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Helene Kringel - One of the best experts on this subject based on the ideXlab platform.
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molecular and metabolomic changes in the proximal colon of pigs infected with Trichuris suis
Scientific Reports, 2020Co-Authors: Harry D Dawson, Helene Kringel, D E Hill, Robert W Li, Ethiopia Beshah, Celine Chen, Lauren Nicole Bell, Terez Sheadonohue, Joseph F UrbanAbstract:The pig whipworm Trichuris suis is important in swine production because of its negative effects on pig performance and, notably, to some humans with inflammatory bowel disease as a therapeutic agent that modulates inflammation. The proximal colon of T. suis-infected pigs exhibited general inflammation around day 21 after inoculation with infective eggs that is transcriptionally characterized by markers of type-2 immune activation, inflammation, cellular infiltration, tissue repair enzymes, pathways of oxidative stress, and altered intestinal barrier function. Prominent gene pathways involved the Th2-response, de novo cholesterol synthesis, fructose and glucose metabolism, basic amino acid metabolism, and bile acid transport. Upstream regulatory factor analysis implicated the bile acid/farnesoid X receptor in some of these processes. Metabolic analysis indicated changes in fatty acids, antioxidant capacity, biochemicals related to methylation, protein glycosylation, extracellular matrix structure, sugars, Krebs cycle intermediates, microbe-derived metabolites and altered metabolite transport. Close to 1,200 differentially expressed genes were modulated in the proximal colon of pigs with a persistent adult worm infection that was nearly 90% lower in pigs that had expelled worms. The results support a model to test diets that favorably alter the microbiome and improve host intestinal health in both pigs and humans exposed to Trichuris.
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the whipworm Trichuris suis secretes prostaglandin e2 to suppress proinflammatory properties in human dendritic cells
The FASEB Journal, 2017Co-Authors: Lisa C Laan, Andrew R Williams, Kathrin Stavenhagen, Martin Giera, Gijs Kooij, Iliyan Vlasakov, Hakan Kalay, Helene KringelAbstract:Clinical trials have shown that administration of the nematode Trichuris suis can be beneficial in treating various immune disorders. To provide insight into the mechanisms by which this worm suppr...
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the whipworm Trichuris suis secretes prostaglandin e2 to suppress proinflammatory properties in human dendritic cells
The FASEB Journal, 2017Co-Authors: Lisa C Laan, Andrew R Williams, Kathrin Stavenhagen, Martin Giera, Gijs Kooij, Iliyan Vlasakov, Hakan Kalay, Helene KringelAbstract:Clinical trials have shown that administration of the nematode Trichuris suis can be beneficial in treating various immune disorders. To provide insight into themechanisms by which this wormsuppresses inflammatory responses, an active component was purified from T. suis soluble products (TsSPs) that suppress TNF and IL-12 secretion from LPS-activated human dendritic cells (DCs). Analysis by liquid chromatography tandem mass spectrometry identifiedthis compoundasprostaglandin(PG)E2.Thepurifiedcompoundshowedsimilarproperties compared with TsSPs and commercial PGE2 in modulating LPS-induced expression of many cytokines and chemokines and inmodulating Rab7Band P2RX7 expression in human DCs. Furthermore, theTsSP-induced reduction of TNF secretion from DCs is reversed by receptor antagonists for EP2 and EP4, indicating PGE2 action. T. suis secretes extremely high amounts of PGE2 (45-90 ng/mg protein) within their excretory/secretory products but few related lipidmediators as establishedbymetabololipidomic analysis.Culture of T. suiswith several cyclooxygenase (COX) inhibitors that inhibit mammalian prostaglandin synthesis affected the worm's motility but did not inhibit PGE2 secretion, suggesting that theworms can synthesize PGE2 via aCOX-independent pathway.Weconclude that T. suis secretesPGE2to suppress proinflammatory responses inhumanDCs, therebymodulating the host's immune response.-Laan, L. C., Williams, A. R., Stavenhagen, K., Giera, M., Kooij, G., Vlasakov, I., Kalay, H., Kringel, H., Nejsum, P., Thamsborg, S.M., Wuhrer, M., Dijkstra, C. D., Cummings, R. D., van Die, I. The whipworm (Trichuris suis) secretes prostaglandin E2 to suppress proinflammatory properties in human dendritic cells. FASEB J. 31, 719-731 (2017). www.fasebj.org.
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Trichuris suis secrete products that reduce disease severity in a multiple sclerosis model
Acta Parasitologica, 2017Co-Authors: Christine Søholm Hansen, Stig Milan Thamsborg, Henrik Hasseldam, Idahella Hyldgaard Bacher, Flemming Fryd Johansen, Helene KringelAbstract:Multiple sclerosis is a chronic inflammatory central nervous system (CNS) disease, which affects about 1 in 1000 individuals in the western world. It has been suggested that this relatively high prevalence is linked to a high level of hygiene, i.e. a reduced exposure to various microorganisms, including parasites. Parasites are known to employ different immunomodulatory and anti-inflammatory strategies, which enable them to evade destruction by the immune system. We have investigated the immunomodulation by the swine whipworm, Trichuris suis , by measuring the impact of oral administration of T. suis ova as well as of intraperitoneal administration of T. suis excretory/secretory products on the development and progression of experimental autoimmune encephalomyelitis — an animal model that shares clinical and pathological characteristics with multiple sclerosis. Intraperitoneal administration of excretory/secretory products before disease onset, resulted in a significant decrease in disease severity as well as markedly reduced T_H1 and T_H17 T-cell responses, centrally in the spinal cord as well as in the periphery, i.e. the spleen. Thus, parenteral administration of T. suis -derived products results in a skewing of the immune response with a significant impact on disease severity in a CNS inflammatory disease model.
