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Lamminpää I, Boem F, Amedei A. Health-promoting worms? Prospects and pitfalls of helminth therapy. Bioessays 2024; 46:e2400080. [PMID: 39263744 DOI: 10.1002/bies.202400080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 08/28/2024] [Accepted: 09/02/2024] [Indexed: 09/13/2024]
Abstract
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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Affiliation(s)
- Ingrid Lamminpää
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Federico Boem
- Institut für Philosophie I, Ruhr-Universität Bochum, Bochum, Germany
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
- Interdisciplinary Internal Medicine Unit, Careggi University Hospital, Florence, Italy
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2
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Szuba M, Stachera W, Piwko A, Misiak M, Rutkevich R, Sota M, Atrushi L, Bennacer L, Nzekea D, Wu YC, Kim AT, Yu S, Ribeiro N, Dybicz M. Geohelminths: Use in the Treatment of Selected Human Diseases. Pathogens 2024; 13:703. [PMID: 39204303 PMCID: PMC11356798 DOI: 10.3390/pathogens13080703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 08/12/2024] [Accepted: 08/16/2024] [Indexed: 09/04/2024] Open
Abstract
Research on the therapeutic use of parasites has been ongoing since the development of the "hygiene hypothesis". Parasites can stimulate the Th2-dependent response and suppress the Th1-dependent response, which is intensified in many diseases, especially allergic and autoinflammatory ones. In this review, we present the types of parasites used in helminth therapy and the range of diseases in which they may be useful. We also present the results of clinical trials conducted so far, which confirm the safety of such therapy and provide promising outcomes.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | - Monika Dybicz
- Department of General Biology and Parasitology, Medical University of Warsaw, 02-004 Warsaw, Poland; (M.S.); (W.S.); (A.P.); (M.M.); (R.R.); (M.S.); (L.A.); (L.B.); (D.N.); (Y.C.W.); (A.T.K.); (S.Y.); (N.R.)
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D'heedene M, Vanuytsel T, Wauters L. Celiac disease: Hope for new treatments beyond a gluten-free diet. Clin Nutr 2024; 43:1240-1249. [PMID: 38648685 DOI: 10.1016/j.clnu.2024.04.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 04/02/2024] [Accepted: 04/11/2024] [Indexed: 04/25/2024]
Abstract
BACKGROUND & AIMS Celiac disease (CD) is a chronic inflammatory disease of the small intestine induced and maintained by gluten ingestion in susceptible individuals. Current treatment consists of strict adherence to a lifelong gluten-free diet (GFD) which is considered safe and effective in the large majority of patients. However, since adherence to a GFD is difficult and has a negative impact on quality of life, an increasing interest in other treatment options has emerged. Moreover, in some individuals a GFD is not sufficiently effective, necessitating alternative treatments. METHODS By performing a systematic search, we constructed a detailed narrative review. Only treatment options considered relevant and conducted in a phase I, II or III clinical trial were included. RESULTS Based on the pathophysiology of CD, four major therapeutic approaches can be distinguished: firstly, by focusing on intraluminal gluten detoxification before absorption occurs, secondly, by modulating intestinal permeability and preventing paracellular uptake, thirdly, by enhancing immunological tolerance to gluten and finally, by regulating gluten auto-immunity. CONCLUSIONS Despite significant efforts, no treatment has yet completed a phase III clinical trial. Future studies will likely focus on the use of supplemental drugs in conjunction to a GFD, with ALV003 and ZED-1227 currently being the most promising therapeutic options.
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Affiliation(s)
| | - Tim Vanuytsel
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Herestraat, 49 3000, Leuven, Belgium
| | - Lucas Wauters
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Herestraat, 49 3000, Leuven, Belgium.
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González-Fernández J, Ullate L, Fernández-Fígares V, Rodero M, Daschner A, Cuéllar C. Serum IgA contributes to the comprehension of Anisakis simplex associated chronic urticaria. Int Immunopharmacol 2024; 129:111602. [PMID: 38330800 DOI: 10.1016/j.intimp.2024.111602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 01/15/2024] [Accepted: 01/24/2024] [Indexed: 02/10/2024]
Abstract
The phenotype of allergic diseases associated with Anisakis determines the pattern of cytokines related to antibody production. However, the role of serum IgA and the immunomodulatory mechanisms exerted by active infection of L3 or passive mucosal contact with A. simplex specific antigens has not been studied before. We measured serum cytokine by flow cytometry (IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ, IL-17A, TGF-β1) and antibody levels (IgE, IgG4, IgA) by ELISA against total and excretory-secretory (ES) antigens, Ani s 3,and the group of major allergens Ani s 1, Ani s 7, and Ani s 13 in sera from 10 patients with gastro-allergic anisakiasis (GAA), 11 Anisakis sensitization associated chronic urticaria (CU+) as well as 17 non-Anisakis-sensitized patients with chronic urticaria (CU-), compared with the urticaria control group (18 subjects). Specific IgE, IgG4 and IgA were high in the GAA, but IgA levels were significantly higher in the CU+ with respect the CONTROL group. We observed higher levels of the ratio IgA/IgG4 in CU+ than GAA group for Ani s 1, Ani s 7, Ani s 13 and ES. Furthermore, chronic urticaria (CU) patients showed significant lower levels of IL-10, IFN-γ and IL-17A than patients without CU. The anti-Ani s 13 IgA/IgG4 ratio correlated positively with pro-inflammatory cytokines and ratios (TNF-α, IL-17A, Th17/Th2, Type1/Type2 and TNF-α/IL-10) in CONTROL group. In general, Anti-Anisakis IgA/G4 ratio was high in CU patients. In conclusion, this study demonstrates the importance of serum IgA because it is associated with chronic urticaria independently of Anisakis sensitization.
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Affiliation(s)
- Juan González-Fernández
- Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain.
| | - Laura Ullate
- Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Virginia Fernández-Fígares
- Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Marta Rodero
- Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Alvaro Daschner
- Instituto de Investigación Sanitaria (IIS)- Servicio de Alergia, Hospital Universitario de La Princesa, 28006 Madrid, Spain
| | - Carmen Cuéllar
- Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
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Oxford JS, Catchpole A, Mann A, Bell A, Noulin N, Gill D, Oxford JR, Gilbert A, Balasingam S. A Brief History of Human Challenge Studies (1900-2021) Emphasising the Virology, Regulatory and Ethical Requirements, Raison D'etre, Ethnography, Selection of Volunteers and Unit Design. Curr Top Microbiol Immunol 2024; 445:1-32. [PMID: 35704095 DOI: 10.1007/82_2022_253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Venetian quarantine 400 years ago was an important public health measure. Since 1900 this has been refined to include "challenge" or deliberate infection with pathogens be they viruses, bacteria, or parasites. Our focus is virology and ranges from the early experiments in Cuba with Yellow Fever Virus to the most widespread pathogen of our current times, COVID-19. The latter has so far caused over four million deaths worldwide and 190 million cases of the disease. Quarantine and challenge were also used to investigate the Spanish Influenza of 1918 which caused over 100 million deaths. We consider here the merits of the approach, that is the speeding up of knowledge in a practical sense leading to the more rapid licensing of vaccines and antimicrobials. At the core of quarantine and challenge initiatives is the design of the unit to allow safe confinement of the pathogen and protection of the staff. Most important though is the safety of volunteers. We can see now, as in 1900, that members of our society are prepared and willing to engage in these experiments for the public good. Our ethnology study, where the investigator observed the experiment from within the quarantine, gave us the first indication of changing attitudes amongst volunteers whilst in quarantine. These quarantine experiments, referred to as challenge studies, human infection studies, or "controlled human infection models" involve thousands of clinical samples taken over two to three weeks and can provide a wealth of immunological and molecular data on the infection itself and could allow the discovery of new targets for vaccines and therapeutics. The Yellow Fever studies from 121 years ago gave the impetus for development of a successful vaccine still used today whilst also uncovering the nature of the Yellow Fever agent, namely that it was a virus. We outline how carefully these experiments are approached and the necessity to have high quality units with self-contained air-flow along with extensive personal protective equipment for nursing and medical staff. Most important is the employment of highly trained scientific, medical and nursing staff. We face a future of emerging pathogens driven by the increasing global population, deforestation, climate change, antibiotic resistance and increased global travel. These emerging pathogens may be pathogens we currently are not aware of or have not caused outbreaks historically but could also be mutated forms of known pathogens including viruses such as influenza (H7N9, H5N1 etc.) and coronaviruses. This calls for challenge studies to be part of future pandemic preparedness as an additional tool to assist with the rapid development of broad-spectrum antimicrobials, immunomodulators and new vaccines.
