The combination of natural bioactive compounds with 5-ASA represents a significant advancement in UC therapy, aligning with the emerging trend toward multi-target regulation and synergistic efficacy. This integrated approach capitalizes on the multi-mechanistic actions of natural compounds to complement and enhance the therapeutic effects of 5-ASA, thereby addressing the multifaceted pathology of UC—from acute inflammatory flare-ups to chronic mucosal damage and impaired repair. Consequently, it markedly improves clinical outcomes and disease control. This subsection focuses on natural bioactive compounds that exert direct synergistic effects with 5-ASA at the molecular and tissue levels. These compounds act through relatively defined mechanisms, thereby complementing the pharmacological action of 5-ASA. Table 1 summarizes recent advances (over the past 5 years) in the combined application of natural bioactive compounds and 5-ASA.

During active disease, UC is characterized by excessive activation of immune pathways and a surge in pro-inflammatory mediators. Natural bioactive compounds synergize with 5-ASA to potently suppress these acute inflammatory responses through multiple, complementary mechanisms (Tang et al., 2025). In terms of immune and inflammatory regulation, several natural active ingredients demonstrates multi-target synergistic effects with 5-ASA. Meta-analyses based on randomized controlled trials (RCTs) have provided evidence that tanshinone IIA enhances the anti-inflammatory efficacy of 5-ASA by inhibiting major histocompatibility complex class II (MHC-II)-mediated antigen presentation and reducing levels of tumor necrosis factor-alpha (TNF-α) and C-reactive protein (CRP) (Chen et al., 2024). Berberine promotes M2 macrophage polarization through activation of the interleukin-4/signal transducer and activator of transcription 6 (IL-4/STAT6) pathway. In parallel, it modulates the CD4⁺/CD8⁺ T-cell balance, which is associated with significant reductions in the Baron endoscopic score and disease activity index (DAI) (Li et al., 2024). Curcumin not only exerts synergistic anti-inflammatory effects by inhibiting the NF-κB signaling pathway but also regulates the T helper 1/T helper 2 (Th1/Th2) cell balance, leading to a significant improvement in clinical response rates (Chandan et al., 2020). In animal models, cannabidiol demonstrates multi-receptor regulatory potential by acting on cannabinoid receptor 1/cannabinoid receptor 2 (CB1/CB2) and G protein-coupled receptor 35 (GPR35). Through these receptors, cannabidiol synergistically inhibits NF-κB signaling, reduces the release of pro-inflammatory cytokines such as IL-6 and IL-1β, and enhances the therapeutic efficacy of olsalazine and cyclosporine (Thapa et al., 2025).

Concurrently, these compounds combat oxidative stress, a key driver of tissue damage in acute inflammation (Muro et al., 2024). Animal studies have indicated that arbutin inhibits the NF-κB pathway, reduces the expression of inflammatory cytokines such as TNF-α, IL-6, and IL-1β, and enhances the activity of antioxidant enzymes including glutathione peroxidase (GPx) and superoxide dismutase (SOD), thereby effectively alleviating oxidative damage and mucosal tissue injury (Alemdar et al., 2024). D-Glucosamine has been shown to decrease IL-1β and TNF-α levels while increasing glutathione (GSH) content, synergizing with 5-ASA to ameliorate colonic histopathological structure (Roy et al., 2023). Similarly, Ganoderma lucidum extract exerts its effects through dual antioxidant and anti-inflammatory mechanisms, involving reduction of malondialdehyde (MDA), elevation of SOD activity, and suppression of TNF-α and IL-6 expression, leading to marked attenuation of intestinal mucosal damage (Özden et al., 2022).

Following the suppression of acute inflammation, successful UC therapy necessitates active promotion of mucosal healing and restoration of intestinal homeostasis (Otte et al., 2023). The combination therapy excels in this phase by enhancing barrier function and modulating the gut microenvironment. Certain natural polymers enhance drug delivery and mucosal retention. Chitosan acts as both a mucosal protective effects and a delivery-enhancing carrier, improving 5-ASA delivery and anti-inflammation efficacy (Jhundoo et al., 2020). Hyaluronic acid, through CD44 targeting capability and strong mucosal adhesiveness, prolongs 5-ASA retention at inflammatory sites, enables sustained release, and promotes epithelial cell migration and differentiation. Consequently, the combined treatment exhibits significantly enhanced efficacy over monotherapy in severe colitis models (Jhundoo et al., 2021a). Arabic gum and guar gum form protective gel layer via mucin interactions, enhancing barrier function. Notably, the combination of Arabic gum with 5-ASA achieves therapeutic effects nearly comparable to those observed in healthy control groups (Jhundoo et al., 2021b).