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profiling circulating mirnas in serum from pigs infected with the porcine whipworm Trichuris suis
Veterinary Parasitology, 2016Co-Authors: Eline Palm Hansen, Stig Milan Thamsborg, Helene Kringel, Peter NejsumAbstract:Abstract microRNAs (miRNAs) are recently discovered as key regulators of gene translation and are becoming increasingly recognized for their involvement in various diseases. This study investigates the miRNA profile in pig serum during the course of an infection with the gastrointestinal parasite, Trichuris suis. Of this panel, the expression of selected miRNAs in serum from T. suis infected and uninfected pigs were determined by quantitative real time PCR using Exiqon Human Panel assays at 0, 2, 4, 6, 8 and 10 weeks post first infection (wpi). One miRNA, ssc-let-7d-3p, was significantly up-regulated in infected pigs 8 wpi. Interestingly, ssc-let-7d-3p shows high complementary to tsu-let-7a, which is the most highly transcribed miRNA in T. suis. The let-7 family miRNAs have been shown to post-transcriptionally regulate the translation of the helminth-controlling cytokine, IL-13, in a murine model for asthma and we hypothesize possible interactions between these host- and parasite-derived miRNAs and their immunomodulating roles.
Allan Roepstorff - One of the best experts on this subject based on the ideXlab platform.
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temperature dependent embryonic development of Trichuris suis eggs in a medicinal raw material
Veterinary Parasitology, 2016Co-Authors: Nermina Vejzagic, Stig Milan Thamsborg, Helene Kringel, Allan Roepstorff, Johan Musaeus Bruun, Anette Blak Grossi, Christian Moliin Outzen KapelAbstract:Abstract The therapeutic potential of infective pig whipworm eggs, Trichuris suis ova (TSO), is currently tested in several clinical trials on immune-mediated diseases. This paper studied the embryonic development of TSO in a medicinal raw product, where the parasite eggs were suspended in sulphuric acid (pH1). Unembryonated T. suis egg batches were stored at 5, 10, 15, 20, 25, 30, and 40 °C (±1 °C) and examined at 2, 4, 8, and 14 weeks. Subsequently, sub-batches from each temperature were allowed to embryonate for additional 14 weeks at 25 °C, and selected samples were tested for infectivity in Gottingen minipigs. Both male and female pigs were used to evaluate eventual gender specific infectivity. Storage at 30 °C up to 14 weeks and subsequent embryonation for 14 weeks at 25 °C did not significantly reduce the overall larval establishment in minipigs, as compared to storage at 5 °C and subsequent embryonation at 25 °C. As marked impairment of egg development was observed during storage at 40 °C, a second set of unembryonated egg batches were incubated at 30, 32, 34, 36, 38, and 40 °C (±1 °C) for 1–8 weeks. The development of the eggs was repeatedly examined by manual light microscopy, multispectral analysis (OvaSpec), and an egg hatching assay prior to the final testing in minipigs (Trial 1). These methods showed that the development started earlier at higher temperatures, but the long-term storage at higher temperature affected the egg development. The present study further documents tolerance of the TSO to storage at temperature 5–15 °C, at which temperature development of larvae is not initiated.
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in vitro hatching of Trichuris suis eggs
Parasitology Research, 2015Co-Authors: Nermina Vejzagic, Stig Milan Thamsborg, Helene Kringel, Allan Roepstorff, Johan Musaeus Bruun, Christian Moliin Outzen KapelAbstract:Eggs of the pig whipworm, Trichuris suis ova (TSO), are currently tested in human clinical trials for their potential immunomodulatory capacity. The biological potency of TSO (egg viability and infectivity) is traditionally assessed in Gottingen minipigs as the establishment of intestinal larvae after inoculation with a known number of eggs. To minimize testing in animal models, development of an in vitro egg hatching assay is proposed as a reliable, cost-effective, and a faster alternative to test the egg viability. The present study aimed to investigate the influence of different chemical, physical, and biological factors on egg hatching. Thus, in a series of experiments and in different combinations, the eggs were stimulated with glass beads, artificial gastric juice, bile salt and trypsin solution, fermentation gut medium, or stimulated with mucosal scrapings from the ileum and the large intestine of the infected and uninfected Gottingen minipig. Mechanical stimulation with glass beads presented a simple and reproducible method for egg hatching. However, incubation of eggs with mucosal scrapings from the ileum, caecum, and colon for 24 h at 38 °C significantly increased hatching.
