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In this manuscript, we explore the potential therapeutic use of helminths. After analyzing helminths' role in connection with human health from the perspective of their symbiotic and evolutionary relationship, we critically examine some studies on their therapeutic applications. In doing so, we focus on some prominent mechanisms of action and potential benefits, but also on the exaggerations and theoretical and methodological difficulties of such proposals. We conclude that further studies are needed to fully explore the potential benefits of this perspective, and we encourage the scientific community in doing so.

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We implicate a phenotype of trained immunity in bone-marrow-derived macrophages in the onset and progression of type 1 diabetes in nonobese diabetic mice. Treatment with FhHDM-1 reversed immune training, reducing histone methylation and glycolysis, and decreasing proinflammatory cytokine production to the same level as macrophages from nondiabetic immune-competent BALB/c mice.

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There is now sufficient evidence to support an inverse association between helminth infection and secreted products with allergic/autoimmune disorders. Accordingly, several experimental studies have shown that Echinococcus granulosus infection and hydatid cyst compounds are able to suppress immune responses in allergic airway inflammation. This is the first study on effects of somatic antigens of E. granulosus on chronic allergic airway inflammation in BALB/c mice. Mice in OVA group were intraperitoneally (IP) sensitized with OVA/Alum. Subsequently, were challenged by nebulizing of OVA 1%. The treatment groups received somatic antigens of protoscoleces on the specified days. Mice in PBS group were received PBS in both sensitization and challenge. The effects of somatic products on development of chronic allergic airway inflammation were evaluated by examining histopathological changes, the recruitment of inflammatory cells in the bronchoalveolar lavage, cytokines production in the homogenized lung tissue, and total antioxidant capacity in serum. Our findings show that the co-administration of somatic antigens of protoscoleces simultaneously with the development of asthma intensifies allergic airway inflammation. The identification of effective components involved in exacerbation of allergic airway inflammation manifestations will be a crucial approach to understanding the mechanism of these interactions.

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Spinal cord injury (SCI) can cause severe loss of locomotor and sensory activities, with no ideal treatment. Emerging reports suggest that the helminth therapy is highly effective in relieving numerous inflammatory diseases. Proteomic profiling is often used to elucidate the underlying mechanism behind SCI. Herein, we systematically compared the protein expression profiles of murine SCI spinal cord and Trichinella spiralis treated murine SCI spinal cord, using a 4D label-free technique known for its elevated sensitivity. Relative to the SCI mice, the T. spiralis-treated mice exhibited marked alterations in 91 proteins (31 up- and 60 down-regulated). Based on our Gene Ontology (GO) functional analysis, the differentially expressed proteins (DEPs) were primarily enriched in the processes of metabolism, biological regulation, cellular process, antioxidant activity, and other cell functions. In addition, according to the Clusters of Orthologous Groups of protein/EuKaryotic Orthologous Groups (COG/KOG) functional stratification, proteins involved in signaling transduction mechanisms belonged to the largest category. Over-expressed DEPs were also enriched in the "NADPH oxidase complex", "superoxide anion generation", "other types of O-glycan biosynthesis", and "HIF-1 signaling pathway". Furthermore, the protein-protein interaction (PPI) network identified the leading 10 hub proteins. In conclusion, we highlighted the dynamic proteomic profiling of T. spiralis-treated SCI mice. Our findings provide significant insight into the molecular mechanism behind T. spiralis regulation of SCI.

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Despite the tremendous progress in healthcare sectors, a number of life-threatening infectious, inflammatory, and autoimmune diseases are continuously challenging mankind throughout the globe. In this context, recent successes in utilizing helminth parasite-derived bioactive macromolecules viz. glycoproteins, enzymes, polysaccharides, lipids/lipoproteins, nucleic acids/nucleotides, and small organic molecules for treating various disorders primarily resulted from inflammation. Among the several parasites that infect humans, helminths (cestodes, nematodes, and trematodes) are known as efficient immune manipulators owing to their explicit ability to modulate and modify the innate and adaptive immune responses of humans. These molecules selectively bind to immune receptors on innate and adaptive immune cells and trigger multiple signaling pathways to elicit anti-inflammatory cytokines, expansion of alternatively activated macrophages, T-helper 2, and immunoregulatory T regulatory cell types to induce an anti-inflammatory milieu. Reduction of pro-inflammatory responses and repair of tissue damage by these anti-inflammatory mediators have been exploited for treating a number of autoimmune, allergic, and metabolic diseases. Herein, the potential and promises of different helminths/helminth-derived products as therapeutic agents in ameliorating immunopathology of different human diseases and their mechanistic insights of function at cell and molecular level alongside the molecular signaling cross-talks have been reviewed by incorporating up-to-date findings achieved in the field.

