Immunology and pathology of echinostomes and other intestinal trematodes.

Intestinal trematodes constitute a major group of helminths that parasitize humans and animals with relevant morbidity and mortality. Despite the importance of the intestinal trematodes in medical and veterinary sciences, immunology and pathology of these helminth infections have been neglected for years. Apart from the work focused on the members of the family Echnistomatidae, there are only very isolated and sporadic studies on the representatives of other families of digeneans, which makes a compilation of all these studies necessary. In the present review, the most salient literature on the immunology and pathology of intestinal trematodes in their definitive hosts in examined. Emphasis will be placed on members of the echinostomatidae family, since it is the group in which the most work has been carried out. However, we also review the information on selected species of the families Brachylaimidae, Diplostomidae, Gymnophallidae, and Heterophyidae. For most of these families, coverage is considered under the following headings: (i) Background; (ii) Pathology of the infection; (iii) Immunology of the infection; and (iv) Human infections.

Modulation of intestinal epithelial permeability by chronic small intestinal helminth infections.

Increased permeability of the intestinal epithelial layer is linked to the pathogenesis and perpetuation of a wide range of intestinal and extra-intestinal diseases. Infecting humans with controlled doses of helminths, such as human hookworm (termed hookworm therapy), is proposed as a treatment for many of the same diseases. Helminths induce immunoregulatory changes in their host which could decrease epithelial permeability, which is highlighted as a potential mechanism through which helminths treat disease. Despite this, the influence of a chronic helminth infection on epithelial permeability remains unclear. This study uses the chronically infecting intestinal helminth Heligmosomoides polygyrus to reveal alterations in the expression of intestinal tight junction proteins and epithelial permeability during the infection course. In the acute infection phase (1 week postinfection), an increase in intestinal epithelial permeability is observed. Consistent with this finding, jejunal claudin-2 is upregulated and tricellulin is downregulated. By contrast, in the chronic infection phase (6 weeks postinfection), colonic claudin-1 is upregulated and epithelial permeability decreases. Importantly, this study also investigates changes in epithelial permeability in a small human cohort experimentally challenged with the human hookworm, Necator americanus. It demonstrates a trend toward small intestinal permeability increasing in the acute infection phase (8 weeks postinfection), and colonic and whole gut permeability decreasing in the chronic infection phase (24 weeks postinfection), suggesting a conserved epithelial response between humans and mice. In summary, our findings demonstrate dynamic changes in epithelial permeability during a chronic helminth infection and provide another plausible mechanism by which chronic helminth infections could be utilized to treat disease.

Magnitude and associated factors of Intestinal Parasitosis and Tuberculosis among Tuberculosis suspected patients attending Kuyu General Hospital, North Shewa, Oromia, Ethiopia.

BACKGROUND: Intestinal parasites and Tuberculosis (TB) co-infection is a major public health problem. The parasitic infection suppresses the cell mediated immunity that protects tuberculosis. Helminthes-induced immune modulation promotes progression to active tuberculosis. However, there is paucity of evidences on the intestinal parasites-tuberculosis co-infection in Ethiopia. This study explores the magnitude and associated factors of intestinal parasitic infection and TB among suspected pulmonary Tuberculosis (PTB) patients. METHODOLOGY: A cross-sectional study design was conducted in Kuyu General Hospital from December 2019-March 2020. The socio-demographic data and associated factors were collected by structured questionnaire and then spot-spot sputum and fresh stool samples were collected following standard guidelines and were processed. Descriptive analysis was conducted and reported in frequency and percentage. Bivariate analysis was computed and a multivariable analysis was conducted to provide an adjusted odds ratio (AOR). P-value <0.05 at 95% confidence interval was considered as statistically significant. RESULTS: The burden of intestinal parasites was 20.2% (49/ 242) and 6.1% (20/ 242) of them were helminths infections and 14.1% (29/ 242) were protozoa infections. Of 242 patients, 14.9% (36/242) were sputum smear-positive for acid fast-bacilli. Of 36 smear positive patients, 9(25%) had TB-intestinal parasites co-infection. Dwelling in rural areas and having untrimmed fingernails were statistically significantly associated with intestinal parasites. Having a contact history of Tb patients was significantly associated with pulmonary tuberculosis. CONCLUSIONS: The magnitude of intestinal parasites and TB among PTB suspected patients were high. Hookworm infection was the predominant helmenthic infection. It is important to consider screening TB patients for intestinal parasites and treat co-infection properly.

Investigation of the relationship between lymphocyte subsets and intestinal parasites.