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dose dependent establishment of Trichuris suis larvae in gottingen minipigs
Veterinary Parasitology, 2015Co-Authors: Nermina Vejzagic, Stig Milan Thamsborg, Helene Kringel, Allan Roepstorff, Mads Parup Nielsen, Christian Moliin Outzen KapelAbstract:Abstract Embryonated eggs of the pig whipworm Trichuris suis (TSOee) constitute the active pharmaceutical ingredient (API) in a medicinal product explored in human clinical trials against several immune-mediated diseases. The measurement of TSO biological potency (hatchability and infectivity) is a requirement for the assessment of TSO's pharmacological potency in human clinical trials. The present study aims to validate the dose-dependent establishment of T. suis larvae in Gottingen minipigs and eventual clinical implication of a dose range (1000–10,000 TSO). Four groups of 5 minipigs were inoculated with doses of 1000, 2500, 7500, and 10,000 TSOee, respectively, to evaluate a range of concentrations of TSOee in a minipig infectivity model. Unembryonated eggs (TSOue) were added to keep the total egg number in the inoculum constant at 10,000 eggs. Two groups received 2500 and 7500 TSOee per pig without the addition of TSOue as controls. The intestinal larval establishment at 21 days post inoculation (dpi) demonstrated a clear positive linear dose–response relationship between numbers of inoculated TSOee and recovered larvae. There was a low level of variation in larval counts in all study groups. Thus, the infectivity model in minipigs within the tested dose range offers a reliable, sensitive and accurate assay for testing biological potency of TSO.
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Trichuris suis ova therapy in relapsing multiple sclerosis is safe but without signals of beneficial effect
Multiple Sclerosis Journal, 2015Co-Authors: A Voldsgaard, Stig Milan Thamsborg, Christian Moliin Outzen Kapel, Allan Roepstorff, Peter Bager, Ellen Garde, Per Akeson, Annemette Leffers, Camilla Gobel Madsen, Mads MelbyeAbstract:Background:An observational study has suggested that relapsing–remitting multiple sclerosis patients with helminth infections have lower disease activity and progression than uninfected multiple sclerosis patients.Objective:To evaluate the safety and efficacy on MRI activity of treatment with TSO in relapsing MS.Methods:The study was an open-label, magnetic resonance imaging assessor-blinded, baseline-to-treatment study including ten patients with relapsing forms of multiple sclerosis. Median (range) age was 41 (24–55) years, disease duration 9 (4–34) years, Expanded Disability Status Scale score 2.5 (1–5.0), and number of relapses within the last two years 3 (2–5). Four patients received no disease modifying therapy, while six patients received IFN-β. After an observational period of 8 weeks, patients received 2500 ova from the helminth Trichuris suis orally every second week for 12 weeks. Patients were followed with serial magnetic resonance imaging, neurological examinations, laboratory safety tests an...
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ovaspec a vision based instrument for assessing concentration and developmental stage of Trichuris suis parasite egg suspensions
Computers in Biology and Medicine, 2014Co-Authors: Johan Musaeus Bruun, Nermina Vejzagic, Allan Roepstorff, Jens Michael Carstensen, Svend Christensen, C M O KapelAbstract:BackgroundOvaSpec is a new, fully automated, vision-based instrument for assessing the quantity (concentration) and quality (embryonation percentage) of Trichuris suis parasite eggs in liquid suspension. The eggs constitute the active pharmaceutical ingredient in a medicinal drug for the treatment of immune-mediated diseases such as Crohn?s disease, ulcerative colitis, and multiple sclerosis. MethodsThis paper describes the development of an automated microscopy technology, including methodological challenges and design decisions of relevance for the future development of comparable vision-based instruments. Morphological properties are used to distinguish eggs from impurities and two features of the egg contents under brightfield and darkfield illumination are used in a statistical classification to distinguish eggs with undifferentiated contents (non-embryonated eggs) from eggs with fully developed larvae inside (embryonated eggs). ResultsFor assessment of the instrument?s performance, six egg suspensions of varying quality were used to generate a dataset of unseen images. Subsequently, annotation of the detected eggs and impurities revealed a high agreement with the manual, image-based assessments for both concentration and embryonation percentage (both error rates <1.0%). Similarly, a strong correlation was demonstrated in a final, blinded comparison with traditional microscopic assessments performed by an experienced laboratory technician. ConclusionsThe present study demonstrates the applicability of computer vision in the production, analysis, and quality control of T. suis eggs used as an active pharmaceutical ingredient for the treatment of autoimmune diseases. A scalable, objective method for in-process drug testing was developed.OvaSpec automatically assess concentration and embryonation percentage of TSO.Algorithms were tested on a large, annotated dataset of 42,894 eggs in 2970 images.Darkfield scattering and larval morphology enables classification accuracies of 99%.Computer vision agrees with manual microscopy but has superior precision.
Stig Milan Thamsborg - One of the best experts on this subject based on the ideXlab platform.