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Affiliation(s)
- J S Oxford
- Blizzard Institute of Cell and Molecular Science, Queen Mary University of London, London, E1 2AT, UK
| | | | | | | | | | - D Gill
- Blizzard Institute of Cell and Molecular Science, Queen Mary University of London, London, E1 2AT, UK
| | - J R Oxford
- Inveresk Medical Practice, Edinburgh, E21 7BP, UK
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6
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Chakraborty P, Aravindhan V, Mukherjee S. Helminth-derived biomacromolecules as therapeutic agents for treating inflammatory and infectious diseases: What lessons do we get from recent findings? Int J Biol Macromol 2023; 241:124649. [PMID: 37119907 DOI: 10.1016/j.ijbiomac.2023.124649] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/20/2023] [Accepted: 04/24/2023] [Indexed: 05/01/2023]
Abstract
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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Affiliation(s)
- Pritha Chakraborty
- Integrative Biochemistry & Immunology Laboratory, Department of Animal Science, Kazi Nazrul University, Asansol 713340, India
| | | | - Suprabhat Mukherjee
- Integrative Biochemistry & Immunology Laboratory, Department of Animal Science, Kazi Nazrul University, Asansol 713340, India.
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Yeshi K, Ruscher R, Loukas A, Wangchuk P. Immunomodulatory and biological properties of helminth-derived small molecules: Potential applications in diagnostics and therapeutics. FRONTIERS IN PARASITOLOGY 2022; 1:984152. [PMID: 39816468 PMCID: PMC11731824 DOI: 10.3389/fpara.2022.984152] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 08/23/2022] [Indexed: 01/18/2025]
Abstract
Parasitic helminths secrete and excrete a vast array of molecules known to help skew or suppress the host's immune response, thereby establishing a niche for sustained parasite maintenance. Indeed, the immunomodulatory potency of helminths is attributed mainly to excretory/secretory products (ESPs). The ESPs of helminths and the identified small molecules (SM) are reported to have diverse biological and pharmacological properties. The available literature reports only limited metabolites, and the identity of many metabolites remains unknown due to limitations in the identification protocols and helminth-specific compound libraries. Many metabolites are known to be involved in host-parasite interactions and pathogenicity. For example, fatty acids (e.g., stearic acid) detected in the infective stages of helminths are known to have a role in host interaction through facilitating successful penetration and migration inside the host. Moreover, excreted/secreted SM detected in helminth species are found to possess various biological properties, including anti-inflammatory activities, suggesting their potential in developing immunomodulatory drugs. For example, helminths-derived somatic tissue extracts and whole crude ESPs showed anti-inflammatory properties by inhibiting the secretion of proinflammatory cytokines from human peripheral blood mononuclear cells and suppressing the pathology in chemically-induced experimental mice model of colitis. Unlike bigger molecules like proteins, SM are ideal candidates for drug development since they are small structures, malleable, and lack immunogenicity. Future studies should strive toward identifying unknown SM and isolating the under-explored niche of helminth metabolites using the latest metabolomics technologies and associated software, which hold potential keys for finding new diagnostics and novel therapeutics.
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Affiliation(s)
- Karma Yeshi
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine (AITHM), James Cook University, Cairns, QLD, Australia
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8
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Chang D, O’Shea D, Therrien A, Silvester JA. Review article: Becoming and being coeliac-special considerations for childhood, adolescence and beyond. Aliment Pharmacol Ther 2022; 56 Suppl 1:S73-S85. [PMID: 35815825 PMCID: PMC9441244 DOI: 10.1111/apt.16851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 02/10/2022] [Accepted: 02/13/2022] [Indexed: 12/09/2022]
Abstract
Classically considered a disease of early childhood characterised by malabsorption and failure to thrive, coeliac disease is now recognised to arise in genetically susceptible individuals at any age. Although permissive HLA genotypes are the strongest predictor of coeliac disease, they are not sufficient. Several prospective cohort studies enrolling genetically at-risk infants have investigated the role of potential triggers of coeliac disease autoimmunity, such as timing of gluten introduction, viral infections and dietary patterns. Much less is known about triggers of coeliac disease in adulthood. Better understanding of factors leading to coeliac disease may be helpful in the management of those with potential coeliac disease (elevated serum celiac antibodies without villous atrophy in the small intestine), many of whom initiate a gluten-free diet without demonstration of villous atrophy. There are a range of clinical presentations of celiac disease in childhood and patterns of coeliac serology, including fluctuation and spontaneous reversion on a gluten-containing diet, vary. There is a current debate over best strategies to manage adults and children with potential coeliac disease to avoid over-treatment and under-treatment. Childhood and adolescence carry unique issues pertaining to the diagnosis and management of coeliac disease, and include nutrition and growth, rescreening, repeat biopsy, dietary adherence concerns and transition to adult care. In conclusion, while coeliac disease has similar pathogenesis and general clinical manifestations in paediatric and adult populations, diagnostic and management approaches need to adapt to the developmental stages.
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Affiliation(s)
- Denis Chang
- 1. Boston Children’s Hospital, Boston, MA,2. Harvard Celiac Research Program, Harvard Medical School, Boston, MA
| | - Delia O’Shea
- 1. Boston Children’s Hospital, Boston, MA,2. Harvard Celiac Research Program, Harvard Medical School, Boston, MA
| | - Amelie Therrien
- 2. Harvard Celiac Research Program, Harvard Medical School, Boston, MA,3. Beth Israel Deaconess Medical Center, Boston, MA
| | - Jocelyn A Silvester
- 1. Boston Children’s Hospital, Boston, MA,2. Harvard Celiac Research Program, Harvard Medical School, Boston, MA,3. Beth Israel Deaconess Medical Center, Boston, MA
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Loke P, Lee SC, Oyesola OO. Effects of helminths on the human immune response and the microbiome. Mucosal Immunol 2022; 15:1224-1233. [PMID: 35732819 DOI: 10.1038/s41385-022-00532-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 05/17/2022] [Accepted: 05/22/2022] [Indexed: 02/04/2023]
Abstract
Helminths have evolved sophisticated immune regulating mechanisms to prevent rejection by their mammalian host. Our understanding of how the human immune system responds to these parasites remains poor compared to mouse models of infection and this limits our ability to develop vaccines as well as harness their unique properties as therapeutic strategies against inflammatory disorders. Here, we review how recent studies on human challenge infections, self-infected individuals, travelers, and endemic populations have improved our understanding of human type 2 immunity and its effects on the microbiome. The heterogeneity of responses between individuals and the limited access to tissue samples beyond the peripheral blood are challenges that limit human studies on helminths, but also provide opportunities to transform our understanding of human immunology. Organoids and single-cell sequencing are exciting new tools for immunological analysis that may aid this pursuit. Learning about the genetic and immunological basis of resistance, tolerance, and pathogenesis to helminth infections may thus uncover mechanisms that can be utilized for therapeutic purposes.
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Affiliation(s)
- P'ng Loke
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA.
| | - Soo Ching Lee
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Oyebola O Oyesola
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20892, USA
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10
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Shalash AO, Hussein WM, Skwarczynski M, Toth I. Hookworm infection: Toward development of safe and effective peptide vaccines. J Allergy Clin Immunol 2021; 148:1394-1419.e6. [PMID: 34872650 DOI: 10.1016/j.jaci.2021.10.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 10/07/2021] [Accepted: 10/18/2021] [Indexed: 11/28/2022]
Abstract
Hookworms are hematophagous nematode parasites that have infected a billion people worldwide. Anthelmintic drugs have limited efficacy and do not prevent reinfection. Therefore, prophylactic vaccines are in high demand. Whole parasite vaccines are allergic and unsafe; thus, research into subunit vaccines has been warranted. A comprehensive overview of protein or peptide subunit vaccines' safety, protective efficacy, and associated immune responses is provided herein. The differences between the immune responses against hookworm infection by patients from epidemic versus nonepidemic areas are discussed in detail. Moreover, the different immunologic mechanisms of protection are discussed, including those that rely on allergic and nonallergic humoral and antibody-dependent cellular responses. The allergic and autoimmune potential of hookworm antigens is also explored, as are the immunoregulatory responses induced by the hookworm secretome. The potential of oral mucosal immunizations has been overlooked. Oral immunity against hookworms is a long-lived and safer immune response that is associated with elimination of infection and protective against reinfections. However, the harsh conditions of the gastrointestinal environment necessitates special oral delivery systems to unlock vaccines' protective potential. The potential for development of safer and more effective peptide- and protein-based anthelmintic vaccines is explored herein.