We analyzed the peripheral blood lymphocyte subsets of cancer patients infected with intestinal parasites, with an aim to find out the relationship between the levels of different types of lymphocytes with the prognosis of patients. 201 cancer patients aged 18 and over were included. Stool samples of the patients were examined using native-lugol, trichrome, modified trichrome (Weber's Trichrome stain), and modified Ziehl-Neelsen staining methods. Microsporidia and Cryptosporidium parvum were investigated at the genus and species levels using PCR. Lymphocyte subsets were determined by flow cytometry in blood samples. One or more parasite species were detected in 115 (56.7%) patients. The most common parasite species were Microsporidia, Blastocystis and Entamoeba coli, respectively. The frequency of parasites was high in patients with low lymphocyte percentage, CD3+ T cell and CD3+ CD4+ T (Th) cell levels in blood samples studied by flow cytometry. Microsporidia infection was significantly higher in patients with low lymphocyte percentage and Th cell levels. Similarly, C. parvum infection was found to be significantly higher in patients with low T lymphocyte percentage and Th cell level. Finally, Blastocystis infection was significantly higher in patients with low lymphocyte percentage and CD4/CD8 ratio higher than 1. The decrease in lymphocyte percentage, CD3+ T cell and Th cell count, and low CD4/CD8 ratio in cancer patients increase the frequency of intestinal parasitic infections. Based on these results, lymphocyte subsets may help identify cancer patients at high risk of opportunistic parasites. We suggest that opportunistic parasitic infections affecting the clinical course of the disease should be considered by clinicians during the follow-up and treatment of patients.

Tuft Cells Increase Following Ovine Intestinal Parasite Infections and Define Evolutionarily Conserved and Divergent Responses.

Helminth parasite infections of humans and livestock are a global health and economic problem. Resistance of helminths to current drug treatment is an increasing problem and alternative control approaches, including vaccines, are needed. Effective vaccine design requires knowledge of host immune mechanisms and how these are stimulated. Mouse models of helminth infection indicate that tuft cells, an unusual type of epithelial cell, may 'sense' infection in the small intestine and trigger a type 2 immune response. Currently nothing is known of tuft cells in immunity in other host species and in other compartments of the gastrointestinal (GI) tract. Here we address this gap and use immunohistochemistry and single cell RNA-sequencing to detail the presence and gene expression profile of tuft cells in sheep following nematode infections. We identify and characterize tuft cells in the ovine abomasum (true stomach of ruminants) and show that they increase significantly in number following infection with the globally important nematodes Teladorsagia circumcincta and Haemonchus contortus. Ovine abomasal tuft cells show enriched expression of tuft cell markers POU2F3, GFI1B, TRPM5 and genes involved in signaling and inflammatory pathways. However succinate receptor SUCNR1 and free fatty acid receptor FFAR3, proposed as 'sensing' receptors in murine tuft cells, are not expressed, and instead ovine tuft cells are enriched for taste receptor TAS2R16 and mechanosensory receptor ADGRG6. We also identify tuft cell sub-clusters at potentially different stages of maturation, suggesting a dynamic process not apparent from mouse models of infection. Our findings reveal a tuft cell response to economically important parasite infections and show that while tuft cell effector functions have been retained during mammalian evolution, receptor specificity has diverged. Our data advance knowledge of host-parasite interactions in the GI mucosa and identify receptors that may potentiate type 2 immunity for optimized control of parasitic nematodes.

Group 2 Innate Lymphoid Cells Exhibit Tissue-Specific Dynamic Behaviour During Type 2 Immune Responses.

Group 2 innate lymphoid cells (ILC2s) are early effectors of mucosal type 2 immunity, producing cytokines such as interleukin (IL)-13 to mediate responses to helminth infection and allergen-induced inflammation. ILC2s are also present in lymph nodes (LNs) and can express molecules required for antigen presentation, but to date there are limited data on their dynamic behaviour. We used a CD2/IL-13 dual fluorescent reporter mouse for in vivo imaging of ILC2s and Th2 T cells in real time following a type 2 priming helminth infection or egg injection. After helminth challenge, we found that ILC2s were the main source of IL-13 in lymphoid organs (Peyer's patches and peripheral LNs), and were located in T cell areas. Intravital imaging demonstrated an increase in IL-13+ ILC2 size and movement following helminth infection, but reduced duration of interactions with T cells compared with those in homeostasis. In contrast, in the intestinal mucosa, we observed an increase in ILC2-T cell interactions post-infection, including some of prolonged duration, as well as increased IL-13+ ILC2 movement. These data suggest that ILC2 activation enhances cell motility, with the potential to increase the area of distribution of cytokines to optimise the early generation of type 2 responses. The prolonged ILC2 interactions with T cells within the intestinal mucosa are consistent with the conclusion that contact-based T cell activation may occur within inflamed tissues rather than lymphoid organs. Our findings have important implications for our understanding of the in vivo biology of ILC2s and the way in which these cells facilitate adaptive immune responses.