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The tapeworm Hymenolepis diminuta is a common parasite of the small intestine in rodents but it can also infect humans. Due to its characteristics and ease of maintenance in the laboratory, H. diminuta is also an important model species in studies of cestodiasis, including the search for new drugs, treatments, diagnostics and biochemical processes, as well as its host-parasite interrelationships. A great deal of attention has been devoted to the immune response caused by H. diminuta in the host, and several studies indicate that infection with H. diminuta can reduce the severity of concomitant disease. Here, we present a critical review of the experimental research conducted with the use of H. diminuta as a model organism for over more than two decades (in the 21st century). The present review evaluates the tapeworm H. diminuta as a model organism for studying the molecular biology, biochemistry and immunology aspects of parasitology, as well as certain clinical applications. It also systematizes the latest research on this species. Its findings may contribute to a better understanding of the biology of tapeworms and their adaptation to parasitism, including complex correlations between H. diminuta and invertebrate and vertebrate hosts. It places particular emphasis on its value for the further development of modern experimental parasitology.

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BACKGROUND: There is ample evidence demonstrating a reverse relationship between helminth infection and immune-mediated diseases. Accordingly, several studies have shown that Echinococcus granulosus infection and hydatid cyst compounds are able to suppress immune responses in allergic airway inflammation. Previous studies have documented the ability of hydatid cysts to suppress aberrant Th2 immune response in a mouse model of allergic asthma. However, there is a paucity of research on the effects of protoscoleces on allergic asthma. Thus, this study was designed to evaluate the effects of somatic antigens of protoscoleces in a murine model of allergic airway inflammation. METHODS: Ovalbumin (OVA)/aluminum hydroxide (alum) was injected intraperitoneally to sensitize BALB/c mice over a period of 0 to 7 days, followed by challenge with 1% OVA. The treatment group received somatic antigens of protoscoleces emulsified with PBS on these days in each sensitization before being challenged with 1% OVA on days 14, 15, and 16. The effects of somatic antigens of protoscoleces on allergic airway inflammation were evaluated by examining histopathological changes, the recruitment of inflammatory cells in the bronchoalveolar lavage, cytokine production in the homogenized lung tissue (IL-4, IL-5, IL-10, IL-17, and IFN-γ), and total antioxidant capacity in serum. RESULTS: Overall, administration of somatic antigens of protoscoleces exacerbated allergic airway inflammation via increased Th2 cytokine levels in the lung homogenate, recruitment of eosinophils into bronchoalveolar lavage fluid, and pathological changes. In addition, total antioxidant capacity and IFN-γ levels declined following the administration of somatic antigens. CONCLUSIONS: The results revealed that the co-administration of somatic products of protoscoleces with OVA/alum contributed to the exacerbation of allergic airway inflammation in BALB/c mice. Currently, the main cause of allergic-type inflammation exacerbation is unknown, and further research is needed to understand the mechanism of these interactions.

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Inflammatory bowel disease and allergic asthma, as typical immune-mediated inflammatory diseases (IMIDs), are associated with immune imbalance caused by complex interactions among environmental, genetic and bacterial factors. The changing immune imbalance of IMIDs not only causes serious pathological damages but also increases the difficulty of treatment. Helminths or helminth-derived molecules have been increasingly employed to treat IMIDs due to their immunoregulatory ability. Since helminth infection is not an appropriate treatment direction due to the complex immunoregulation and safety concerns, one of the new therapies is to harness the immunoregulation induced by the identified helminth-derived molecules using immune indexes as a guide. This review discusses the pathogenesis of inflammatory bowel disease and allergic asthma, and summarizes the therapeutic effect of helminths and the immunoregulatory mechanisms induced by helminth-derived molecules proposing therapeutic regimens.

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The incidence rate of inflammatory bowel diseases is increasing in developed countries. As such there is an increasing demand for new therapies. The aim of this systematic review was to investigate whether there is evidence to support the use of helminth therapy for the management of Crohn's disease and ulcerative colitis. Four databases (PubMed, Embase, Medline and the Cochrane Central Register of Control Trials) were searched for primary evidence in the form of clinical studies. Nine studies were suitable for inclusion: five double-blind randomized control trials and four open-label studies. This review divided the results of the studies into two categories: (a) the efficacy of helminth therapy and (b) the safety of helminth therapy. Results regarding the efficacy were mixed and a conclusive answer could not be reached, as there was not enough evidence to rule out a placebo effect. More research is needed, particularly studies with control groups to address the possibility of a placebo effect. Despite this, all nine studies concluded helminth therapy was safe and tolerable, and therefore there is currently no evidence against further exploration of this treatment option.

