With the socio-economic development of human society, the global incidence of Inflammatory Bowel Disease (IBD) continues to rise. IBD patients have multiple burdens: 10%-15% of IBD-related deaths are attributed to ulcerative colitis (UC)-associated cancer (1); patients’ quality of life is severely impaired, with symptoms such as fatigue, abdominal pain, and bloody stools being particularly prominent in females and Crohn’s disease (CD) populations, while gut microbial dysbiosis and immune imbalance exacerbate disease progression (2); pediatric patients may experience growth retardation; the global medical expenditure for IBD remains exorbitant, and recurrent flare-ups reduce labor productivity, constituting a heavy socio-economic burden (3).

Currently, chemical drugs and biologics are the most widely used agents for the IBD treatment, yet their limitations are evident. Immunosuppressants such as azathioprine and methotrexate can significantly increase risks of lymphoma, non-melanoma skin cancer, and urinary tract malignancies, while also causing bone marrow toxicity, hepatotoxicity, and infections (4, 5); glucocorticoids which used for induction remission, can cause osteoporosis, infection, and adrenal suppression with long-term use (6, 7); Biologics and novel small-molecule drugs may lead to severe infections or malignancies, while also increasing the risk of cardiovascular events and thrombosis (8, 9); 5-aminosalicylic acid (5-ASA) demonstrates limited therapeutic efficacy (6). In conclusion, current therapeutic approaches either have limited efficacy or may cause other more severe adverse consequences for patients. Therefore, exploring an efficient and low-toxicity therapeutic approach for IBD is an urgent priority in the field.

Trichuris suis (TS), which belong to the family Trichuridae and genus Trichuris, primarily parasitizes the cecum and colon of pigs (10). Its physiological metabolism adapts to the intestinal anaerobic environment, primarily relying on glycolysis to obtain energy (11). After pigs ingest Trichuris Suis Ova (TSO), larvae hatch in the intestine, penetrate the intestinal wall, migrate through tissues, and ultimately reside in the cecum and colon to mature into adults. Adults survive for months to years in pigs, during which females continuously release eggs that complete the life cycle through fecal excretion (12, 13). It is generally believed that as humans are not natural hosts for TS, its development in humans is restricted, resulting in shorter survival periods, which suggest favorable safety profiles (14, 15).

Infection with TSO is believed to modulate the host’s immune system (16, 17). It may treat immune-mediated diseases such as IBD through multiple mechanisms (18, 19), and this application initially derives from the “hygiene hypothesis”.

At present, TSO is the most well-studied helminth for IBD treatment. The essence of TSO therapy’s value lies in its potential to rectify immune dysregulation through mimicking natural symbiosis. It offer a physiologically aligned alternative that may circumvent the interpatient variability in drug efficacy and toxicities associated with conventional therapies. Theoretically, TSO therapy holds significant promise. Our research systematically analyzes the potential mechanisms, and reviews existing clinical trials of TSO in IBD treatment. It not only analyzes variations in results and core conclusions across trials, but also focuses on examining inherent limitations. Based on these and integrating clinical practical needs, it also clarifies current challenges in clinical application translation, while proposing targeted, feasible solutions. Ultimately, our work aims to facilitate the early, individualized, precision-based and standardized use of TSO in IBD clinical management.

IBD is a chronic inflammatory disease of the gastrointestinal tract. Its pathogenesis is believed to be linked to genetic, gut microbial, environmental, and immune factor (20, 21). Among these contributors, immune dysregulation is recognized as the most critical factor. Current evidence indicates that genetic, gut microbial, and environmental factors most likely induce IBD by disrupting immune homeostasis. Meanwhile, immune factors play a pivotal role in IBD treatment, as many currently available therapeutics exert their effects by targeting aberrant inflammatory signaling pathways.