Trichuris muris infection drives cell-intrinsic IL4R alpha independent colonic RELMα+ macrophages.

The intestinal nematode parasite Trichuris muris dwells in the caecum and proximal colon driving an acute resolving intestinal inflammation dominated by the presence of macrophages. Notably, these macrophages are characterised by their expression of RELMα during the resolution phase of the infection. The RELMα+ macrophage phenotype associates with the presence of alternatively activated macrophages and work in other model systems has demonstrated that the balance of classically and alternatively activated macrophages is critically important in enabling the resolution of inflammation. Moreover, in the context of type 2 immunity, RELMα+ alternatively activated macrophages are associated with the activation of macrophages via the IL4Rα. Despite a breadth of inflammatory pathologies associated with the large intestine, including those that accompany parasitic infection, it is not known how colonic macrophages are activated towards an alternatively activated phenotype. Here, we address this important knowledge gap by using Trichuris muris infection, in combination with transgenic mice (IL4Rαfl/fl.CX3CR1Cre) and IL4Rα-deficient/wild-type mixed bone marrow chimaeras. We make the unexpected finding that education of colonic macrophages towards a RELMα+, alternatively activated macrophage phenotype during T. muris infection does not require IL4Rα expression on macrophages. Further, this independence is maintained even when the mice are treated with an anti-IFNγ antibody during infection to create a strongly polarised Th2 environment. In contrast to RELMα, PD-L2 expression on macrophages post infection was dependent on IL4Rα signalling in the macrophages. These novel data sets are important, revealing a surprising cell-intrinsic IL4R alpha independence of the colonic RELMα+ alternatively activated macrophage during Trichuris muris infection.

Gut Helminth Infection-Induced Immunotolerance and Consequences for Human Papillomavirus Persistence.

Cervical cancer, a malignancy caused by persistent human papillomavirus (HPV) infection, develops in more than 500,000 women annually. More than 90% of deaths from cervical cancer occur in low- and middle-income countries. A common epidemiological feature of countries with high cervical cancer incidence is a high burden of intestinal helminth infection. The ability of intestinal helminths to trigger immunoregulation, resulting in a "tolerogenic" systemic immune environment, provides fertile soil for the persistence of oncogenic viruses such as HPV. Animal models have shown that intestinal helminth infection permits the persistence of some viruses, however, HPV-specific and human studies are lacking. Large, well-organized trials evaluating the consequences of intestinal helminth infection on the human immune system and HPV persistence may lead to improved strategies for HPV prevention in helminth-endemic regions of the world. Additionally, such studies would offer insight into the specific ways that intestinal helminth infection contributes to immunomodulation, which could identify new therapeutic targets for a range of diseases, from inflammatory disorders to cancer. In this review, we discuss the evidence for helminth-induced systemic and local immune dysregulation, discuss possible mechanisms by which chronic intestinal helminth infection may facilitate HPV persistence, and suggest novel helminth-related interventions that could offer a high leverage (if somewhat unconventional) approach to HPV and cervical cancer control in resource-constrained regions.

Investigating the Prevalence of Intestinal Parasites in Immunocompromised Patients in Bushehr Province, Southwest Iran: A Conventional and Molecular Study

Objective: The aim of this study was to determine the status of intestinal parasitic infections in immunocompromised patients in Bushehr province, southwest Iran by conventional and molecular methods. Methods: A total of 201 stool samples were collected from kidney transplant recipients, AIDS patients and patients under chemotherapy. Samples were collected from healthy people as the control group. The specimens were tested using various conventional methods. Polymerase chain reaction (PCR) testing was performed on samples identified as positive for Coccidia by direct microscopic examination. Results: Approximately 32.45% were infected with at least one type of intestinal parasite. The highest (46.8%) and lowest rates of infection (24%) were observed in AIDS and chemotherapy patients, respectively, while the infection rate of the control group was 16%. Isospora spp. and Cryptosporidium spp. were observed in all patient groups, and Sarcocystis spp. sporocysts were detected in one of the transplant recipients. All identified coccidia were confirmed by PCR. There was a significant relationship between the rate of intestinal parasite infection and certain variables. Conclusion: Given the potential risk of certain intestinal parasites in people with immune deficiency, it is recommended that diagnosis of parasitic infections in such patients be based on specific parasitological methods. Thus, it is advisable that physicians refer them to a parasitology laboratory prior to drug administration.