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effects of the dietary fibre inulin and Trichuris suis products on inflammatory responses in lipopolysaccharide stimulated macrophages
Molecular Immunology, 2020Co-Authors: Laura J Myhill, Stig Milan Thamsborg, Peter Nejsum, Helena Mejer, Penille Jensen, Amin Zakeri, Lars F Nielsen, Simon R Jakobsen, Andrew R WilliamsAbstract:Consumption of fermentable dietary fibres, such as inulin, or administration of helminth products (e.g. Trichuris suis ova) have independently been shown to alleviate inflammation in vivo. We recently found that dietary inulin and T. suis infection in pigs co-operatively suppressed type-1 inflammatory responses in the gut, suggesting the potential of dietary components to augment anti-inflammatory responses induced by certain helminths. Here, we explored whether T. suis antigens and inulin could directly suppress inflammatory responses in vitro in a cooperative manner. T. suis soluble products (TsSP) strongly suppressed lipopolysaccharide (LPS)-induced IL-6 and TNF-α secretion from murine macrophages and induced an anti-inflammatory phenotype as evidenced by transcriptomic and gene pathway analyses. Inulin regulated the expression of a small number of genes and transcriptional pathways in macrophages after exposure to LPS, but did not enhance the suppressive activity of TsSP, either directly or in co-culture experiments with intestinal epithelial cells. Culture of macrophages with short-chain fatty acids, the products of microbial fermentation of inulin, did however appear to enhance TsSP-mediated inhibition of TNF-α production. Our results confirm a direct role for helminth products in suppressing inflammatory responses in macrophages. In contrast, inulin had little capacity to directly modulate LPS-induced responses. Our results suggest distinct mode-of-actions of T. suis and inulin in regulating inflammatory responses, and that the role of inulin in modulating the response to helminth infection may be dependent on other factors such as production of metabolites by the gut microbiota.
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dietary inulin and Trichuris suis infection promote beneficial bacteria throughout the porcine gut
Frontiers in Microbiology, 2020Co-Authors: Sophie Stolzenbach, Andrew R Williams, Peter Nejsum, Laura J Myhill, Lee Obrien Andersen, Lukasz Krych, Helena Mejer, Rune C Stensvold, Dennis S Nielsen, Stig Milan ThamsborgAbstract:The gut microbiota displays a profound ability to adapt to extrinsic factors, such as gastrointestinal pathogens and/or dietary alterations. Parasitic worms (helminths) and host-associated gut microbiota share a long co-evolutionary relationship, exerting mutually modulatory effects which may impact the health of the host. Moreover, dietary components such as prebiotic fibres (e.g. inulin) are capable of modulating microbiota towards a composition often associated with a healthier gut function. The effect of helminth infection on the host microbiota is still equivocal, and it is also unclear how parasites and prebiotic dietary components interact to influence the microbiota and host health status. Some helminths, such as Trichuris suis (porcine whipworm) also exhibit strong immunomodulatory and anti-inflammatory effects. We therefore explored the effects of T. suis, alone and in interaction with inulin, both in faecal microbiota during the infection period and luminal microbiota across four intestinal segments at the end of a four-week infection period. We observed that T. suis generally had minimal, but mainly positive, effects on the microbiota. T. suis increased the relative abundance of bacterial genera putatively associated with gut health such as Prevotella, and decreased bacteria such as Proteobacteria that have been associated with dysbiosis. Interestingly, dietary inulin interacted with T. suis to enhance these effects, thereby modulating the microbiota towards a composition associated with reduced inflammation. Our results show that administration of T. suis together with the consumption of prebiotic inulin may have the potential to positively affect gut health.
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Trichuris suis secrete products that reduce disease severity in a multiple sclerosis model
Acta Parasitologica, 2017Co-Authors: Christine Søholm Hansen, Stig Milan Thamsborg, Henrik Hasseldam, Idahella Hyldgaard Bacher, Flemming Fryd Johansen, Helene KringelAbstract:Multiple sclerosis is a chronic inflammatory central nervous system (CNS) disease, which affects about 1 in 1000 individuals in the western world. It has been suggested that this relatively high prevalence is linked to a high level of hygiene, i.e. a reduced exposure to various microorganisms, including parasites. Parasites are known to employ different immunomodulatory and anti-inflammatory strategies, which enable them to evade destruction by the immune system. We have investigated the immunomodulation by the swine whipworm, Trichuris suis , by measuring the impact of oral administration of T. suis ova as well as of intraperitoneal administration of T. suis excretory/secretory products on the development and progression of experimental autoimmune encephalomyelitis — an animal model that shares clinical and pathological characteristics with multiple sclerosis. Intraperitoneal administration of excretory/secretory products before disease onset, resulted in a significant decrease in disease severity as well as markedly reduced T_H1 and T_H17 T-cell responses, centrally in the spinal cord as well as in the periphery, i.e. the spleen. Thus, parenteral administration of T. suis -derived products results in a skewing of the immune response with a significant impact on disease severity in a CNS inflammatory disease model.