UC and CD are widely accepted to be driven by exaggerated Th1(T helper type 1 cells)/Th17(T helper type 17 cells) immune responses (21). Nevertheless, subtle differences distinguish the two conditions. For example, Th9 cells(T helper type 9 cells) are primarily involved in the pathogenesis of UC (20). Additionally, there may be potential differences in the role of IL-17 between in UC and CD (22). Regulatory T cells (Treg cells) sustain immune homeostasis via multiple mechanisms, especially within the intestinal immune microenvironment (23). Beyond their immunomodulatory roles, Treg cells also exhibit non-immunomodulatory functions, such as mediating tissue repair through the secretion of the growth factor amphiregulin (24). The development of IBD is thought to be associated with functional impairments and numerical reductions in Treg cells (25, 26). Collectively, the onset of IBD is currently believed to be predominantly driven by exaggerated Th1/Th17 immune responses, underpinned by dysregulation between Th1/Th17 and Th2 (T helper type 2 cells) immune responses, and functional and numerical deficits in Treg cells.

Numerous parasites have been explored as potential agents for IBD. Specifically, several helminths, including Trichuris, Trichinella, and Ancylostoma, have been regarded as promising candidates. The effects of various helminths have been validated in animal experiments, such as Schistosoma mansoni, Trichinella spiralis, Trichuris muris, Trichuris trichiura, and Heligmosomoides polygyrus. However, due to multiple factors, research on these organisms remains confined to the preclinical stage. To date, only two live helminths have progressed to human clinical trials, TS and Necator americanus (27, 28).

Similar to TS, the therapeutic efficacy of Necator americanus against IBD is likewise attributed to its immunomodulatory properties, as their common foundation is based on the “Hygiene Hypothesis” (27, 29). And they are most likely to regulate immune responses by stimulating the regulatory cytokine network primarily produced by Tregs (30), including modulating the balance between Th1/Th17 and Th2 immune responses. However, owing to the divergence in antigenic profiles and secreted products between them, whether their specific immunomodulatory mechanisms are consistent requires further experimental validation, as in the field, the mechanisms of effect by different helminths are rarely considered to be identical (31).

TS is the most commonly used, attributed to its demonstrated advantages over Necator americanus. First, TS’s anti-inflammatory and immunomodulatory efficacy in humans has been well validated. Besides IBD, it has also exhibited some effect for other autoimmune diseases. Its roles and mechanisms are also the most extensively studied. Then, unlike other parasites, humans are not regarded as the natural hosts of TS, rendering it unable to persist long-term in the human body. In contrast, Necator americanus requires only a single administration, as humans are its natural hosts. Chronic infection with it may induce intestinal bleeding, anemia, and nutrient deficiencies, which may be detrimental to the long-term health of patients (32, 33). Furthermore, this helminth can proliferate in human, a process largely influenced by factors such as the patient’s immune competence. It makes controlling helminth burden and invasiveness is more challenging. More importantly, TS is administered orally as TSO, which boasts a rapid action with generally mild and stable efficacy. In contrast, after Necator americanus inoculation, it takes approximately six weeks for the larvae to reach the intestinal tract, and longer period may be required to exert immunomodulatory effects. This indicates that patients with active disease, who demand prompt responses, are not ideal candidates for Necator americanus. Meanwhile, the early phase of Necator americanus infection (approximately 12 weeks post-inoculation) is characterized by a marked Th2 response. Initially, larval migration can induce serpiginous vesicular skin lesions accompanied by intense pruritus; subsequently, it may exacerbate rather than alleviate intestinal inflammation and trigger systemic acute inflammatory responses (28, 34).