Protective Effect of Intestinal Helminthiasis Against Tuberculosis Progression Is Abrogated by Intermittent Food Deprivation.

Background: Tuberculosis (TB) is still a major challenge for humankind. Because regions with the highest incidence also have a high prevalence of helminthiasis and nutritional scarcity, we wanted to understand the impact of these on TB progression. Methods: We have developed an experimental murine model for active TB in C3HeB/FeJ, coinfected with Trichuris muris and Heligmosomoides polygyrus nematodes, and exposed to an environmental mycobacterium (M. manresensis) and intermittent fasting. Cause-effect relationships among these factors were explored with Partial Least Squares Path modelling (PLSPM). Results: Previous parasitization had a major anti-inflammatory effect and reduced systemic levels of ADA, haptoglobin, local pulmonary levels of IL-1ß, IL-6, TNF-α, CXCL-1, CXCL-5 and IL-10. Oral administration of heat-killed M. manresensis resulted in a similar outcome. Both interventions diminished pulmonary pathology and bacillary load, but intermittent food deprivation reduced this protective effect increasing stress and inflammation. The PLSPM revealed nematodes might have protective effects against TB progression. Conclusions: Significantly higher cortisol levels in food-deprivation groups showed it is a stressful condition, which might explain its deleterious effect. This highlights the impact of food security on TB eradication policies and the need to prioritize food supply over deworming activities.

Context-dependent roles of B cells during intestinal helminth infection.

The current approaches to reduce the burden of chronic helminth infections in endemic areas are adequate sanitation and periodic administration of deworming drugs. Yet, resistance against some deworming drugs and reinfection can still rapidly occur even after treatment. A vaccine against helminths would be an effective solution at preventing reinfection. However, vaccines against helminth parasites have yet to be successfully developed. While T helper cells and innate lymphoid cells have been established as important components of the protective type 2 response, the roles of B cells and antibodies remain the most controversial. Here, we review the roles of B cells during intestinal helminth infection. We discuss the potential factors that contribute to the context-specific roles for B cells in protection against diverse intestinal helminth parasite species, using evidence from well-defined murine model systems. Understanding the precise roles of B cells during resistance and susceptibility to helminth infection may offer a new perspective of type 2 protective immunity.

Investigation of Intestinal Protozoon Prevalence in Immunocompromised Patients at a University Hospital

Objective: Immunocompromised patients are at a greater risk of developing intestinal parasite infections. In this study, we examined the presence of Enterocytozoon bieneusi, Encaphalitozoon intestinalis and other intestinal protozoa in stool samples of immunosuppressed patients. Methods: A total of 100 stool samples were obtained from patients receiving chemotherapy because of solid organ tumour with haematological malignancies and those receiving immunosuppressive treatment because of rheumatic diseases, organ transplant patients and patients receiving treatment for HIV-related infections. Stool samples were examined by using the native-lugol method in which the stool concentration, modified Kinyoun acid-fast and trichrome staining methods and parasite presence were analysed. The stool samples were also examined for the presence of Enterocytozoon bieneusi and Encephalitozoon intestinalis using an indirect fluorescent antibody method. Results: Intestinal parasites were detected in 12% of all patients. The distribution of intestinal parasites in patients were 7% Blastocystis spp., 2% Blastocystis spp. + Dientamoeba fragilis, 1% Blastocystis spp. + Entamoeba coli, 1% Blastocystis spp. + Giardia intestinalis and 1% G. intestinalis. Microsporidia spp. were detected in 4% of all patients by the IFAT method and in 8% of all patients by calcoflour staining method. Conclusion: In our study, the most prevalent parasite detected in the immunosuppressed patients was Blastocystis spp. The pathogenesis of Blastocystis spp. remains to be controversial, and their role in immunocompromised patients continues to remain unknown. Although these rates detected in our study are similar to the prevalence in the normal population, it is important to study these microorganisms in immunocompromised patients in terms of the associated decreasing morbidity and mortality rates.

Gut CD4+ T cell phenotypes are a continuum molded by microbes, not by TH archetypes.