Natural components also modulate the gut microbiota and metabolism microenvironment. Acacia and guar gums exert synergistic therapeutic effects by promoting the production of short-chain fatty acids (SCFAs; e.g., acetate, propionate, butyrate) and restoring the gut microbiota structure (Jhundoo et al., 2021b). Arabinoxylan markedly enhances the abundance of beneficial bacteria, including Lactobacillus and Lachnospiraceae_NK4A136_group, along with increased butyrate production. Concomitantly, it upregulates mucin-2 (MUC-2) and key tight junction proteins such as Occludin, zonula occludens-1 (ZO-1), and Claudin-1. Collectively, these changes translate into a more pronounced improvement in mucosal barrier repair than that achieved with 5-ASA alone (Huang et al., 2025). Lactulose enhances the levels of beneficial bacteria including Lachnospiraceae and Prevotellaceae, promotes the generation of SCFAs such as acetate, propionate, and butyrate, and simultaneously inhibits the Toll-like receptor/NF-κB (TLR/NF-κB) pathway, thereby alleviating intestinal inflammation and pathological damage through coordinated actions on microbiota remodeling, metabolite-mediated effects, and immunomodulation (Cui et al., 2025). Notably, by promoting beneficial bacteria and suppressing potential pathogens, these natural components not only directly exert anti-inflammatory and barrier-protective effects but may also reshape the microbial ecology to reduce the abundance of bacteria with 5-ASA-metabolizing activity (e.g., some Proteobacteria), thereby protecting 5-ASA from microbial enzymatic inactivation and enhancing the synergistic effect of combination therapy via improved drug bioavailability (Mehta et al., 2023).

The combination of natural bioactive compounds with 5-ASA offers a novel therapeutic strategy for ulcerative colitis through a stage-specific, multi-target synergistic approach.These complementary mechanisms—spanning acute immunomodulation, antioxidative damage, followed by active mucosal repair, and microbiota-metabolic regulation—are visually integrated in Figure 2, which provides a comprehensive overview of their temporally coordinated actions. This approach not only produces synergistic effects across these levels but also enhances drug delivery efficiency and mucosal retention through the use of natural polymeric materials, thereby comprehensively improving the efficacy of 5-ASA (Jhundoo et al., 2020; Jhundoo et al., 2021a; Jhundoo et al., 2021b). Studies have demonstrated that such integrated treatment significantly improves clinical response rates and quality of mucosal healing. In particular, the combination of hyaluronic acid and 5-ASA has shown remarkable therapeutic benefits in severe colitis (Jhundoo et al., 2021a). Furthermore, combination therapy exhibits a favorable safety profile, with certain natural compounds such as curcumin and cannabidiol demonstrating the potential to enhance efficacy while reducing toxicity (Chandan et al., 2020; Thapa et al., 2025), opening new avenues for the systematic treatment of ulcerative colitis. Importantly, the upstream molecular basis underlying the synergistic actions of many promising natural compounds remains insufficiently defined. Beyond their well-recognized antioxidant and anti-inflammatory effects, compounds such as tanshinone IIA, berberine, and curcumin are likely to interact with 5-ASA through modulation of key upstream signaling pathways, including MAPK/ERK and PI3K/AKT (Zhang et al., 2023; Zhou et al., 2025; Patnaik et al., 2025). Accordingly, systematically delineating the temporal and spatial coordination between these natural agents and 5-ASA along these pathways represents a critical direction and a major opportunity for future mechanistic studies.

The combination of TCM formulations with 5-ASA demonstrates multidimensional synergistic advantages in clinical efficacy, mechanisms of action, and safety, significantly expanding the scope of disease management beyond conventional 5-ASA monotherapy. In contrast to single bioactive compounds, traditional Chinese medicine formulations are characterized by multi-component and system-level regulatory effects. This subsection emphasizes the broader and more holistic mechanisms by which TCM formulations synergize with 5-ASA. Table 2 systematically summarizes key research advances in the combined application of TCM formulations and 5-ASA over the past 5 years.

In terms of clinical efficacy, the combination therapy demonstrated comprehensive and significant improvements. High-level evidence from multiple meta-analyses of RCTs indicates that the combination of Chinese herbal formulas with 5-ASA significantly enhances clinical response rates, mucosal healing rates, and clinical remission rates. For instance, Gegen Qinlian Decoction increased the clinical response rate by 22% (Chen et al., 2025), while Xileisan not only improved the clinical response rate by 22% but also significantly increased the mucosal improvement rate by 25%, effectively alleviating core symptoms such as diarrhea and bloody stool (Yang et al., 2024). Notably, the combination therapy also exhibited systemic regulatory effects on extraintestinal manifestations. For example, Salvia-based and rhubarb-based formulations improved microcirculation, modulated platelet function, and ameliorated hypercoagulability (Zhang W et al., 2024; Li X et al., 2022). Jianpi Qingchang Decoction improved energy metabolism and significantly relieved fatigue (Liu et al., 2024); and Wuling Powder concurrently alleviated intestinal inflammation and depression-like behaviors through brain–gut axis modulation, highlighting the holistic regulatory characteristics of traditional Chinese medicine (Wang JJ et al., 2025).