The specific mechanisms through which TS exerts effects on IBD remain inadequately explored. To date, mechanisms of TS-mediated IBD treatment are relatively scarce. Based on existing evidence, it is hypothesized to involve the synergistic crosstalk of multiple pathways (Figure 1). Potential mechanisms include: it can suppress the secretion of tumor necrosis factor (TNF) and interleukin-12 (IL-12) via the secretion of prostaglandin-E2 (PGE2) or other pathways, thereby promoting the polarization of dendritic cells toward a Th2 cell-inducing phenotype (35–37). Additionally, activating Rab7b protein to facilitate the degradation of Toll-like receptor 4 on the cell, which in turn mitigates the conversion of CD4⁺T cells to Th1/Th17 cell subsets induced by endotoxins derived from the intestinal flora. Meanwhile, TS can downregulate host immune responsiveness to other unrelated antigens (38), and also can suppresses the expression of proinflammatory genes in the intestinal mucosa while stimulating the production of Th2 response, inhibiting Th1/Th17 response (16, 39). Furthermore, TS can induce the generation of regulatory T cells (Tregs) and promote the secretion of immunomodulatory molecules (transforming growth factor-β [TGF-β], interleukin-10 [IL-10]), which contributes to maintaining host mucosal immune homeostasis (16, 40). Apart from these, a serine protease secreted by TS can regulate mast cell-related protease-mediated host immune responses in the intestinal mucosa (41). It also secretes thioredoxin and thioredoxin-like protein which exhibit antioxidant activity and facilitate tissue repair (42). Notably, TS may also modulate the gut microbiota, although the underlying mechanisms remain poorly elucidated (43), and this interaction maybe bidirectional. For example, helminths may induce alterations in the abundance and diversity of the gut microbiota by releasing antimicrobial peptides or modifying the nutritional microenvironment of local tissues. Conversely, the gut microbiota may promote helminth egg hatching and even regulate the immune system’s ability to clear parasites (44). In vitro studies, the excretory-secretory products (ESP) of adult TS have been shown to exhibit antibacterial activity, with Gram-negative bacteria (e.g., Campylobacter spp., Escherichia coli) and Gram-positive bacteria (Staphylococcus aureus) showing sensitivity to ESP (45). It is critical to emphasize, however, that this conclusion is solely derived from in vitro experiments.

Furthermore, infection with various helminths, including TS, may induce changes in intestinal mucosal barrier function. Theoretically, Th2 cells exhibit significantly increased numbers and enhanced functional activity in this context, and their cytokines (particularly IL-13) together with IL-22 exert profound effects on colonic epithelial cell function. These effects include stimulating the differentiation of goblet cells and Paneth cells via associated mucus production and antimicrobial peptide expression, as well as activating anti-apoptotic signaling pathways. Additionally, accessory cells recruited and activated by Th2 response, especially alternatively activated macrophages, can promote mucosal healing (46). Meanwhile, TS can also contribute to the repair of damaged mucosa through the modulation of Treg cell activity (47, 48). However, empirical evidence has demonstrated that helminths, including TS, do not consistently exert a mucosal protective effect; instead, they may occasionally induce mucosal impairment (49, 50). Trichuris muris, a helminth species closely related to TS, secretes serine proteases that alter mucus barrier properties by degrading mucin components within the mucus gel, rendering it more porous (51). Similarly, TS encodes a repertoire of serine proteases (52), but whether they would show analogous effects remains to be elucidated. Thus, the impact of helminths on the intestinal mucosa is likely contingent upon factors such as species, distinct survival states, environmental conditions, and host-specific traits, etc.

Notably, despite the multiplicity of proposed mechanisms, none adequately account for the lack of efficacy of TS in certain clinical trials. Therefore, further research is required to identify the factors that modulate the functionality of these mechanisms, representing a critical knowledge gap that warrants further exploration.

Currently, in addition to its use in the treatment of IBD, TSO has also shown pharmacological effects in multiple sclerosis (MS),allergic rhinitis (AR) and autism spectrum disorder (ASD). For multiple sclerosis, TSO treatment has been reported to reduce pro-inflammatory factors, elevate anti-inflammatory factor concentrations, lower disease severity scores, and improve neurological imaging outcomes (53–56); For allergic rhinitis, it has been shown to reduce the number of days during the grass pollen season when participants required rescue medication (57); Although these therapeutic effects are generally mild to moderate. In adult autism spectrum disorder, TSO has exhibited large effect sizes specifically in improving rigidity and repetitive behaviors (58). Notably, all these positive outcomes are attributed to TSO’s inherent anti-inflammatory and immunomodulatory activities.