CD4+ effector lymphocytes (Teff) are traditionally classified by the cytokines they produce. To determine the states that Teff cells actually adopt in frontline tissues in vivo, we applied single-cell transcriptome and chromatin analyses to colonic Teff cells in germ-free or conventional mice or in mice after challenge with a range of phenotypically biasing microbes. Unexpected subsets were marked by the expression of the interferon (IFN) signature or myeloid-specific transcripts, but transcriptome or chromatin structure could not resolve discrete clusters fitting classic helper T cell (TH) subsets. At baseline or at different times of infection, transcripts encoding cytokines or proteins commonly used as TH markers were distributed in a polarized continuum, which was functionally validated. Clones derived from single progenitors gave rise to both IFN-γ- and interleukin (IL)-17-producing cells. Most of the transcriptional variance was tied to the infecting agent, independent of the cytokines produced, and chromatin variance primarily reflected activities of activator protein (AP)-1 and IFN-regulatory factor (IRF) transcription factor (TF) families, not the canonical subset master regulators T-bet, GATA3 or RORγ.

IL-33 facilitates rapid expulsion of the parasitic nematode Strongyloides ratti from the intestine via ILC2- and IL-9-driven mast cell activation.

Parasitic helminths are sensed by the immune system via tissue-derived alarmins that promote the initiation of the appropriate type 2 immune responses. Here we establish the nuclear alarmin cytokine IL-33 as a non-redundant trigger of specifically IL-9-driven and mast cell-mediated immunity to the intestinal parasite Strongyloides ratti. Blockade of endogenous IL-33 using a helminth-derived IL-33 inhibitor elevated intestinal parasite burdens in the context of reduced mast cell activation while stabilization of endogenous IL-33 or application of recombinant IL-33 reciprocally reduced intestinal parasite burdens and increased mast cell activation. Using gene-deficient mice, we show that application of IL-33 triggered rapid mast cell-mediated expulsion of parasites directly in the intestine, independent of the adaptive immune system, basophils, eosinophils or Gr-1+ cells but dependent on functional IL-9 receptor and innate lymphoid cells (ILC). Thereby we connect the described axis of IL-33-mediated ILC2 expansion to the rapid initiation of IL-9-mediated and mast cell-driven intestinal anti-helminth immunity.

Interleukin-25-mediated resistance against intestinal trematodes does not depend on the generation of Th2 responses.

BACKGROUND: The cytokine interleukin-25 (IL-25) is recognized as the most relevant initiator of protective T helper 2 (Th2) responses in intestinal helminth infections. This cytokine induces resistance against several species of intestinal helminths, including the trematode Echinostoma caproni. E. caproni has been extensively used as an experimental model to study the factors determining resistance to intestinal infections. In the study reported here, we assessed the role of IL-25 in the generation of resistance in mice infected with E. caproni. METHODS: The factors that determine the production of IL-25 in mice experimentally infected with E. caproni were determined, as were the consequences of IL-25 production in terms of polarization of the immune response and resistance to infection. RESULTS: Our results show that the role of IL-25 in the polarization of the immune response differs between the primary and secondary immune responses. IL-25 is required for the development of a Th2 phenotype in primary E. caproni infections, but it can also promote the differentiation to Th2 memory cell subsets that enhance type-2 immunity in memory responses. However, the development of Th2 responses does not induce resistance to infection. The Th2 phenotype does not elicit resistance, and IL-25 is responsible for the resistance regardless of its type-2 cytokine activity and activation of signal transducer and activator of transcription (STAT6). Alternative activation of macrophages induced by IL-25 can be implicated in the resistance to infection. CONCLUSIONS: In contrast to primary infection, secondary infection elicits a type-2 immune response even in the absence of IL-25 expression. Despite the development of a type-2 response, mice are susceptible to secondary infection associated with the lack of IL-25. Resistance to infection is due to the production of IL-25, which acts autonomously from Th2 response in terms of parasite clearance.

Non-hierarchical cluster analysis for determination of resistance to worm infection in meat sheep.