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Affiliation(s)
- Ahmed O Shalash
- School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland, Australia
| | - Waleed M Hussein
- School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland, Australia
| | - Mariusz Skwarczynski
- School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland, Australia.
| | - Istvan Toth
- School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, Queensland, Australia; School of Pharmacy, The University of Queensland, Woolloongabba, Queensland, Australia.
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Chapman PR, Giacomin P, Loukas A, McCarthy JS. Experimental human hookworm infection: a narrative historical review. PLoS Negl Trop Dis 2021; 15:e0009908. [PMID: 34882670 PMCID: PMC8659326 DOI: 10.1371/journal.pntd.0009908] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
In 1896, a serendipitous laboratory accident led to the understanding that hookworms propagate infection by penetrating skin, a theory that was then confirmed with the first experimental human infection, reported in 1901. Experimental human infections undertaken in the 20th century enabled understanding of the natural history of infection and the immune response. More recently, experimental hookworm infection has been performed to investigate the immunomodulatory potential of hookworm infection and for the evaluation of hookworm vaccines and chemotherapeutic interventions. Experimental human hookworm infection has been proven to be safe, with no deaths observed in over 500 participants (although early reports predate systematic adverse event reporting) and no serious adverse events described in over 200 participants enrolled in contemporary clinical trials. While experimental human hookworm infection holds significant promise, as both a challenge model for testing anti-hookworm therapies and for treating various diseases of modernity, there are many challenges that present. These challenges include preparation and storage of larvae, which has not significantly changed since Harada and Mori first described their coproculture method in 1955. In vitro methods of hookworm larval culture, storage, and the development of meaningful potency or release assays are required. Surrogate markers of intestinal infection intensity are required because faecal egg counts or hookworm faecal DNA intensity lack the fidelity required for exploration of hookworm infection as a vaccine/drug testing platform or as a regulated therapy.
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Affiliation(s)
- Paul R. Chapman
- Clinical Tropical Medicine, QIMR Berghofer Medical Research Institute, Herston, Australia
- Infectious Diseases Unit, Royal Brisbane and Women’s Hospital, Herston, Australia
| | - Paul Giacomin
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia
| | - Alex Loukas
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia
| | - James S. McCarthy
- Clinical Tropical Medicine, QIMR Berghofer Medical Research Institute, Herston, Australia
- Infectious Diseases Unit, Royal Brisbane and Women’s Hospital, Herston, Australia
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12
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Anderson RP. Emergence of an adaptive immune paradigm to explain celiac disease: a perspective on new evidence and implications for future interventions and diagnosis. Expert Rev Clin Immunol 2021; 18:75-91. [PMID: 34767744 DOI: 10.1080/1744666x.2021.2006636] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Recent patient studies have shown that gluten-free diet is less effective in treating celiac disease than previously believed, and additionally patients remain vulnerable to gluten-induced acute symptoms and systemic cytokine release. Safe and effective pharmacological adjuncts to gluten-free diet are in preclinical and clinical development. Clear understanding of the pathogenesis of celiac disease is critical for drug target identification, establishing efficacy endpoints and to develop non-invasive biomarkers suitable to monitor and potentially diagnose celiac disease. AREAS COVERED The role and clinical effects of CD4+ T cells directed against deamidated gluten in the context of an "adaptive immune paradigm" are reviewed. Alternative hypotheses of gluten toxicity are discussed and contrasted. In the context of recent patient studies, implications of the adaptive immune paradigm for future strategies to prevent, diagnose, and treat celiac disease are outlined. EXPERT OPINION Effective therapeutics for celiac disease are likely to be approved and necessitate a variety of new clinical instruments and tests to stratify patient need, monitor remission, and confirm diagnosis in uncertain cases. Sensitive assessments of CD4+ T cells specific for deamidated gluten are likely to play a central role in clinical management, and to facilitate research and pharmaceutical development.
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Naidoo P, Ghazi T, Chuturgoon AA, Naidoo RN, Ramsuran V, Mpaka-Mbatha MN, Bhengu KN, Nembe N, Duma Z, Pillay R, Singh R, Mkhize-Kwitshana ZL. SARS-CoV-2 and helminth co-infections, and environmental pollution exposure: An epidemiological and immunological perspective. ENVIRONMENT INTERNATIONAL 2021; 156:106695. [PMID: 34171587 PMCID: PMC8205275 DOI: 10.1016/j.envint.2021.106695] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 06/02/2021] [Accepted: 06/03/2021] [Indexed: 05/17/2023]
Abstract
Soil-transmitted helminths infect billions of people globally, particularly those residing in low- and middle-income regions with poor environmental sanitation and high levels of air and water pollution. Helminths display potent immunomodulatory activity by activating T helper type 2 (Th2) anti-inflammatory and Th3 regulatory immune responses. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus that causes Coronavirus disease 2019 (COVID-19), can exacerbate Th1/Th17 pro-inflammatory cytokine production in humans, leading to a cytokine storm. Air pollutants (particulate matter, oxygen radicals, hydrocarbons and volatile organic compounds) and water pollutants (metals and organic chemicals) can also intensify Th1/Th17 immune response and could exacerbate SARS-CoV-2 related respiratory distress and failure. The present review focused on the epidemiology of SARS-CoV-2, helminths and fine particulate matter 2.5 µm or less in diameter (PM2.5) air pollution exposure in helminth endemic regions, the possible immunomodulatory activity of helminths against SARS-CoV-2 hyper-inflammatory immune response, and whether air and water pollutants can further exacerbate SARS-CoV-2 related cytokine storm and in the process hinder helminths immunomodulatory functionality. Helminth Th2/Th3 immune response is associated with reductions in lung inflammation and damage, and decreased expression levels of angiotensin-converting enzyme 2 (ACE2) receptors (SARS-CoV-2 uses the ACE2 receptors to infect cells and associated with extensive lung damage). However, air pollutants are associated with overexpression of ACE2 receptors in the epithelial cell surface of the respiratory tract and exhaustion of Th2 immune response. Helminth-induced immunosuppression activity reduces vaccination efficacy, and diminishes vital Th1 cytokine production immune responses that are crucial for combating early stage infections. This could be reversed by continuous air pollution exposure which is known to intensify Th1 pro-inflammatory cytokine production to a point where the immunosuppressive activities of helminths could be hindered. Again, suppressed activities of helminths can also be disadvantageous against SARS-CoV-2 inflammatory response. This "yin and yang" approach seems complex and requires more understanding. Further studies are warranted in a cohort of SARS-CoV-2 infected individuals residing in helminths and air pollution endemic regions to offer more insights, and to impact mass periodic deworming programmes and environmental health policies.
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Affiliation(s)
- Pragalathan Naidoo
- Department of Biological Sciences, School of Life Sciences, College of Agriculture, Engineering and Science, Westville Campus, University of KwaZulu-Natal, Westville, Durban 3629, South Africa; Department of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, Howard College, University of KwaZulu-Natal, Glenwood, Durban 4041, South Africa; Division of Research Capacity Development (RCD), South African Medical Research Council (SAMRC), Tygerberg, Cape Town 7505, South Africa.