Compared with TS-mediated mechanisms in treating other diseases, the actions in IBD may exhibit distinct nuances. MS is also characterized by dysregulation between Th1/Th17 and Th2 immune responses, alongside functional and numerical deficiencies in regulatory Treg cells (59–61). Thus, the mechanism of TS in MS is generally considered analogous to that in IBD. The key distinction lies in the anatomical locus of inflammation: MS is centered on central nervous system inflammation, whereas IBD is driven by Th1/Th17-dominant inflammation and intestinal mucosal barrier impairment. This underscores the need to clarify whether TS exerts local or systemic effects-particularly whether the effect and ESP can cross the blood-brain barrier (37, 60). Notably, current clinical trials suggest such concerns may be unwarranted, as TSO has demonstrated partial efficacy in MS. (55, 56). ASD is a heterogeneous group of multifactorial neurodevelopmental conditions. Its pathogenesis involves multiple contributors, with the immune hypothesis emerging as a key mechanism. Current evidence indicates that T lymphocyte dysregulation in ASD encompasses an abnormal T helper-suppressor cell ratio, systemic Treg cell depletion, and aberrant cytokine release (62, 63). For example, increased hyperactivity correlates with low levels of anti-inflammatory cytokines (IL-10, TGF-β) and elevated proinflammatory cytokines (IL-1β, IL-6) (64, 65), while a Th1 response is associated with more severe developmental impairments (66). Additionally, ASD has been linked to intestinal barrier dysfunction and gut microbiota dysbiosis (67). Thus, analogous to IBD, TS is hypothesized to treat ASD through a synergistic mechanism involving Th2-response induction, inhibition of Toll-like receptor-mediated Th1/Th17 activation, intestinal barrier enhancement, and gut microbiota modulation (17, 58). However, similar to MS, TS colonizes the intestinal tract, and the specific pathway by which it modulates gut-brain axis function remains elusive.

In allergic diseases, TS may exert distinct mechanisms. Excessive Th 2 responses—hallmarks of asthma and allergies-represent an overactivated state that typically does not involve Th1/Th17 activation (17, 68). In this context, both Th1 responses and Treg cell function are markedly suppressed. Specifically, insufficient Treg-mediated control drives Th2 overactivation. Unlike classical type 2 immunity, helminth infection induces a “modified type 2 immune response” that fails to trigger allergic inflammation following allergen exposure (69). This modified response is attributed to helminth-induced enhancement of Treg and regulatory B cell (Breg) activity, coupled with upregulation of the key anti-inflammatory cytokines IL-10 and TGF-β (68). Treg activation augments anti-inflammatory cytokine release, while Breg activation inhibits pathogenic antibody production (e.g., IgE in allergies), elevates allergen-specific IgG4 levels, and attenuates autoreactive B cell activation (69–71).

Collectively, helminths including TS exhibit disease-specific mechanisms of action, reflecting their capacity to comprehensively restore immune homeostasis by regulating Th1/Th17-Th2 balance, while concurrently enhancing Treg cell number and function.

Nevertheless, critical knowledge gaps persist. First, the precise mechanisms underlying TS’s effects on immune-mediated diseases remain incompletely elucidated. While ESP are implicated as primary immunomodulatory mediators, the potential contribution of the TS worm itself remains unclear. Regarding ESP, the specific molecules responsible for immunomodulation versus proinflammatory effects, their interactions, and the contextual factors governing ESP secretion profiles require clarification. Additionally, alternative mechanisms (e.g., TS-gut microbiota crosstalk in humans) have not been fully explored. Furthermore, TS ESP functions vary across life cycle stages (72), but the molecular basis for these stage-specific differences is unknown. Most importantly, whether TS consistently exhibits beneficial effects in humans—mirroring its in vitro activity—requires further validation (Figure 2).

