Baitouweng Decoction restore IPA production and epithelial necroptosis regulation, while Gegen Qinlian Decoction activates AhR/IL-22 to upregulate tight junction proteins, as demonstrated in DSS-induced colitis models.
What are the principal failure mechanisms of current biologic therapies in UC, and how do TCM multi-target approaches address them?
Biologics targeting single cytokines (e.g., TNF-α, IL-12/23) frequently fail due to redundant inflammatory pathways, immunogenicity, and loss of response over time. TCM formulas simultaneously modulate multiple nodes: Lizhong Decoction regulates the gut microbiota-SCFAs-Th17/Treg axis; Sishen Pill inhibits TLR4/NF-κB/NLRP3 signaling; and Huazhuo Jiedu formulas reduce NLRP3 inflammasome, IL-18, and IL-1β. This multi-target action addresses pathway redundancy and reduces the likelihood of compensatory escape mechanisms, offering a more durable therapeutic strategy.
What are the scalability and quality control bottlenecks for translating TCM formulas into standardized UC therapeutics?
Key bottlenecks include batch-to-batch variability in herbal raw materials, complex multi-component pharmacokinetics, and lack of standardized biomarkers for patient stratification. For example, the active constituents of Baitouweng Decoction and Gegen Qinlian Decoction vary with geographic origin and extraction methods, affecting IPA production and AhR activation. Addressing these requires rigorous Good Manufacturing Practice (GMP) protocols, fingerprinting, and biomarker-guided clinical trials to ensure reproducible efficacy and safety.
How does the 'turbidity-toxin' theory mechanistically align with modern molecular findings in UC, and what clinical evidence supports it?
The 'turbidity-toxin' theory posits that accumulated toxic pathogens and metabolic waste disrupt the intestinal microenvironment, mirroring modern findings of dysbiosis, impaired barrier function, and cell pyroptosis. Clinical studies on Huazhuo Jiedu formulas show significant reductions in serum NLRP3 inflammasome, IL-18, and IL-1β levels, alongside improved gut microbiota diversity and mucosal barrier integrity. This alignment provides a theoretical bridge between traditional TCM diagnosis and molecular targets, facilitating the development of evidence-based TCM interventions.
What are the cost-effectiveness and clinical outcome benchmarks for TCM versus biologics in UC management?
Biologics such as anti-TNF agents cost tens of thousands of USD annually per patient and have a 30–40% primary non-response rate. TCM formulas, while requiring standardization, offer substantially lower costs and multi-target efficacy. Clinical studies on formulas like Banxia Xiexin Decoction and Lizhong Decoction demonstrate reduced disease activity index (DAI) scores and improved mucosal healing in DSS-induced colitis models, with p-values < 0.01 for key inflammatory markers. However, large-scale randomized controlled trials with long-term follow-up are needed to establish cost-effectiveness and durability of remission.
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