| | - Terisha Ghazi
- Department of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, Howard College, University of KwaZulu-Natal, Glenwood, Durban 4041, South Africa
| | - Anil A Chuturgoon
- Department of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, Howard College, University of KwaZulu-Natal, Glenwood, Durban 4041, South Africa
| | - Rajen N Naidoo
- Discipline of Occupational and Environmental Health, School of Nursing and Public Health, College of Health Sciences, Howard College, University of KwaZulu-Natal, Glenwood, Durban 4041, South Africa
| | - Veron Ramsuran
- School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa
| | - Miranda N Mpaka-Mbatha
- Department of Biological Sciences, School of Life Sciences, College of Agriculture, Engineering and Science, Westville Campus, University of KwaZulu-Natal, Westville, Durban 3629, South Africa; Division of Research Capacity Development (RCD), South African Medical Research Council (SAMRC), Tygerberg, Cape Town 7505, South Africa; Department of Medical Microbiology, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, Howard College, University of KwaZulu-Natal, Glenwood, Durban 4041, South Africa; Department of Biomedical Sciences, Faculty of Natural Sciences, Mangosuthu University of Technology, Umlazi, Durban 4031, South Africa
| | - Khethiwe N Bhengu
- Department of Biological Sciences, School of Life Sciences, College of Agriculture, Engineering and Science, Westville Campus, University of KwaZulu-Natal, Westville, Durban 3629, South Africa; Division of Research Capacity Development (RCD), South African Medical Research Council (SAMRC), Tygerberg, Cape Town 7505, South Africa; Department of Medical Microbiology, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, Howard College, University of KwaZulu-Natal, Glenwood, Durban 4041, South Africa; Department of Biomedical Sciences, Faculty of Natural Sciences, Mangosuthu University of Technology, Umlazi, Durban 4031, South Africa
| | - Nomzamo Nembe
- Department of Biological Sciences, School of Life Sciences, College of Agriculture, Engineering and Science, Westville Campus, University of KwaZulu-Natal, Westville, Durban 3629, South Africa; Division of Research Capacity Development (RCD), South African Medical Research Council (SAMRC), Tygerberg, Cape Town 7505, South Africa; Department of Medical Microbiology, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, Howard College, University of KwaZulu-Natal, Glenwood, Durban 4041, South Africa; Department of Biomedical Sciences, Faculty of Natural Sciences, Mangosuthu University of Technology, Umlazi, Durban 4031, South Africa
| | - Zamathombeni Duma
- Department of Biological Sciences, School of Life Sciences, College of Agriculture, Engineering and Science, Westville Campus, University of KwaZulu-Natal, Westville, Durban 3629, South Africa; Division of Research Capacity Development (RCD), South African Medical Research Council (SAMRC), Tygerberg, Cape Town 7505, South Africa; Department of Medical Microbiology, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, Howard College, University of KwaZulu-Natal, Glenwood, Durban 4041, South Africa
| | - Roxanne Pillay
- Department of Biological Sciences, School of Life Sciences, College of Agriculture, Engineering and Science, Westville Campus, University of KwaZulu-Natal, Westville, Durban 3629, South Africa; Division of Research Capacity Development (RCD), South African Medical Research Council (SAMRC), Tygerberg, Cape Town 7505, South Africa; Department of Medical Microbiology, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, Howard College, University of KwaZulu-Natal, Glenwood, Durban 4041, South Africa; Department of Biomedical Sciences, Faculty of Natural Sciences, Mangosuthu University of Technology, Umlazi, Durban 4031, South Africa
| | - Ravesh Singh
- Department of Medical Microbiology, School of Laboratory Medicine and Medical Sciences, College of Health Sciences, Howard College, University of KwaZulu-Natal, Glenwood, Durban 4041, South Africa
| | - Zilungile L Mkhize-Kwitshana
- Department of Biological Sciences, School of Life Sciences, College of Agriculture, Engineering and Science, Westville Campus, University of KwaZulu-Natal, Westville, Durban 3629, South Africa; Division of Research Capacity Development (RCD), South African Medical Research Council (SAMRC), Tygerberg, Cape Town 7505, South Africa
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14
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Burman A, Kaji I. Luminal Chemosensory Cells in the Small Intestine. Nutrients 2021; 13:nu13113712. [PMID: 34835968 PMCID: PMC8620795 DOI: 10.3390/nu13113712] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 10/19/2021] [Accepted: 10/20/2021] [Indexed: 12/23/2022] Open
Abstract
In addition to the small intestine's well-known function of nutrient absorption, the small intestine also plays a major role in nutrient sensing. Similar to taste sensors seen on the tongue, GPCR-coupled nutrient sensors are expressed throughout the intestinal epithelium and respond to nutrients found in the lumen. These taste receptors respond to specific ligands, such as digested carbohydrates, fats, and proteins. The activation of nutrient sensors in the intestine allows for the induction of signaling pathways needed for the digestive system to process an influx of nutrients. Such processes include those related to glucose homeostasis and satiety. Defects in intestinal nutrient sensing have been linked to a variety of metabolic disorders, such as type 2 diabetes and obesity. Here, we review recent updates in the mechanisms related to intestinal nutrient sensors, particularly in enteroendocrine cells, and their pathological roles in disease. Additionally, we highlight the emerging nutrient sensing role of tuft cells and recent work using enteroids as a sensory organ model.
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Affiliation(s)
- Andreanna Burman
- Cell and Developmental Biology and Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA;
| | - Izumi Kaji
- Epithelial Biology Center and Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, TN 37232, USA
- Correspondence:
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15
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Randomized, Placebo Controlled Trial of Experimental Hookworm Infection for Improving Gluten Tolerance in Celiac Disease. Clin Transl Gastroenterol 2021; 11:e00274. [PMID: 33512796 PMCID: PMC7678792 DOI: 10.14309/ctg.0000000000000274] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION: Celiac disease is an autoimmune disorder where intestinal immunopathology arises after gluten consumption. Previous studies suggested that hookworm infection restores gluten tolerance; however, these studies were small (n = 12) and not placebo controlled. METHODS: We undertook a randomized, placebo-controlled trial of hookworm infection in 54 people with celiac disease. The 94-week study involved treatment with either 20 or 40 Necator americanus third-stage larvae (L3-20 or L3-40) or placebo, followed by escalating gluten consumption (50 mg/d for 12 weeks, 1 g intermittent twice weekly for 12 weeks, 2 g/d sustained for 6 weeks, liberal diet for 1 year). RESULTS: Successful study completion rates at week 42 (primary outcome) were similar in each group (placebo: 57%, L3-20: 37%, and L3-40: 44%; P = 0.61), however gluten-related adverse events were significantly reduced in hookworm-treated participants: Median (range) adverse events/participant were as follows: placebo, 4 (1–9); L3-20, 1 (0–9); and L3-40, 0 (0–3) (P = 0.019). Duodenal villous height:crypt depth deteriorated similarly compared with their enrolment values in each group (mean change [95% confidence interval]: placebo, −0.6 [−1.3 to 0.2]; L3-20, −0.5 [−0.8 to 0.2]; and L3-40, −1.1 [−1.8 to 0.4]; P = 0.12). A retrospective analysis revealed that 9 of the 40 L3-treated participants failed to establish hookworm infections. Although week 42 completion rates were similar in hookworm-positive vs hookworm-negative participants (48% vs 44%, P = 0.43), quality of life symptom scores were lower in hookworm-positive participants after intermittent gluten challenge (mean [95% confidence interval]: 38.9 [33.9–44] vs 45.9 [39.2–52.6]). DISCUSSION: Hookworm infection does not restore tolerance to sustained moderate consumption of gluten (2 g/d) but was associated with improved symptom scores after intermittent consumption of lower, intermittent gluten doses.
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16
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Douglas B, Oyesola O, Cooper MM, Posey A, Tait Wojno E, Giacomin PR, Herbert DR. Immune System Investigation Using Parasitic Helminths. Annu Rev Immunol 2021; 39:639-665. [PMID: 33646858 DOI: 10.1146/annurev-immunol-093019-122827] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Coevolutionary adaptation between humans and helminths has developed a finely tuned balance between host immunity and chronic parasitism due to immunoregulation. Given that these reciprocal forces drive selection, experimental models of helminth infection are ideally suited for discovering how host protective immune responses adapt to the unique tissue niches inhabited by these large metazoan parasites. This review highlights the key discoveries in the immunology of helminth infection made over the last decade, from innate lymphoid cells to the emerging importance of neuroimmune connections. A particular emphasis is placed on the emerging areas within helminth immunology where the most growth is possible, including the advent of genetic manipulation of parasites to study immunology and the use of engineered T cells for therapeutic options. Lastly,we cover the status of human challenge trials with helminths as treatment for autoimmune disease, which taken together, stand to keep the study of parasitic worms at the forefront of immunology for years to come.