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profiling circulating mirnas in serum from pigs infected with the porcine whipworm Trichuris suis
Veterinary Parasitology, 2016Co-Authors: Eline Palm Hansen, Stig Milan Thamsborg, Helene Kringel, Peter NejsumAbstract:Abstract microRNAs (miRNAs) are recently discovered as key regulators of gene translation and are becoming increasingly recognized for their involvement in various diseases. This study investigates the miRNA profile in pig serum during the course of an infection with the gastrointestinal parasite, Trichuris suis. Of this panel, the expression of selected miRNAs in serum from T. suis infected and uninfected pigs were determined by quantitative real time PCR using Exiqon Human Panel assays at 0, 2, 4, 6, 8 and 10 weeks post first infection (wpi). One miRNA, ssc-let-7d-3p, was significantly up-regulated in infected pigs 8 wpi. Interestingly, ssc-let-7d-3p shows high complementary to tsu-let-7a, which is the most highly transcribed miRNA in T. suis. The let-7 family miRNAs have been shown to post-transcriptionally regulate the translation of the helminth-controlling cytokine, IL-13, in a murine model for asthma and we hypothesize possible interactions between these host- and parasite-derived miRNAs and their immunomodulating roles.
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temperature dependent embryonic development of Trichuris suis eggs in a medicinal raw material
Veterinary Parasitology, 2016Co-Authors: Nermina Vejzagic, Stig Milan Thamsborg, Helene Kringel, Allan Roepstorff, Johan Musaeus Bruun, Anette Blak Grossi, Christian Moliin Outzen KapelAbstract:Abstract The therapeutic potential of infective pig whipworm eggs, Trichuris suis ova (TSO), is currently tested in several clinical trials on immune-mediated diseases. This paper studied the embryonic development of TSO in a medicinal raw product, where the parasite eggs were suspended in sulphuric acid (pH1). Unembryonated T. suis egg batches were stored at 5, 10, 15, 20, 25, 30, and 40 °C (±1 °C) and examined at 2, 4, 8, and 14 weeks. Subsequently, sub-batches from each temperature were allowed to embryonate for additional 14 weeks at 25 °C, and selected samples were tested for infectivity in Gottingen minipigs. Both male and female pigs were used to evaluate eventual gender specific infectivity. Storage at 30 °C up to 14 weeks and subsequent embryonation for 14 weeks at 25 °C did not significantly reduce the overall larval establishment in minipigs, as compared to storage at 5 °C and subsequent embryonation at 25 °C. As marked impairment of egg development was observed during storage at 40 °C, a second set of unembryonated egg batches were incubated at 30, 32, 34, 36, 38, and 40 °C (±1 °C) for 1–8 weeks. The development of the eggs was repeatedly examined by manual light microscopy, multispectral analysis (OvaSpec), and an egg hatching assay prior to the final testing in minipigs (Trial 1). These methods showed that the development started earlier at higher temperatures, but the long-term storage at higher temperature affected the egg development. The present study further documents tolerance of the TSO to storage at temperature 5–15 °C, at which temperature development of larvae is not initiated.
Joseph F Urban - One of the best experts on this subject based on the ideXlab platform.
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molecular and metabolomic changes in the proximal colon of pigs infected with Trichuris suis
Scientific Reports, 2020Co-Authors: Harry D Dawson, Helene Kringel, D E Hill, Robert W Li, Ethiopia Beshah, Celine Chen, Lauren Nicole Bell, Terez Sheadonohue, Joseph F UrbanAbstract:The pig whipworm Trichuris suis is important in swine production because of its negative effects on pig performance and, notably, to some humans with inflammatory bowel disease as a therapeutic agent that modulates inflammation. The proximal colon of T. suis-infected pigs exhibited general inflammation around day 21 after inoculation with infective eggs that is transcriptionally characterized by markers of type-2 immune activation, inflammation, cellular infiltration, tissue repair enzymes, pathways of oxidative stress, and altered intestinal barrier function. Prominent gene pathways involved the Th2-response, de novo cholesterol synthesis, fructose and glucose metabolism, basic amino acid metabolism, and bile acid transport. Upstream regulatory factor analysis implicated the bile acid/farnesoid X receptor in some of these processes. Metabolic analysis indicated changes in fatty acids, antioxidant capacity, biochemicals related to methylation, protein glycosylation, extracellular matrix structure, sugars, Krebs cycle intermediates, microbe-derived metabolites and altered metabolite transport. Close to 1,200 differentially expressed genes were modulated in the proximal colon of pigs with a persistent adult worm infection that was nearly 90% lower in pigs that had expelled worms. The results support a model to test diets that favorably alter the microbiome and improve host intestinal health in both pigs and humans exposed to Trichuris.
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immune and inflammatory responses in pigs infected with Trichuris suis and oesophagostomum dentatum
Veterinary Parasitology, 2015Co-Authors: Annette Andreasen, Helene Kringel, Joseph F Urban, Heidi Huus Petersen, Harry D Dawson, Kerstin Skovgaard, Tine Iburg, S M ThamsborgAbstract:The aim of the present study was to investigate parasite induced immune responses in pigs co-infected with Trichuris suis and Oesophagostomum dentatum as compared to mono-species infected pigs. T. suis is known to elicit a strong immune response leading to rapid expulsion, and a strong antagonistic effect on O. dentatum populations has been observed in co-infected pigs. Forty-eight helminth naive pigs were allocated into 4 groups in a 2-factorial design. Two groups were trickle inoculated with either 10 T. suis eggs/kg/day (Group T) or 20 O. dentatum L3/kg/day (Group O). Group OT was infected with same levels of both T. suis and O. dentatum (Group OT) and Group C remained uninfected. In each group, six pigs were necropsied after 35 days and the remaining pigs after 71 days. Parasite E/S-antigen specific serum antibodies were quantified by an in-direct ELISA. qPCR was used to measure the expression of immune function related genes in the mucosa of proximal colon and the draining lymph node. Highly significant interactions were identified for O. dentatum specific IgG1 (p < 0.0001) and IgG2 (p < 0.0006) antibodies with a remarkable 2-fold higher antibody response in group OT pigs as compared to group O. These findings indicated that T. suis enhanced the antibody response against O. dentatum in Group OT. The gene expression data confirmed a strong Type 2 response to T. suis (e.g. marked increase in IL-13, ARG1 and CCL11) and clearly weaker in amplitude and/or delayed onset response to O. dentatum in the single infected group. Interactions were found between the two nematodes with regard to several cytokines, e.g. the increase in IL-13 observed in Group T was absent in Group OT (p = 0.06, proximal colon mucosa, 35 and 71 p.i.). Some of these immune response-related interactions may support, or even partially explain, the observed interactions between the two worm populations in co-infected pigs.