The current clinical evidence does not strongly support TSO as an effective therapy for IBD. However, its promising preclinical data (including animal studies), potential benefits observed in secondary endpoints, and the limitations of existing pharmacotherapies (e.g., toxicity, variable efficacy) continue to maintain interest in TSO treatment. Meanwhile, as previously noted, TSO has demonstrated certain therapeutic efficacy in other human autoimmune diseases. Given these considerations, TSO may remain a promising therapeutic strategy for IBD. Negative trial results may stem from methodological limitations (e.g., heterogeneous populations, confounding concomitant therapies) rather than inherent inefficacy. Future trials should address these flaws through more rigorous design. Thus, we will discuss the limitations in existing clinical trials, technical bottlenecks, and potential approaches to overcome the dilemma.

Advancing TSO-based clinical research for IBD treatment requires fundamental investigations into its mechanisms. At present, although some progress has been made in mechanistic studies of TSO for IBD treating, these studies have not elucidate the mechanism comprehensively and macroscopically (144–147). They always only focus on one or a few targets. This may be one of the significant reasons why the effect is remarkable in basic research but the opposite occurs in clinical trials. Therefore, interactions of mechanisms should be carefully investigated. Meantime, given the multitude of influencing factors, in vitro studies should more accurately simulate the parasitic growth environment within the host, particularly considering individual immune profiles and gut microbiota diversity. In animal experiments, researchers must carefully address interspecies differences, as disparities in immune profiles and baseline gut microbiota between species are substantial and exert a significant impact on study outcomes. For outcome assessment, in addition to clinical symptoms, biochemical markers, and endoscopic remission, histological remission should also be included. Moreover, rigorous validation is required to determine whether TSO-induced endoscopic and histological remission are comparable in long-term clinical significance to those achieved by conventional therapeutics. Crucially, the survival rate of TSO must be included as a key endpoint, as live TSO—similar to probiotics—likely yields stronger therapeutic effects than dead organisms, despite the latter’s residual biological activity. To clarify how multifactorial variability influences therapeutic outcomes, TSO-IBD research should employ multi-omics technologies (e.g., transcriptomics, proteomics, metabolomics) integrated with precision medicine principles and artificial intelligence (148). These approaches facilitate comprehensive investigation of molecular changes during host-parasite interactions (149), offering precise and accurate insights into host-microbe interplay. However, multi-omics technologies currently face challenges in managing large-scale population data and limitations arising from our incomplete understanding of gut microbiota and intestinal immunity—particularly in the context of personalized precision medicine. Moreover, leveraging genetically modified TSO and host models, gene editing technologies are critical for dissecting key interaction molecules and signaling pathways. These technologies may even enable the engineering of microbes to exert beneficial effects under hostile conditions. Gene editing has already been applied to single-cell organisms, particularly in probiotics research. For example, suicide plasmids are designed to have limited or no ability to replicate in the recipient bacteria, ensuring they do not persist after facilitating genetic modification and thus preventing unintended effects. This approach represents a novel and feasible concept for enhancing the biosafety of live organism therapies (150). Notably, genetically modified Escherichia coli Nissle 1917 has demonstrated significant beneficial effects in animal models of IBD (151). Demonstrating superior therapeutic efficacy and safety profiles of this modified strain over its wild-type counterpart in human trials would mark a breakthrough in microbial therapeutics, underscoring the potential of rationally designed microorganisms to achieve optimized clinical outcomes. In helminths, beyond basic research, current practical applications of gene editing technology primarily focus on attenuating virulence in human-infecting parasites to inform infection control strategies, rather than engineering these parasites to develop therapeutic benefits (152, 153). Although gene-editing technology for helminths is currently in its early stages, this technology has undoubtedly opened the door to harnessing living organisms for disease treatment. Insights from bacterial engineering can guide the therapeutic optimization of TSO in IBD management. Ultimately, the domestication of TSO to consistently deliver therapeutic benefits represents the field’s ultimate goal.