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Affiliation(s)
- Bonnie Douglas
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; ,
| | - Oyebola Oyesola
- Department of Immunology, University of Washington, Seattle, Washington 98109, USA; ,
| | - Martha M Cooper
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland 4878, Australia; ,
| | - Avery Posey
- Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; .,Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.,Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania 19104, USA
| | - Elia Tait Wojno
- Department of Immunology, University of Washington, Seattle, Washington 98109, USA; ,
| | - Paul R Giacomin
- Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland 4878, Australia; ,
| | - De'Broski R Herbert
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; ,
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17
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Fiuza BSD, Fonseca HF, Meirelles PM, Marques CR, da Silva TM, Figueiredo CA. Understanding Asthma and Allergies by the Lens of Biodiversity and Epigenetic Changes. Front Immunol 2021; 12:623737. [PMID: 33732246 PMCID: PMC7957070 DOI: 10.3389/fimmu.2021.623737] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Accepted: 02/08/2021] [Indexed: 12/12/2022] Open
Abstract
Exposure to different organisms (bacteria, mold, virus, protozoan, helminths, among others) can induce epigenetic changes affecting the modulation of immune responses and consequently increasing the susceptibility to inflammatory diseases. Epigenomic regulatory features are highly affected during embryonic development and are responsible for the expression or repression of different genes associated with cell development and targeting/conducting immune responses. The well-known, "window of opportunity" that includes maternal and post-natal environmental exposures, which include maternal infections, microbiota, diet, drugs, and pollutant exposures are of fundamental importance to immune modulation and these events are almost always accompanied by epigenetic changes. Recently, it has been shown that these alterations could be involved in both risk and protection of allergic diseases through mechanisms, such as DNA methylation and histone modifications, which can enhance Th2 responses and maintain memory Th2 cells or decrease Treg cells differentiation. In addition, epigenetic changes may differ according to the microbial agent involved and may even influence different asthma or allergy phenotypes. In this review, we discuss how exposure to different organisms, including bacteria, viruses, and helminths can lead to epigenetic modulations and how this correlates with allergic diseases considering different genetic backgrounds of several ancestral populations.
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Affiliation(s)
| | | | - Pedro Milet Meirelles
- Instituto de Biologia, Universidade Federal da Bahia, Salvador, Brazil
- Instituto Nacional de Ciência e Tecnologia em Estudos Interdisciplinares e Transdisciplinares em Ecologia e Evolução (IN-TREE), Salvador, Brazil
| | - Cintia Rodrigues Marques
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista, Brazil
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18
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Rennie C, Fernandez R, Donnelly S, McGrath KCY. The Impact of Helminth Infection on the Incidence of Metabolic Syndrome: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne) 2021; 12:728396. [PMID: 34456879 PMCID: PMC8397462 DOI: 10.3389/fendo.2021.728396] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 07/20/2021] [Indexed: 12/30/2022] Open
Abstract
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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Affiliation(s)
- Claire Rennie
- School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia
| | - Ritin Fernandez
- School of Nursing, University of Wollongong, Wollongong, NSW, Australia
- Centre for Research in Nursing and Health, St George Hospital, Sydney, NSW, Australia
- Centre for Evidence Based Initiatives in Health Care a JBI Centre of Excellence, Sydney, NSW, Australia
| | - Sheila Donnelly
- School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia
- *Correspondence: Kristine CY McGrath, ; Sheila Donnelly,
| | - Kristine CY McGrath
- School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia
- *Correspondence: Kristine CY McGrath, ; Sheila Donnelly,
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19
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Ducarmon QR, Hoogerwerf MA, Janse JJ, Geelen AR, Koopman JPR, Zwittink RD, Goeman JJ, Kuijper EJ, Roestenberg M. Dynamics of the bacterial gut microbiota during controlled human infection with Necator americanus larvae. Gut Microbes 2020; 12:1-15. [PMID: 33222610 PMCID: PMC7714523 DOI: 10.1080/19490976.2020.1840764] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Hookworms are soil-transmitted helminths that use immune-evasive strategies to persist in the human duodenum where they are responsible for anemia and protein loss. Given their location and immune regulatory effects, hookworms likely impact the bacterial microbiota. However, microbiota studies struggle to deconvolute the effect of hookworms from confounders such as coinfections and malnutrition. We thus used an experimental human hookworm infection model to explore temporal changes in the gut microbiota before and during hookworm infection. Volunteers were dermally exposed to cumulative dosages of 50, 100 or 150 L3 Necator americanus larvae. Fecal samples were collected for microbiota profiling through 16S rRNA gene amplicon sequencing at weeks zero, four, eight, fourteen and twenty. During the acute infection phase (trial week zero to eight) no changes in bacterial diversity were detected. During the established infection phase (trial week eight to twenty), bacterial richness (Chao1, p = .0174) increased significantly over all volunteers. No relation was found between larval dosage and diversity, stability or relative abundance of individual bacterial taxa. GI symptoms were associated with an unstable microbiota during the first eight weeks and rapid recovery at week twenty. Barnesiella, amongst other taxa, was more abundant in volunteers with more GI symptoms throughout the study. In conclusion, this study showed that clinical GI symptoms following N. americanus infection are associated with temporary microbiota instability and relative abundance of specific bacterial taxa. These results suggest a possible role of hookworm-induced enteritis on microbiota stability.
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Affiliation(s)
- Q. R. Ducarmon
- Center for Microbiome Analyses and Therapeutics, Leiden University Medical Center, Leiden, The Netherlands,Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands,CONTACT Meta Roestenberg Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands; Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands
| | - M. A. Hoogerwerf
- Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands
| | - J. J. Janse
- Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands
| | - A. R. Geelen
- Center for Microbiome Analyses and Therapeutics, Leiden University Medical Center, Leiden, The Netherlands,Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
| | - J. P. R. Koopman
- Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands
| | - R. D. Zwittink
- Center for Microbiome Analyses and Therapeutics, Leiden University Medical Center, Leiden, The Netherlands,Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
| | - J. J. Goeman
- Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, Netherlands
| | - E. J. Kuijper
- Center for Microbiome Analyses and Therapeutics, Leiden University Medical Center, Leiden, The Netherlands,Department of Medical Microbiology, Leiden University Medical Center, Leiden, The Netherlands
| | - M. Roestenberg
- Department of Parasitology, Leiden University Medical Center, Leiden, The Netherlands,Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands
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20
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Mourão Dias Magalhães L, Silva Araújo Passos L, Toshio Fujiwara R, Lacerda Bueno L. Immunopathology and modulation induced by hookworms: From understanding to intervention. Parasite Immunol 2020; 43:e12798. [PMID: 33012113 DOI: 10.1111/pim.12798] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 08/21/2020] [Accepted: 09/25/2020] [Indexed: 12/15/2022]
Abstract
Hookworm infection is considered the most prevalent human soil-transmitted helminth infection affecting approximately 500 million people and accounting for 3.2 million disability-adjusted life years lost annually. As with many other neglected tropical diseases, no international surveillance mechanisms that show accurate data on the prevalence of hookworm infection are in place, thus hindering strategies to control parasite transmission. In this review, we unravel the current knowledge in immunopathology and immunoregulation of hookworm infection and present discoveries in drug therapies based on the capability of hookworms to regulate inflammation to treat allergic, inflammatory and metabolic diseases. Additionally, we highlight potential vaccine development and treatments and propose avenues for further inquiry.
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Affiliation(s)
| | - Livia Silva Araújo Passos
- Department of Parasitology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Ricardo Toshio Fujiwara
- Department of Parasitology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Lilian Lacerda Bueno
- Department of Parasitology, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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21
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Cepon-Robins TJ, Gildner TE. Old friends meet a new foe: A potential role for immune-priming parasites in mitigating COVID-19 morbidity and mortality. Evol Med Public Health 2020; 2020:234-248. [PMID: 33235797 PMCID: PMC7665448 DOI: 10.1093/emph/eoaa037] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 10/07/2020] [Indexed: 02/06/2023] Open
Abstract
The novel virus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and the associated Coronavirus Disease 2019 (COVID-19) represent a pathogen to which human beings have limited to no evolved immune response. The most severe symptoms are associated with overactive inflammatory immune responses, leading to a cytokine storm, tissue damage, and death, if not balanced and controlled. Hypotheses within Evolutionary Medicine, including the Hygiene/Old Friends Hypothesis, provide an important lens through which to understand and possibly control this overactive immune response. In this article, we explore the role that infection with soil-transmitted helminths (STHs; i.e. intestinal parasitic worms) may play in dampening SARS-CoV-2 symptoms and mitigating the worst COVID-19 outcomes. Specifically, STHs stimulate the immunosuppressive and regulatory T-helper 2 (TH2) branch of the immune system, which decreases ACE2-receptor expression (i.e. receptors SARS-CoV-2 uses to infect host cells), balances the inflammatory TH1/TH17 branches of the immune system triggered by SARS-CoV-2 infection, and reduces inflammation through the release of anti-inflammatory/regulatory cytokines. Because STHs are common and affect the most vulnerable and marginalized members of society, it is especially important to consider how these parasites may impact COVID-19 outcomes. Areas experiencing endemic STH infections are often characterized by a lack of preventative infrastructure and medical care, which may further exacerbate risk of SARS-CoV-2 infection and COVID-19 development. For this reason, we also explore biocultural factors that contribute to disease outcomes for both SARS-CoV-2 and STH infections. Biocultural and Evolutionary Medicine perspectives on COVID-19 are crucial for understanding the global impact of the disease. Lay summary: An evolutionary perspective is required to understand the global impact and various presentations of COVID-19. We consider how coinfection with soil-transmitted helminths (common parasitic worms that coevolved with humans) may suppress inflammatory immune activity, thereby potentially reducing COVID-19 disease severity. Structural and lifestyle factors shaping coinfection patterns are also discussed.