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Inflammatory bowel disease (IBD) is associated with a dysregulated mucosal immune response in the gastrointestinal tract. The number of patients with IBD has increased worldwide, especially in highly industrialized western societies. The population of patients with IBD in North America is forecasted to reach about four million by 2030; meanwhile, there is no definitive therapy for IBD. Current anti-inflammatory, immunosuppressive, or biological treatment may induce and maintain remission, but not all patients respond to these treatments. Recent studies explored parasitic helminths as a novel modality of therapy due to their potent immunoregulatory properties in humans. Research using IBD animal models infected with a helminth or administered helminth-derived products such as excretory-secretory products has been promising, and helminth-microbiota interactions exert their anti-inflammatory effects by modulating the host immunity. Recent studies also indicate that evidence that helminth-derived metabolites may play a role in anticolitic effects. Thus, the helminth shows a potential benefit for treatment against IBD. Here we review the current feasibility of "helminth therapy" from the laboratory for application in IBD management.

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BACKGROUND: Self-administration of helminths has gained attention among patients as a potential but unproven therapy for autoimmune disease. We present a case of rapidly progressive respiratory failure in a patient with systemic sclerosis (SSc) and pulmonary arterial hypertension (PAH) as a result of self-administration of parasitic organisms. CASE: A 45-year-old woman with a history of interstitial lung disease and PAH due to limited cutaneous SSc presented to pulmonary clinic with worsening dyspnea, cough, and new onset hypoxemia. Three months prior to presentation she started oral helminth therapy with Necator americanus as an alternative treatment for SSc. Laboratory evaluation revelaed eosinophilia and elevated IgE levels. IgG antibodies to Strongyloides were detected. High resolution computed tomography of the chest revealed progressive ILD and new diffuse ground glass opacities. Transthoracic echocardiogram and right heart catheterization illustrated worsening PAH and right heart failure. The patient was admitted to the hospital and emergently evaluated for lung transplantation but was not a candidate for transplantation due to comorbidities. Despite aggressive treatment for PAH and right heart failure, her respiratory status deteriorated, and the patient transitioned to comfort-focused care. CONCLUSION: Although ingestion of helminths poses a risk of infection, helminth therapy has been investigated as a potential treatment for autoimmune diseases. In this case, self-prescribed helminth ingestion precipitated fatal acute worsening of lung inflammation, hypoxemia, and right heart dysfunction, highlighting the risk of experimental helminth therapy in patients, especially those with underlying respiratory disease.

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Background: There are a growing number of publications that report an absence of inflammatory based disease among populations that are endemic to parasitic worms (helminths) demonstrating the ability of these parasites to potentially regulate human immune responses. The aim of this systematic review and meta-analysis was to determine the impact of helminth infection on metabolic outcomes in human populations. Methods: Using PRISMA guidelines, six databases were searched for studies published up to August 2020. Random effects meta-analysis was performed to estimate pooled proportions with 95% confidence intervals using the Review Manager Software version 5.4.1. Results: Fourteen studies were included in the review. Fasting blood glucose was significantly lower in persons with infection (MD -0.22, 95% CI -0.40- -0.04, P=0.02), HbA1c levels were lower, although not significantly, and prevalence of the metabolic syndrome (P=0.001) and type 2 diabetes was lower (OR 1.03, 95% CI 0.34-3.09, P<0.0001). Infection was negatively associated with type 2 diabetes when comparing person with diabetes to the group without diabetes (OR 0.44, 95% CI 0.29-0.67, P=0.0001). Conclusions: While infection with helminths was generally associated with improved metabolic function, there were notable differences in efficacy between parasite species. Based on the data assessed, live infection with S. mansoni resulted in the most significant positive changes to metabolic outcomes. Systematic Review Registration: Website: PROSPERO Identified: CRD42021227619.

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Two experimental paradigms were adopted to explore host-helminth interactions involved in the regulation of colitis and to understand if colitis affects the outcome of helminth infection. First, male BALB/c mice infected with H. diminuta were challenged 4 days later with dinitrobenzene sulphonic acid (DNBS) and necropsied 3 days later. Second, mice were infected with H. diminuta 3 days after DNBS treatment and necropsied 11 or 14 days post-DNBS. Mice were assessed for colitic disease severity and infectivity with H. diminuta upon necropsy. Supporting the concept of helminth therapy, mice are protected from DNBS-colitis when infected with H. diminuta only 4 days previously, along with parallel increases in splenic production of Th2 cytokines. In the treatment regimen, H. diminuta infection produced a subtle, statistically significant, enhanced recovery from DNBS. Mice regained body weight quicker, had normalized colon lengths, and showed no overt signs of disease, in comparison to the DNBS-only mice, some of which displayed signs of mild disease at 14 days post-DNBS. Unexpectedly, colitis did not affect the hosts' anti-worm response. The impact of inflammatory disease on helminth infection is deserving of study in a variety of models as auto-inflammatory diseases emerge in world regions where parasitic helminths are endemic.