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alterations in the porcine colon microbiota induced by the gastrointestinal nematode Trichuris suis
Infection and Immunity, 2012Co-Authors: Robert W Li, D E Hill, Sitao Wu, Weizhong Li, Karl Navarro, Robin D Couch, Joseph F UrbanAbstract:ABSTRACT Helminth parasites ensure their survival by regulating host immunity through mechanisms that dampen inflammation. These properties have recently been exploited therapeutically to treat human diseases. The biocomplexity of the intestinal lumen suggests that interactions between the parasite and the intestinal microbiota would also influence inflammation. In this study, we characterized the microbiota in the porcine proximal colon in response to Trichuris suis (whipworm) infection using 16S rRNA gene-based and whole-genome shotgun (WGS) sequencing. A 21-day T. suis infection in four pigs induced a significant change in the composition of the proximal colon microbiota compared to that of three parasite-naive pigs. Among the 15 phyla identified, the abundances of Proteobacteria and Deferribacteres were changed in infected pigs. The abundances of approximately 13% of genera were significantly altered by infection. Changes in relative abundances of Succinivibrio and Mucispirillum, for example, may relate to alterations in carbohydrate metabolism and niche disruptions in mucosal interfaces induced by parasitic infection, respectively. Of note, infection by T. suis led to a significant shift in the metabolic potential of the proximal colon microbiota, where 26% of all metabolic pathways identified were affected. Besides carbohydrate metabolism, lysine biosynthesis was repressed as well. A metabolomic analysis of volatile organic compounds (VOCs) in the luminal contents showed a relative absence in infected pigs of cofactors for carbohydrate and lysine biosynthesis, as well as an accumulation of oleic acid, suggesting altered fatty acid absorption contributing to local inflammation. Our findings should facilitate development of strategies for parasitic control in pigs and humans.
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worm burden dependent disruption of the porcine colon microbiota by Trichuris suis infection
PLOS ONE, 2012Co-Authors: Sitao Wu, Robert W Li, Weizhong Li, Ethiopia Beshah, Harry D Dawson, Joseph F UrbanAbstract:Helminth infection in pigs serves as an excellent model for the study of the interaction between human malnutrition and parasitic infection and could have important implications in human health. We had observed that pigs infected with Trichuris suis for 21 days showed significant changes in the proximal colon microbiota. In this study, interactions between worm burden and severity of disruptions to the microbial composition and metabolic potentials in the porcine proximal colon microbiota were investigated using metagenomic tools. Pigs were infected by a single dose of T. suis eggs for 53 days. Among infected pigs, two cohorts were differentiated that either had adult worms or were worm-free. Infection resulted in a significant change in the abundance of approximately 13% of genera detected in the proximal colon microbiota regardless of worm status, suggesting a relatively persistent change over time in the microbiota due to the initial infection. A significant reduction in the abundance of Fibrobacter and Ruminococcus indicated a change in the fibrolytic capacity of the colon microbiota in T. suis infected pigs. In addition, ∼10% of identified KEGG pathways were affected by infection, including ABC transporters, peptidoglycan biosynthesis, and lipopolysaccharide biosynthesis as well as α-linolenic acid metabolism. Trichuris suis infection modulated host immunity to Campylobacter because there was a 3-fold increase in the relative abundance in the colon microbiota of infected pigs with worms compared to naive controls, but a 3-fold reduction in worm-free infected pigs compared to controls. The level of pathology observed in infected pigs with worms compared to worm-free infected pigs may relate to the local host response because expression of several Th2-related genes were enhanced in infected pigs with worms versus those worm-free. Our findings provided insight into the dynamics of the proximal colon microbiota in pigs in response to T. suis infection.