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Affiliation(s)
- Tara J Cepon-Robins
- Department of Anthropology, University of Colorado Colorado Springs, Centennial Hall 120, 1420 Austin Bluffs Parkway, Colorado Springs, CO 80918, USA
| | - Theresa E Gildner
- Department of Anthropology, Dartmouth College, Silsby Hall, 3 Tuck Drive, Hanover, NH 03755, USA
- Department of Anthropology, Washington University, Campus Box 1114, One Brookings Drive, St. Louis, MO 63130, USA
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22
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Serena G, D'Avino P, Fasano A. Celiac Disease and Non-celiac Wheat Sensitivity: State of Art of Non-dietary Therapies. Front Nutr 2020; 7:152. [PMID: 33015123 PMCID: PMC7506149 DOI: 10.3389/fnut.2020.00152] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 07/28/2020] [Indexed: 12/12/2022] Open
Abstract
Gluten related disorders (GRD), which include celiac disease, non-celiac wheat sensitivity and wheat allergy are heterogeneous conditions triggered by ingestion of gluten-containing grains. Together, their prevalence is estimated to be ~5% in the general population, however, in the last years the number of diagnoses has been rapidly increasing. To this day, the gold standard treatment for these disorders is the complete removal of gluten-containing grains from the diet. Although this therapy results effective in the majority of patients, up to 30% of individuals affected by GRD continue to present persistent symptoms. In addition, gluten-free diet has been shown to have poor nutritional quality and to cause a socio-economic burden in patients' quality of life. In order to respond to these issues, the scientific community has been focusing on finding additional and adjuvant non-dietary therapies. In this review, we focus on two main gluten related disorders, celiac disease and non-celiac wheat sensitivity. We delineate the actual knowledge about potential treatments and their relative efficacy in pre-clinical and clinical trials.
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Affiliation(s)
- Gloria Serena
- Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, United States
| | - Paolo D'Avino
- Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, United States.,Vita-Salute San Raffaele University, Milan, Italy
| | - Alessio Fasano
- Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, United States.,European Biomedical Research Institute of Salerno (EBRIS), Salerno, Italy
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23
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White MPJ, McManus CM, Maizels RM. Regulatory T-cells in helminth infection: induction, function and therapeutic potential. Immunology 2020; 160:248-260. [PMID: 32153025 PMCID: PMC7341546 DOI: 10.1111/imm.13190] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 03/04/2020] [Accepted: 03/05/2020] [Indexed: 12/11/2022] Open
Abstract
Helminth parasites infect an alarmingly large proportion of the world's population, primarily within tropical regions, and their ability to down‐modulate host immunity is key to their persistence. Helminths have developed multiple mechanisms that induce a state of hyporesponsiveness or immune suppression within the host; of particular interest are mechanisms that drive the induction of regulatory T‐cells (Tregs). Helminths actively induce Tregs either directly by secreting factors, such as the TGF‐β mimic Hp‐TGM, or indirectly by interacting with bystander cell types such as dendritic cells and macrophages that then induce Tregs. Expansion of Tregs not only enhances parasite survival but, in cases such as filarial infection, Tregs also play a role in preventing parasite‐associated pathologies. Furthermore, Tregs generated during helminth infection have been associated with suppression of bystander immunopathologies in a range of inflammatory conditions such as allergy and autoimmune disease. In this review, we discuss evidence from natural and experimental infections that point to the pathways and molecules involved in helminth Treg induction, and postulate how parasite‐derived molecules and/or Tregs might be applied as anti‐inflammatory therapies in the future.
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Affiliation(s)
- Madeleine P J White
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Caitlin M McManus
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
| | - Rick M Maizels
- Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK
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24
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Huh WJ, Roland JTE, Asai M, Kaji I. Distribution of duodenal tuft cells is altered in pediatric patients with acute and chronic enteropathy. Biomed Res 2020; 41:113-118. [PMID: 32307399 PMCID: PMC10037909 DOI: 10.2220/biomedres.41.113] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Clinical interest into the function of tuft cells in human intestine has increased in recent years. However, no quantitative study has examined intestinal tuft cells in pathological specimens from patients. This study quantified tuft cell density by using a recently identified marker, specific for tyrosine phosphorylation (pY1798) of girdin (also known as CCDC88A or GIV) in the duodenum of pediatric patients. Deidentified sections with pathological diagnosis of acute duodenitis, ulcer, or celiac disease, and age-matched normal control were analyzed under double-blind conditions. Immunostaining for pY1798-girdin demonstrated the distinct shape of tuft cells with and filopodia-like basolateral membrane structure and a small apical area, which densely expressed gamma-actin. As compared to normal tissues, the specimens diagnosed as celiac disease and duodenal ulcer had significantly fewer tuft cell numbers. In contrast, acute duodenitis showed varied population of tuft cells. The mucosa with severe inflammation showed lower tuft cell numbers than the specimens with none to mild inflammation. These results suggest that loss of tuft cells may be involved in prolonged inflammation in the duodenal mucosa and disrupted mucosal integrity. pY1798-girdin and gamma-actin are useful markers for investigating the distribution and morphologies of human intestinal tuft cells under healthy and pathological conditions.
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Affiliation(s)
- Won Jae Huh
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Joseph TE Roland
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Masato Asai
- Institute for Developmental Research, Aichi Developmental Disability Center, Kasugai, Japan
| | - Izumi Kaji
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, TN, USA
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25
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Abdoli A, Mirzaian Ardakani H. Potential application of helminth therapy for resolution of neuroinflammation in neuropsychiatric disorders. Metab Brain Dis 2020; 35:95-110. [PMID: 31352539 DOI: 10.1007/s11011-019-00466-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 07/14/2019] [Indexed: 12/19/2022]
Abstract
Neuropsychiatric disorders (NPDs) are among the major debilitating disorders worldwide with multiple etiological factors. However, in recent years, psychoneuroimmunology uncovered the role of inflammatory condition and autoimmune disorders in the etiopathogenesis of different NPDs. Hence, resolution of inflammation is a new therapeutic target of NPDs. On the other hand, Helminth infections are among the most prevalent infectious diseases in underdeveloped countries, which usually caused chronic infections with minor clinical symptoms. Remarkably, helminths are among the master regulator of inflammatory reactions and epidemiological studies have shown an inverse association between prevalence of autoimmune disorders with these infections. As such, changes of intestinal microbiota are known to be associated with inflammatory conditions in various NPDs. Conversely, helminth colonization alters the intestinal microbiota composition that leads to suppression of intestinal inflammation. In animal models and human studies, helminths or their antigens have shown to be protected against severe autoimmune and allergic disorders, decline the intensity of inflammatory reactions and improved clinical symptoms of the patients. Therefore, "helminthic therapy" have been used for modulation of immune disturbances in different autoimmunity illnesses, such as Multiple Sclerosis (MS) and Inflammatory Bowel Disease (IBD). Here, it is proposed that "helminthic therapy" is able to ameliorate neuroinflammation of NPDs through immunomodulation of inflammatory reactions and alteration of microbiota composition. This review discusses the potential application of "helminthic therapy" for resolution of neuroinflammation in NPDs.
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Affiliation(s)
- Amir Abdoli
- Department of Parasitology and Mycology, School of Medicine, Jahrom University of Medical Sciences, POBox 74148-46199, Ostad Motahari Ave, Jahrom, Iran.
- Zoonoses Research Center, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran.