The aim of this study was to determine the resistance to worm infection in Santa Inês sheep by combining different sets of gastrointestinal parasite resistance indicator traits, using the k-means algorithm. Records from 221 animals reared in the Mid-North sub-region of Brazil were used. The following phenotypes were used: hematocrit (HCT); white blood cell count; red blood cell count (RBC); hemoglobin (HGB); platelets; mean corpuscular hemoglobin; mean corpuscular volume; mean corpuscular hemoglobin concentration; fecal egg count (FEC); coloration of the ocular mucosa (FAMACHA score); body condition score (BCS); withers height; and rump height. Two files with phenotypic information of animals were edited: complete, including all traits, and reduced, in which only FAMACHA score, HCT, FEC, and BCS were used. For determination of worm resistance, three groups were formed using the k-means non-hierarchical clustering by combining the traits of the complete and reduced analyses. The animals of the group in which individuals had the lowest values for FEC and FAMACHA score, as well as the highest values for HCT, RBC, HGB, and BCS were classified as resistant. In the group with opposite values for the aforementioned traits, the animals were classified as sensitive. The animals of the group with values between the other two groups were classified as moderately resistant. The results obtained in complete and reduced analyses were equivalent. Thus, it is possible to identify animals of the Santa Inês sheep breed according to their status of resistance to worm infection based on a reduced trait set.

Intestinal Nematode Infection Affects Metastasis of EL4 Lymphoma Cells.

An effective host immune system prevents the growth of most cancer cells. However, as intestinal nematodes are able to induce both immunotolerance and immunosuppression in the host, it is possible that their presence could allow co-occurring cancer cells to proliferate and metastasize. Our findings indicate that previous, subsequent or concurrent intestinal nematode infection affects the formation of lung metastatic nodules in mice experimentally infected with Heligmosomoides polygyrus. In addition, pre-infection with nematodes renders mice resistant to metastasis development in lungs, with the inoculated EL4 cancer cells being located mainly in mesenteric lymph nodes. The present paper discusses the nematode-induced mechanisms which may influence the metastatic process.

Changes in the severity of gastric mucosal inflammation associated with Helicobacter pylori in humans coinfected with intestinal helminths.

BACKGROUND: Though a few studies in animal models suggest that intestinal helminths (IH) favorably affect evolution of gastritis associated with Helicobacter pylori (H. pylori) the studies supporting this concept in humans are only a few and are based on serological data. METHODS: To evaluate the possible influence of IH on the human gastric mucosa, three groups of Venezuelan adults with gastropathy (endoscopically diagnosed) were studied: H. pylori-/IH- (n = 17), H. pylori+/IH- (n = 18), and H. pylori+/IH+ (n = 11). Histological analysis (hematoxylin-eosin) and immunohistochemical staining (peroxidase) for cytokines interleukin-1beta (IL-1ß), tumor necrosis factor alpha (TNF-α), gamma interferon (IFN-γ), and interleukin 4 (IL-4) were undertaken in gastric antral biopsies. RESULTS: Expression of the four cytokines was detected in all individuals in varying degrees, but proinflammatory cytokines were expressed in a higher degree in the H. pylori+/IH- group, mainly IL-1ß (Th1-dominant immune response), associated with a higher degree of both histological inflammation and gastric cancer risk index (GCRI), as compared to the H. pylori-/IH- group. In contrast, an increased expression of IL-4 and a reduced expression of proinflammatory cytokines (Th2-dominant response), plus the tendency to a lower degree of mononuclear infiltration, mucosal atrophy in gastric corpus, and GCRI, were evidenced in the coinfected group. CONCLUSIONS: The findings of the present study is perhaps the first histological evidence of a possible modulatory effect of IH on the gastric mucosal inflammatory response due to H. pylori infection in humans.

IL-33 is essential to prevent high-fat diet-induced obesity in mice infected with an intestinal helminth.

Intestinal helminthes induce immunosuppressive responses as well as type 2 immunity. Their suppressive properties are intended to regulate inflammatory diseases such as allergies and autoimmune diseases. This study evaluated whether helminthic infections suppress obesity, a chronic inflammatory state, using an intestinal nematode, Heligmosomoides polygyrus (Hp). Infection with Hp at the same time as feeding a high-fat diet (HFD) prevented weight gain, dyslipidaemia and glucose intolerance observed in uninfected obese mice. Immunologically, Hp infection skewed M1 macrophages to M2 macrophages and induced type 2 innate lymphoid cells in adipose tissues. The expression of interleukin (IL)-33, a potent initiator of type 2 responses, was also increased in association with uncoupled protein 1 (UCP1). To further investigate the anti-obesity effects of IL-33 in mice infected with Hp, IL-33-deficient mice were fed the HFD and infected with Hp. These mutant mice rapidly gained weight compared with wild-type mice, indicating the anti-obesity effect of IL-33. In the absence of IL-33, the rapid increase in weight was not prevented, and type 2 responses and UCP1 expression were not observed even during Hp infection. These results suggested that the suppression of obesity by Hp is dependent on IL-33.