At the mechanistic level, the combined application of Chinese herbal formulas and 5-ASA achieved multi-dimensional, multi-target synergistic regulation. Gegen Qinlian Decoction and Qingchang Huashi Granule inhibited key inflammatory pathways such as NF-κB, MAPK, and TLR, synergistically downregulating pro-inflammatory cytokines including TNF-α, IL-6, and IL-1β, thereby enhancing anti-inflammatory effects (Chen et al., 2025; Shen et al., 2021). In terms of barrier repair, Xilei San upregulated the expression of tight junction proteins such as Occludin and Claudin-1, while rhubarb-based formulations protected endothelial barrier integrity by antagonizing MMP-9, collectively promoting the restoration of intestinal mucosal barrier function (Yang et al., 2024; Li Y et al., 2022). Regarding immunomodulation, Xileisan also promoted the secretion of secretory immunoglobulin A (sIgA), contributing to the maintenance of immune homeostasis (Yang et al., 2024). Furthermore, formulations such as Jianpi Qingchang Decoction and Shenling Baizhu Powder remodeled the gut microbiota structure by increasing the abundance of beneficial bacteria such as Bacteroides and Lactobacillus. Shenling Baizhu San additionally promotes the production of beneficial metabolites, including indolepropionic acid and indoleacetic acid. It also activates protective signaling pathways such as AhR/PXR, thereby exerting synergistic regulatory effects at the microbiota–metabolism interface (Liu et al., 2024; Jiao et al., 2022). On the other hand, Salvia-based and rhubarb-based formulations improved intestinal microcirculation and alleviated hypercoagulability by modulating platelet count, P-selectin, and thromboxane levels (Zhang W et al., 2024; Li X et al., 2022); Wuling Powder mediated brain–gut interactions via the BDNF/TrkB/sortilin and proBDNF/p75NTR signaling pathways, simultaneously improving intestinal inflammation and emotional disorders, reflecting the holistic concept of “simultaneous regulation of the intestine and brain” in traditional Chinese medicine (Wang JJ et al., 2025).

Regarding safety, the combination therapy generally exhibited a favorable tolerance profile. Multiple studies indicated that the combined medication did not increase adverse reactions. Moreover, Gegen Qinlian Decoction reduced the incidence of adverse reactions by 41% (Chen et al., 2025), and the complication rate in the Qingchang Yuyang Decoction group was lower than that in the control group (Wang J et al., 2025). These results suggest that the combination of Chinese herbal formulas with 5-ASA not only did not increase safety risks but may also possess the potential to reduce toxicity and enhance efficacy.

Compared with 5-ASA monotherapy, the combination strategy with Chinese herbal formulas not only enhanced anti-inflammatory effects but also addressed the limitations of monotherapy across multiple aspects including immunomodulation, mucosal barrier repair, microbiota–metabolite balance, microcirculation improvement, and brain–gut axis regulation, achieving a transition from local anti-inflammation to systemic holistic regulation (Figure 2). Furthermore, a meta-analysis based on RCTs provided high-level evidence indicating that this combination regimen significantly improved clinical efficacy while effectively reducing the recurrence rate and incidence of adverse reactions in ulcerative colitis patients, highlighting its notable advantage in “toxicity reduction” (Zhang M et al., 2024). The multi-component, multi-target nature of Chinese herbal formulas may further contribute to this holistic benefit by modulating upstream signaling networks. For example, Gegen Qinlian Decoction and rhubarb-based formulations have been reported to ameliorate intestinal inflammation through integrated regulation of pathways such as PI3K/AKT/NF-κB (Chen et al., 2023; Li Y et al., 2022). In summary, the combination of Chinese herbal formulas with 5-ASA operates via multi-target mechanisms and demonstrates comprehensive therapeutic value for the long-term management of ulcerative colitis.

The clinical benefits outlined in Figure 1 are further corroborated by accumulating data. Gegen Qinlian Decoction with 5-ASA increases clinical response rates by approximately 22%, while Xilei San improves mucosal healing by about 25% (Chen et al., 2025; Yang et al., 2024). Combination therapy also shows significantly lower adverse reaction incidence compared to 5-ASA alone (Chen et al., 2025). Beyond intestinal outcomes, TCM formulations exhibit broader regulatory effects Salvia- and rhubarb-based preparations ameliorate intestinal microcirculation and hypercoagulability (Zhang W et al., 2024; Li X et al., 2022), while Wuling Powder modulates both intestinal inflammation and depressive-like behaviors via the brain-gut axis (Wang JJ et al., 2025). Natural carriers such as hyaluronic acid further enhance local drug retention and bioavailability, improving outcomes in severe colitis models (Jhundoo et al., 2021a). These findings collectively validate the therapeutic advantages of integrating TCM and natural bioactive compounds with 5-ASA for the long-term management of ulcerative colitis.