- Research Center for Noncommunicable Diseases, School of Medicine, Jahrom University of Medical Sciences, Jahrom, Iran.
| | - Hoda Mirzaian Ardakani
- Department of Parasitology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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26
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Shariati A, Aslani HR, Shayesteh MR, Taghipour A, Nasser A, Safari H, Alizade-Sani M, Dehghan A, Azimi T. Are Viruses and Parasites Linked to Celiac Disease? A Question that Still has no Definite Answer. Curr Pharm Biotechnol 2019; 20:1181-1193. [PMID: 31456516 DOI: 10.2174/1389201020666190828124924] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 07/01/2019] [Accepted: 08/07/2019] [Indexed: 12/17/2022]
Abstract
Celiac Disease (CD) is a complex autoimmune enteropathy of the small intestine that commonly
occurs in genetically predisposed individuals due to intake of gluten and related proteins. Gluten
consumption, duration of breast-feeding, various infections, especially frequent intestinal infections,
vaccinations and use of antibiotics can be linked to CD. It is predicted that it affects 1% of the
global population and its incidence rate is increasing. Most of the people with the HLA-DQ2 or HLADQ8
are at a higher risk of developing this disease. The link between infections and autoimmune diseases
has been very much considered in recent years. In several studies, we explained that pathogenic
and non-pathogenic microorganisms might have multiple roles in initiation, exacerbation, and development
of Irritable Bowel Syndrome (IBS) and Inflammatory Bowel Disease (IBD). In various studies,
the relationship between infections caused by viruses, such as Epstein-Barr Virus (EBV), Rotavirus,
Hepatitis C (HCV), Hepatitis B virus (HBV), Cytomegalovirus (CMV), and Influenza virus, and parasites
including Giardia spp. and Toxoplasma gondii with CD has been raised. However, increasing evidence
proposes that some of these microorganisms, especially helminths, can also have protective and
even therapeutic roles in the CD process. Therefore, in order to determine the role of microorganisms
in the process of this disease, we attempted to summarize the evidence suggesting the role of viral and
parasitic agents in pathogenesis of CD.
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Affiliation(s)
- Aref Shariati
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hamid R. Aslani
- Department of Clinical Pharmacy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad R.H. Shayesteh
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Taghipour
- Department of Parasitology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Ahmad Nasser
- Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Safari
- Health Promotion Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mahmood Alizade-Sani
- Food Safety and Hygiene Division, Environmental Health Department, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Amin Dehghan
- Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Taher Azimi
- Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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Gazzinelli-Guimaraes PH, de Queiroz Prado R, Ricciardi A, Bonne-Année S, Sciurba J, Karmele EP, Fujiwara RT, Nutman TB. Allergen presensitization drives an eosinophil-dependent arrest in lung-specific helminth development. J Clin Invest 2019; 129:3686-3701. [PMID: 31380805 DOI: 10.1172/jci127963] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 06/11/2019] [Indexed: 12/11/2022] Open
Abstract
This study investigates the relationship between helminth infection and allergic sensitization by assessing the influence of preexisting allergy on the outcome of helminth infections, rather than the more traditional approach in which the helminth infection precedes the onset of allergy. Here we used a murine model of house dust mite-induced (HDM-induced) allergic inflammation followed by Ascaris infection to demonstrate that allergic sensitization drives an eosinophil-rich pulmonary type 2 immune response (Th2 cells, M2 macrophages, type 2 innate lymphoid cells, IL-33, IL-4, IL-13, and mucus) that directly hinders larval development and reduces markedly the parasite burden in the lungs. This effect is dependent on the presence of eosinophils, as eosinophil-deficient mice were unable to limit parasite development or numbers. In vivo administration of neutralizing antibodies against CD4 prior to HDM sensitization significantly reduced eosinophils in the lungs, resulting in the reversal of the HDM-induced Ascaris larval killing. Our data suggest that HDM allergic sensitization drives a response that mimics a primary Ascaris infection, such that CD4+ Th2-mediated eosinophil-dependent helminth larval killing in the lung tissue occurs. This study provides insight into the mechanisms underlying tissue-specific responses that drive a protective response against the early stages of the helminths prior to their establishing long-lasting infections in the host.
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Affiliation(s)
- Pedro H Gazzinelli-Guimaraes
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Rafael de Queiroz Prado
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Alessandra Ricciardi
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Sandra Bonne-Année
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Joshua Sciurba
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Erik P Karmele
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA.,Institute for Biomedical Sciences, The George Washington University, Washington, DC, USA
| | - Ricardo T Fujiwara
- Department of Parasitology, Institute of Biological Sciences (ICB), Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Thomas B Nutman
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
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Cepon‐Robins TJ, Gildner TE, Schrock J, Eick G, Bedbury A, Liebert MA, Urlacher SS, Madimenos FC, Harrington CJ, Amir D, Bribiescas RG, Sugiyama LS, Snodgrass JJ. Soil‐transmitted helminth infection and intestinal inflammation among the Shuar of Amazonian Ecuador. AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY 2019; 170:65-74. [DOI: 10.1002/ajpa.23897] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Revised: 06/18/2019] [Accepted: 06/19/2019] [Indexed: 12/26/2022]
Affiliation(s)
| | | | - Joshua Schrock
- Department of Anthropology University of Oregon Eugene Oregon
| | - Geeta Eick
- Department of Anthropology University of Oregon Eugene Oregon
| | - Ali Bedbury
- Department of Anthropology University of Oregon Eugene Oregon
| | - Melissa A. Liebert
- Department of Anthropology Northern Arizona University Flagstaff Arizona
| | - Samuel S. Urlacher
- Department of Evolutionary Anthropology Duke University Durham North Carolina
- Department of Anthropology Baylor University Waco Texas
| | - Felicia C. Madimenos
- Department of Anthropology Queens College ‐ City University of New York Queens New York
| | | | - Dorsa Amir
- Department of Psychology Boston College Chestnut Hill Massachusetts
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Hookworm-Derived Metabolites Suppress Pathology in a Mouse Model of Colitis and Inhibit Secretion of Key Inflammatory Cytokines in Primary Human Leukocytes. Infect Immun 2019; 87:IAI.00851-18. [PMID: 30670556 DOI: 10.1128/iai.00851-18] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 01/15/2019] [Indexed: 12/13/2022] Open
Abstract
Iatrogenic hookworm therapy shows promise for treating disorders that result from a dysregulated immune system, including inflammatory bowel disease (IBD). Using a murine model of trinitrobenzenesulfonic acid-induced colitis and human peripheral blood mononuclear cells, we demonstrated that low-molecular-weight metabolites derived from both somatic extracts (LMWM-SE) and excretory-secretory products (LMWM-ESP) of the hookworm, Ancylostoma caninum, display anti-inflammatory properties. Administration to mice of LMWM-ESP as well as sequentially extracted fractions of LMWM-SE using both methanol (SE-MeOH) and hexane-dichloromethane-acetonitrile (SE-HDA) resulted in significant protection against T cell-mediated immunopathology, clinical signs of colitis, and impaired histological colon architecture. To assess bioactivity in human cells, we stimulated primary human leukocytes with lipopolysaccharide in the presence of hookworm extracts and showed that SE-HDA suppressed ex vivo production of inflammatory cytokines. Gas chromatography-mass spectrometry (MS) and liquid chromatography-MS analyses revealed the presence of 46 polar metabolites, 22 fatty acids, and five short-chain fatty acids (SCFAs) in the LMWM-SE fraction and 29 polar metabolites, 13 fatty acids, and six SCFAs in the LMWM-ESP fraction. Several of these small metabolites, notably the SCFAs, have been previously reported to have anti-inflammatory properties in various disease settings, including IBD. This is the first report showing that hookworms secrete small molecules with both ex vivo and in vivo anti-inflammatory bioactivity, and this warrants further exploration as a novel approach to the development of anti-inflammatory drugs inspired by coevolution of gut-dwelling hookworms with their vertebrate hosts.
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30
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Salvucci E. The human-microbiome superorganism and its modulation to restore health. Int J Food Sci Nutr 2019; 70:781-795. [DOI: 10.1080/09637486.2019.1580682] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- E. Salvucci
- Instituto de Ciencia y Tecnología de Alimentos Córdoba (ICYTAC-CONICET-UNC), Córdoba, Argentina
- Facultad de Ciencias Exactas, Físicas y Naturales; Facultad de Ciencias Agropecuarias, Universidad Nacional de Córdoba, Córdoba
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Abstract
Helminth parasites are complex metazoans that belong to different taxonomic families but that collectively share the capacity to downregulate the host immune response directed toward themselves (parasite-specific immunoregulation). During long-standing chronic infection, these helminths appear able to suppress immune responses to bystander pathogens/antigens and atopic, autoimmune, and metabolic disorders. Helminth-induced immunoregulation occurs through the induction of regulatory T cells or Th2-type cells (or both). However, secreted or excreted parasite metabolites, proteins, or extracellular vesicles (or a combination of these) may also directly induce signaling pathways in host cells. Therefore, the focus of this review will be to highlight recent advances in understanding the immune responses to helminth infection, emphasizing the strategies/molecules and some of the mechanisms used by helminth parasites to modulate the immune response of their hosts.