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Trichuris suis therapy for active ulcerative colitis a randomized controlled trial
Gastroenterology, 2005Co-Authors: Robert W. Summers, David E Elliott, Robin Thompson, Joseph F Urban, Joel V. WeinstockAbstract:Background & Aims: Ulcerative colitis is most common in Western industrialized countries. Inflammatory bowel disease is uncommon in developing countries where helminths are frequent. People with helminths have an altered immunological response to antigens. In animal models, helminths prevent or improve colitis by the induction of regulatory T cells and modulatory cytokines. This study determined the efficacy and safety of the helminth Trichuris suis in therapy of ulcerative colitis. Methods: This was a randomized, double blind, placebo-controlled trial conducted at the University of Iowa and select private practices. Trichuris suis ova were obtained from the US Department of Agriculture. The trial included 54 patients with active colitis, defined by an Ulcerative Colitis Disease Activity Index of >4. Patients were recruited from physician participants and were randomly assigned to receive placebo or ova treatment. Patients received 2500 Trichuris suis ova or placebo orally at 2-week intervals for 12 weeks. Results: The primary efficacy variable was improvement of the Disease Activity Index to >4. After 12 weeks of therapy, improvement according to the intent-to-treat principle occurred in 13 of 30 patients (43.3%) with ova treatment compared with 4 of 24 patients (16.7%) given placebo (P .04). Improvement was also found with the Simple Index that was significant by week 6. The difference in the proportion of patients who achieved an Ulcerative Colitis Disease Activity Index of 0 –1 was not significant. Treatment induced no side effects. Conclusions: Ova therapy seems safe and effective in patients with active colitis.
Joel V. Weinstock - One of the best experts on this subject based on the ideXlab platform.
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analysis of the Trichuris suis excretory secretory proteins as a function of life cycle stage and their immunomodulatory properties
Scientific Reports, 2018Co-Authors: Mohamad Nasr, Rajesh Valanparambil, Elizabeth Siciliani, Maritza Jaramillo, Bruce A Rosa, Louisphilippe Leroux, D E Hill, Dante S. Zarlenga, Joel V. WeinstockAbstract:Parasitic worms have a remarkable ability to modulate host immune responses through several mechanisms including excreted/secreted proteins (ESP), yet the exact nature of these proteins and their targets often remains elusive. Here, we performed mass spectrometry analyses of ESP (TsESP) from larval and adult stages of the pig whipworm Trichuris suis (Ts) and identified ~350 proteins. Transcriptomic analyses revealed large subsets of differentially expressed genes in the various life cycle stages of the parasite. Exposure of bone marrow-derived macrophages and dendritic cells to TsESP markedly diminished secretion of the pro-inflammatory cytokines TNFα and IL-12p70. Conversely, TsESP exposure strongly induced release of the anti-inflammatory cytokine IL-10, and also induced high levels of nitric oxide (NO) and upregulated arginase activity in macrophages. Interestingly, TsESP failed to directly induce CD4+ CD25+ FoxP3+ regulatory T cells (Treg cells), while OVA-pulsed TsESP-treated dendritic cells suppressed antigen-specific OT-II CD4+ T cell proliferation. Fractionation of TsESP identified a subset of proteins that promoted anti-inflammatory functions, an activity that was recapitulated using recombinant T. suis triosephosphate isomerase (TPI) and nucleoside diphosphate kinase (NDK). Our study helps illuminate the intricate balance that is characteristic of parasite-host interactions at the immunological interface, and further establishes the principle that specific parasite-derived proteins can modulate immune cell functions.
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Analysis of the Trichuris suis excretory/secretory proteins as a function of life cycle stage and their immunomodulatory properties.
Scientific Reports, 2018Co-Authors: Louisphilippe Leroux, Mohamad Nasr, Rajesh Valanparambil, Elizabeth Siciliani, Maritza Jaramillo, Dolores E. Hill, Bruce A Rosa, Dante S. Zarlenga, Joel V. WeinstockAbstract:Parasitic worms have a remarkable ability to modulate host immune responses through several mechanisms including excreted/secreted proteins (ESP), yet the exact nature of these proteins and their targets often remains elusive. Here, we performed mass spectrometry analyses of ESP (TsESP) from larval and adult stages of the pig whipworm Trichuris suis (Ts) and identified ~350 proteins. Transcriptomic analyses revealed large subsets of differentially expressed genes in the various life cycle stages of the parasite. Exposure of bone marrow-derived macrophages and dendritic cells to TsESP markedly diminished secretion of the pro-inflammatory cytokines TNFα and IL-12p70. Conversely, TsESP exposure strongly induced release of the anti-inflammatory cytokine IL-10, and also induced high levels of nitric oxide (NO) and upregulated arginase activity in macrophages. Interestingly, TsESP failed to directly induce CD4+ CD25+ FoxP3+ regulatory T cells (Treg cells), while OVA-pulsed TsESP-treated dendritic cells suppressed antigen-specific OT-II CD4+ T cell proliferation. Fractionation of TsESP identified a subset of proteins that promoted anti-inflammatory functions, an activity that was recapitulated using recombinant T. suis triosephosphate isomerase (TPI) and nucleoside diphosphate kinase (NDK). Our study helps illuminate the intricate balance that is characteristic of parasite-host interactions at the immunological interface, and further establishes the principle that specific parasite-derived proteins can modulate immune cell functions.