In clinical trials, the rigorous integration of emerging foundational insights is imperative. At this stage, beyond standardizing trial design elements (e.g., sample size, auditing criteria, baseline characteristics), identifying responsive subpopulations is urgent. Stratification factors may include IBD etiology, disease severity, lesion location, and genetic predispositions. Additionally, confounding variables (e.g., concomitant medications, diet, socioeconomic factors, and psychological states) must be systematically controlled. Precision medicine principles should be systematically applied to guide the optimization of trial design. Preliminary ideas have been put into practice. In subgroup analysis from a clinical trial in 2017, it aims to determine whether clinical outcomes of TSO treatment differ between patients harboring six functional Nucleotide-binding oligomerization domain 2(NOD2) variants and wild-type counterparts, via retrospective genotyping of 207 CD patients. The result was negative.No consistent significant association was observed between the 6 NOD2 variants and clinical outcomes of TSO treatment (78). Nevertheless, this research has still taken the first step toward precision therapy of TSO for IBD.

Findings from multi - omics approaches (e.g., host-microbe interaction networks, epigenetic regulatory signatures) require prospective validation in interventional cohorts, while avoiding enrollment of heterogeneous IBD populations on large scales in single trials. Cohort studies must implement endophenotype-driven stratification to ensure cohort diversity aligns with the study objectives, accompanied by comprehensive characterization of clinical and demographic profiles (154, 155). Identifying which patient populations would benefit from a specific type of therapy would make treatment decisions more objective compared to current practices (156). This would enable clinical trials to enroll more targeted participants, thereby increasing the likelihood of successful TSO treatment. Following confirmation of safety and efficacy, genetically engineered TSO may be cautiously introduced into human trials at an appropriate stage. TSO-derived products (e.g., helminth-secreted molecules) designed to minimize confounding factors can serve as supplements to clinical trials, though most remain in preclinical stages with limited human trials (157). Additionally, TSO safety must be rigorously evaluated, including short-term risks (e.g., infection, disease exacerbation) and long-term sequelae (e.g., disease progression, carcinogenesis). Overall, the paradigm shift toward precision medicine necessitates fundamental re-engineering of clinical trial frameworks for TSO therapy in IBD. Contemporary trials should transcend conventional symptom-driven endpoints through the integration of multilayered biomarkers.

TSO may exert potential effects on IBD via multiple mechanisms, despite the presence of numerous knowledge gaps in this field. Despite the failure of current clinical trials to demonstrate TSO’s efficacy in IBD, its putative anti-inflammatory potential justifies continued investigation. Future trials should prioritize methodological rigor, multifactorial analysis, and target population screening. Emphasizing the role of precision medicine in TSO-based IBD research, particularly through biomarker-driven patient stratification, is likely to yield more targeted therapeutic outcomes and enhance the efficacy of clinical trials. Genomic engineering technologies possess dual potential: not only to advance the mechanistic understanding of disease pathways but also to enable the targeted domestication of TSO via precise genetic modifications. These modifications may ensure stable anti-inflammatory efficacy and predictable safety profiles in IBD immunotherapy. In addition, safety monitoring— especially in immunocompromised patients— remains paramount. These efforts aim to advance TSO from a “potential anti-inflammatory agent” to a complementary or even dominant strategy within IBD’s multidimensional treatment framework, particularly for patients refractory to conventional therapies. Once proven effective and safe over the long term, TSO could emerge as a transformative alternative to traditional drugs. Breakthroughs in this field will not only deepen our understanding of IBD pathogenesis but also propel microbiome-based interventions from empirical applications toward the precision medicine era.