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Schistosoma japonicum infection showed protective effects against allergic airway inflammation (AAI). However, controversial findings exist especially regarding the timing of the helminth infection and the underlying mechanisms. Most previous studies focused on understanding the preventive effect of S. japonicum infection on asthma (infection before allergen sensitization), whereas the protective effects of S. japonicum infection (allergen sensitization before infection) on asthma were rarely investigated. In this study, we investigated the protective effects of S. japonicum infection on AAI using a mouse model of OVA-induced asthma. To explore how the timing of S. japonicum infection influences its protective effect, the mice were percutaneously infected with cercaria of S. japonicum at either 1 day (infection at lung-stage during AAI) or 14 days before ovalbumin (OVA) challenge (infection at post-lung-stage during AAI). We found that lung-stage S. japonicum infection significantly ameliorated OVA-induced AAI, whereas post-lung-stage infection did not. Mechanistically, lung-stage S. japonicum infection significantly upregulated the frequency of regulatory T cells (Treg cells), especially OVA-specific Treg cells, in lung tissue, which negatively correlated with the level of OVA-specific immunoglobulin E (IgE). Depletion of Treg cells in vivo partially counteracted the protective effect of lung-stage S. japonicum infection on asthma. Furthermore, transcriptomic analysis of lung tissue showed that lung-stage S. japonicum infection during AAI shaped the microenvironment to favor Treg induction. In conclusion, our data showed that lung-stage S. japonicum infection could relieve OVA-induced asthma in a mouse model. The protective effect was mediated by the upregulated OVA-specific Treg cells, which suppressed IgE production. Our results may facilitate the discovery of a novel therapy for AAI.

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BACKGROUND: An increasing body of studies has shown that Fasciola hepatica can affect immune responses. This study explored whether the fatty acid-binding protein (FABP) of F. hepatica can modulate the immune system in a mouse model of experimental autoimmune encephalomyelitis (EAE). METHODS: EAE-induced C57BL/6 mice were treated with vehicle, F. hepatica total extract (TE) or FABP. The clinical signs, body weights, and the expression of IFN-γ, T-bet, IL-4, GATA3, IL-17, RORγ, TGF-ß, FOXP3, IL-10, TNF-α genes and proteins were determined in the isolated CD4+ splenocytes. Besides, the percentage of Treg cells and degree of demyelination were evaluated. RESULTS: We found that TE and FABP treatments decreased the clinical scores, lymphocyte infiltration rate, and demyelinated plaques in EAE mice. The expressions of IL-4 and GATA3 were increased, whereas IL-17 and TNF-α were down-regulated. FABP did not affect the expression of IFN-γ, RORγ, IL-10, and TGF-ß genes or proteins but reduced the expression of T-bet. TE administration did not affect the expression of IL-10 and the Tbet genes, and increased the expression levels of IFN-γ and FOXP3 in CD4+ lymphocytes. Both FABP and TE treatment did not affect the Treg cell percentage. CONCLUSION: This study indicates that F. hepatica FABP and TE can suppress the inflammatory responses in EAE-induced mice and shift the immune system toward Th2 responses. However, FABP exerts stronger anti-inflammatory effects and seems to be more effective than TE for EAE treatment.

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BACKGROUND: Helminth-associated changes in gut microbiota composition have been hypothesised to contribute to the immune-suppressive properties of parasitic worms. Multiple sclerosis is an immune-mediated autoimmune disease of the central nervous system whose pathophysiology has been linked to imbalances in gut microbial communities. RESULTS: In the present study, we investigated, for the first time, qualitative and quantitative changes in the faecal bacterial composition of human volunteers with remitting multiple sclerosis (RMS) prior to and following experimental infection with the human hookworm, Necator americanus (N+), and following anthelmintic treatment, and compared the findings with data obtained from a cohort of RMS patients subjected to placebo treatment (PBO). Bacterial 16S rRNA high-throughput sequencing data revealed significantly decreased alpha diversity in the faecal microbiota of PBO compared to N+ subjects over the course of the trial; additionally, we observed significant differences in the abundances of several bacterial taxa with putative immune-modulatory functions between study cohorts. Parabacteroides were significantly expanded in the faecal microbiota of N+ individuals for which no clinical and/or radiological relapses were recorded at the end of the trial. CONCLUSIONS: Overall, our data lend support to the hypothesis of a contributory role of parasite-associated alterations in gut microbial composition to the immune-modulatory properties of hookworm parasites.