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randomised clinical trial the safety and tolerability of Trichuris suis ova in patients with crohn s disease
Alimentary Pharmacology & Therapeutics, 2013Co-Authors: William J Sandborn, David E Elliott, Joel V. Weinstock, Robert W. Summers, A Landrywheeler, N Silver, M D Harnett, Stephen B HanauerAbstract:BACKGROUND: Recent evidence suggests that embryonated eggs of the porcine whipworm Trichuris suis ova (TSO) may be an effective treatment for inflammatory bowel disease (IBD). AIM: To assess the safety and tolerability of TSO following a single dose in patients with Crohn's disease. METHODS: This was a sequential dose-escalation (500, 2500 and 7500 viable embryonated TSO), randomised, double-blind, placebo-controlled study to evaluate the safety of a single dose of oral suspension TSO in patients with Crohn's disease. Twelve patients were randomised into each of three cohorts. Patients were assessed 1, 3, 5, 7, 9, 11 and 14 days following dosing (via a telephone call and diary symptom collection through 14 days postdose) for adverse events, changes to concomitant medications and gastrointestinal (GI) signs and symptoms. Patients were again assessed at Months 1, 2 and 6. RESULTS: Eighteen males and 18 females were enrolled, ages 20 to 54 years. All patients were dosed and completed the initial 2-month follow-up period (five patients did not attend their 6-month study visit). GI disorders were reported with the highest frequency; 7 (25.9%) TSO-treated patients and 3 (33.3%) placebo-treated patients. No dose-dependent relationship was observed, with 3 (33.3%) placebo, 4 (44.4%) TSO 500, 0 (0.0%) TSO 2500 and 3 (33.3%) TSO 7500 patients experiencing at least one GI event, and no clinically meaningful changes in GI signs and symptoms. CONCLUSIONS: A single dose of Trichuris suis ova up to 7500 ova was well tolerated and did not result in short- or long-term treatment-related side effects. Clinicaltrials.gov NCT01576461.
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randomised clinical trial the safety and tolerability of Trichuris suis ova in patients with crohn s disease
Alimentary Pharmacology & Therapeutics, 2013Co-Authors: William J Sandborn, David E Elliott, Joel V. Weinstock, Robert W. Summers, A Landrywheeler, N Silver, M D Harnett, Stephen B HanauerAbstract:Summary Background Recent evidence suggests that embryonated eggs of the porcine whipworm Trichuris suis ova (TSO) may be an effective treatment for inflammatory bowel disease (IBD). Aim To assess the safety and tolerability of TSO following a single dose in patients with Crohn's disease. Methods This was a sequential dose-escalation (500, 2500 and 7500 viable embryonated TSO), randomised, double-blind, placebo-controlled study to evaluate the safety of a single dose of oral suspension TSO in patients with Crohn's disease. Twelve patients were randomised into each of three cohorts. Patients were assessed 1, 3, 5, 7, 9, 11 and 14 days following dosing (via a telephone call and diary symptom collection through 14 days postdose) for adverse events, changes to concomitant medications and gastrointestinal (GI) signs and symptoms. Patients were again assessed at Months 1, 2 and 6. Results Eighteen males and 18 females were enrolled, ages 20 to 54 years. All patients were dosed and completed the initial 2-month follow-up period (five patients did not attend their 6-month study visit). GI disorders were reported with the highest frequency; 7 (25.9%) TSO-treated patients and 3 (33.3%) placebo-treated patients. No dose-dependent relationship was observed, with 3 (33.3%) placebo, 4 (44.4%) TSO 500, 0 (0.0%) TSO 2500 and 3 (33.3%) TSO 7500 patients experiencing at least one GI event, and no clinically meaningful changes in GI signs and symptoms. Conclusions A single dose of Trichuris suis ova up to 7500 ova was well tolerated and did not result in short- or long-term treatment-related side effects. Clinicaltrials.gov NCT01576461.
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Trichuris suis therapy for active ulcerative colitis a randomized controlled trial
Gastroenterology, 2005Co-Authors: Robert W. Summers, David E Elliott, Robin Thompson, Joseph F Urban, Joel V. WeinstockAbstract:Background & Aims: Ulcerative colitis is most common in Western industrialized countries. Inflammatory bowel disease is uncommon in developing countries where helminths are frequent. People with helminths have an altered immunological response to antigens. In animal models, helminths prevent or improve colitis by the induction of regulatory T cells and modulatory cytokines. This study determined the efficacy and safety of the helminth Trichuris suis in therapy of ulcerative colitis. Methods: This was a randomized, double blind, placebo-controlled trial conducted at the University of Iowa and select private practices. Trichuris suis ova were obtained from the US Department of Agriculture. The trial included 54 patients with active colitis, defined by an Ulcerative Colitis Disease Activity Index of >4. Patients were recruited from physician participants and were randomly assigned to receive placebo or ova treatment. Patients received 2500 Trichuris suis ova or placebo orally at 2-week intervals for 12 weeks. Results: The primary efficacy variable was improvement of the Disease Activity Index to >4. After 12 weeks of therapy, improvement according to the intent-to-treat principle occurred in 13 of 30 patients (43.3%) with ova treatment compared with 4 of 24 patients (16.7%) given placebo (P .04). Improvement was also found with the Simple Index that was significant by week 6. The difference in the proportion of patients who achieved an Ulcerative Colitis Disease Activity Index of 0 –1 was not significant. Treatment induced no side effects. Conclusions: Ova therapy seems safe and effective in patients with active colitis.