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BACKGROUND AND OBJECTIVES: An individual's risk of breast cancer is profoundly affected by evolutionary mismatch. Mismatches in Western society known to increase the risk of breast cancer include a sedentary lifestyle and reproductive factors. Biota alteration, characterized by a loss of biodiversity from the ecosystem of the human body as a result of Western society, is a mismatch known to increase the risk of a variety of inflammation-related diseases, including colitis-associated colon cancer. However, the effect of biota alteration on breast cancer has not been evaluated. METHODOLOGY: In this study, we utilized the C3(1)-TAg mouse model of breast cancer to evaluate the role of biota alteration in the development of breast cancer. This model has been used to recapitulate the role of exercise and pregnancy in reducing the risk of breast cancer. C3(1)-TAg mice were treated with Hymenolepis diminuta, a benign helminth that has been shown to reverse the effects of biota alteration in animal models. RESULTS: No effect of the helminth H. diminuta was observed. Neither the latency nor tumor growth was affected by the therapy, and no significant effects on tumor transcriptome were observed based on RNAseq analysis. CONCLUSIONS AND IMPLICATIONS: These findings suggest that biota alteration, although known to affect a variety of Western-associated diseases, might not be a significant factor in the high rate of breast cancer observed in Western societies. LAY SUMMARY: An almost complete loss of intestinal worms in high-income countries has led to increases in allergic disorders, autoimmune conditions, and perhaps colon cancer. However, in this study, results using laboratory mice suggest that loss of intestinal worms might not be associated with breast cancer.

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Evolutionary medicine argues that disease can arise because modern conditions do not match those in which we evolved. For example, a decline in exposure to commensal microbes and gastrointestinal helminths in developed countries has been linked to increased prevalence of allergic and autoimmune inflammatory disorders (the hygiene hypothesis). Accordingly, probiotic therapies that restore 'old friend' microbes and helminths have been explored as Darwinian treatments for these disorders. A further possibility is that loss of old friend commensals also increases the sterile, aging-associated inflammation known as inflammaging, which contributes to a range of age-related diseases, including cardiovascular disease, dementia, and cancer. Interestingly, Crowe et al., 2020 recently reported that treatment with a secreted glycoprotein from a parasitic nematode can protect against murine aging by induction of anti-inflammatory mechanisms. Here, we explore the hypothesis that restorative helminth therapy would have anti-inflammaging effects. Could worm infections provide broad-spectrum protection against age-related disease?

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Considering their potent immunomodulatory properties, therapeutic applications of Trichuris suis ova (TSO) are studied as potential alternative treatment of autoimmune disorders like multiple sclerosis (MS), rheumatoid arthritis (RA), or inflammatory bowel disease (IBD). Clinical phase 1 and 2 studies have demonstrated TSO treatment to be safe and well tolerated in MS patients, however, they reported only modest clinical efficacy. We therefore addressed the cellular and humoral immune responses directed against parasite antigens in individual MS patients receiving controlled TSO treatment (2500 TSO p.o. every 2 weeks for 12 month). Peripheral blood mononuclear cells (PBMC) of MS patients treated with TSO (n = 5) or placebo (n = 6) were analyzed. A continuous increase of serum IgG and IgE antibodies specific for T. suis excretory/secretory antigens was observed up to 12 months post-treatment. This was consistent with mass cytometry analysis identifying an increase of activated HLA-DRhigh plasmablast frequencies in TSO-treated patients. While stable and comparable frequencies of total CD4+ and CD8+ T cells were detected in placebo and TSO-treated patients over time, we observed an increase of activated HLA-DR+CD4+ T cells in TSO-treated patients only. Frequencies of Gata3+ Th2 cells and Th1/Th2 ratios remained stable during TSO treatment, while Foxp3+ Treg frequencies varied greatly between individuals. Using a T. suis antigen-specific T cell expansion assay, we also detected patient-to-patient variation of antigen-specific T cell recall responses and cytokine production. In summary, MS patients receiving TSO treatment established a T. suis-specific T- and B-cell response, however, with varying degrees of T cell responses and cellular functionality across individuals, which might account for the overall miscellaneous clinical efficacy in the studied patients.