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Affiliation(s)
- Pedro H Gazzinelli-Guimaraes
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 4 Center Drive, Building 4, Room 211, Bethesda, MD, 20892, USA
| | - Thomas B Nutman
- Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 4 Center Drive, Building 4, Room 211, Bethesda, MD, 20892, USA
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32
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McSorley HJ, Chayé MAM, Smits HH. Worms: Pernicious parasites or allies against allergies? Parasite Immunol 2018; 41:e12574. [PMID: 30043455 PMCID: PMC6585781 DOI: 10.1111/pim.12574] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 07/13/2018] [Accepted: 07/18/2018] [Indexed: 12/14/2022]
Abstract
Type 2 immune responses are most commonly associated with allergy and helminth parasite infections. Since the discovery of Th1 and Th2 immune responses more than 30 years ago, models of both allergic disease and helminth infections have been useful in characterizing the development, effector mechanisms and pathological consequences of type 2 immune responses. The observation that some helminth infections negatively correlate with allergic and inflammatory disease led to a large field of research into parasite immunomodulation. However, it is worth noting that helminth parasites are not always benign infections, and that helminth immunomodulation can have stimulatory as well as suppressive effects on allergic responses. In this review, we will discuss how parasitic infections change host responses, the consequences for bystander immunity and how this interaction influences clinical symptoms of allergy.
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Affiliation(s)
- Henry J McSorley
- MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Mathilde A M Chayé
- Department of Parasitology, Leiden Immunology of Parasitic Infections Group, Leiden University Medical Centre, ZA Leiden, The Netherlands
| | - Hermelijn H Smits
- Department of Parasitology, Leiden Immunology of Parasitic Infections Group, Leiden University Medical Centre, ZA Leiden, The Netherlands
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33
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Diemert DJ, Bottazzi ME, Plieskatt J, Hotez PJ, Bethony JM. Lessons along the Critical Path: Developing Vaccines against Human Helminths. Trends Parasitol 2018; 34:747-758. [PMID: 30064902 DOI: 10.1016/j.pt.2018.07.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 07/09/2018] [Accepted: 07/10/2018] [Indexed: 12/16/2022]
Abstract
Helminthic parasites are important targets for vaccine research as they infect an estimated 1 billion people worldwide. Despite significant progress in the discovery of defined antigens as candidates for vaccines, the potential of a helminth vaccine advancing to an investigational product to be tested in humans remains as challenging as it did 50 years ago. Candidate helminth vaccines must still advance along a 'critical path' of preclinical research, vaccine process development (which includes 'chemistry, manufacturing, and controls' or CMC), current good manufacturing practice (cGMP) production of the vaccine, and clinical trials. This path is highly targeted towards meeting the safety, immunogenicity, and efficacy criteria of regulatory bodies such as the US Food and Drug Administration (FDA). For nearly 20 years our product development partnership (PDP), the Texas Children's Hospital Center for Vaccine Development (TCH-CVD), has followed the critical paths of several novel subunit vaccines for the human hookworm Necator americanus and the intestinal trematode Schistosoma mansoni. Herein, we describe the critical lessons learned along this critical path.
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Affiliation(s)
- David J Diemert
- Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University, Washington DC, USA; Department of Medicine, The George Washington University, Washington DC, USA; Texas Children's Hospital Center for Vaccine Development - a Product Development Partnership, Houston, TX, USA
| | - Maria Elena Bottazzi
- Departments of Pediatrics and Molecular Virology and Microbiology, National School of Tropical Medicine, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA; Department of Biology, Baylor University, Waco, TX, USA; Texas Children's Hospital Center for Vaccine Development - a Product Development Partnership, Houston, TX, USA
| | - Jordan Plieskatt
- Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University, Washington DC, USA; Texas Children's Hospital Center for Vaccine Development - a Product Development Partnership, Houston, TX, USA
| | - Peter J Hotez
- Departments of Pediatrics and Molecular Virology and Microbiology, National School of Tropical Medicine, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA; Department of Biology, Baylor University, Waco, TX, USA; Texas Children's Hospital Center for Vaccine Development - a Product Development Partnership, Houston, TX, USA
| | - Jeffrey M Bethony
- Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University, Washington DC, USA; Texas Children's Hospital Center for Vaccine Development - a Product Development Partnership, Houston, TX, USA.
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Diemert D, Campbell D, Brelsford J, Leasure C, Li G, Peng J, Zumer M, Younes N, Bottazzi ME, Mejia R, Pritchard DI, Hawdon JM, Bethony JM. Controlled Human Hookworm Infection: Accelerating Human Hookworm Vaccine Development. Open Forum Infect Dis 2018; 5:ofy083. [PMID: 29780848 PMCID: PMC5952933 DOI: 10.1093/ofid/ofy083] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 04/16/2018] [Indexed: 11/14/2022] Open
Abstract
Background Controlled human hookworm infection (CHHI) is a central component of a proposed hookworm vaccination-challenge model (HVCM) to test the efficacy of candidate vaccines. Critical to CHHI is the manufacture of Necator americanus infective larvae (NaL3) according to current Good Manufacturing Practice (cGMP) and the determination of an inoculum of NaL3 that is safe and reliably induces patent infection. Methods cGMP-grade NaL3 were produced for a phase 1 trial in 20 healthy, hookworm-naïve adults in the United States, who received either 25 or 50 NaL3. Participants were monitored for 12–18 weeks postinfection for safety, tolerability, and patency of N. americanus infection. Results Both NaL3 doses were well tolerated. Early manifestations of infection included pruritus, pain, and papulovesicular rash at the application site. Gastrointestinal symptoms and eosinophilia appeared after week 4 postinfection. The 50 NaL3 inoculum induced patent N. americanus infection in 90% of this dose group. Conclusions The inoculum of 50 NaL3 was well tolerated and consistently induced patent N. americanus infection suitable for future HVCM trials. Clinical Trials Registration NCT01940757.
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Affiliation(s)
- David Diemert
- Department of Microbiology, Immunology and Tropical Medicine, Washington DC.,Department of Medicine, Washington DC
| | - Doreen Campbell
- Department of Microbiology, Immunology and Tropical Medicine, Washington DC
| | - Jill Brelsford
- Department of Microbiology, Immunology and Tropical Medicine, Washington DC
| | - Caitlyn Leasure
- Department of Microbiology, Immunology and Tropical Medicine, Washington DC
| | - Guangzhao Li
- Department of Microbiology, Immunology and Tropical Medicine, Washington DC
| | - Jin Peng
- Department of Microbiology, Immunology and Tropical Medicine, Washington DC
| | | | - Naji Younes
- Milken Institute School of Public Health, The George Washington University, Washington DC
| | - Maria Elena Bottazzi
- Department of Pediatrics, Section of Pediatric Tropical Medicine, Texas Children's Hospital Center for Vaccine Development, National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas
| | - Rojelio Mejia
- Department of Pediatrics, Section of Pediatric Tropical Medicine, Texas Children's Hospital Center for Vaccine Development, National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas
| | - David I Pritchard
- Department of Pharmacy, University of Nottingham, Nottingham, United Kingdom
| | - John M Hawdon
- Department of Microbiology, Immunology and Tropical Medicine, Washington DC
| | - Jeffrey M Bethony
- Department of Microbiology, Immunology and Tropical Medicine, Washington DC
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35
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Haridy J, Lewis D, Newnham ED. Investigational drug therapies for coeliac disease - where to from here? Expert Opin Investig Drugs 2018; 27:225-233. [PMID: 29411655 DOI: 10.1080/13543784.2018.1438407] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
INTRODUCTION Despite decades of research and a detailed knowledge of the immunopathological basis of coeliac disease (CD), adherence to a lifelong gluten-free diet (GFD) remains the single proven and available treatment. The increasing prevalence of CD combined with variable adherence to the GFD in a significant proportion of patients demands new therapeutic strategies. AREAS COVERED Trial registries, clinicaltrials.gov, pharmaceutical company website searches as well as published data from PubMed and conference proceedings were used to extract the most recent outcomes for CD therapeutics. This article aims to review the available therapies from a pathophysiological approach, and propose future directions in this interesting yet largely unfulfilled area of research. EXPERT OPINION Increasingly, the GFD is being challenged by its availability, palatability, practicality and now even efficacy in some populations. Whilst the causative antigens have been well described, it is clear that treatment based on the removal of these immunostimulatory peptides from the diet is far more complex than early experience in CD treatment implied. Despite burgeoning interest and research in experimental therapies for CD over the past twenty years, the only therapy showing promise as a true alternative to a GFD is that of the induction of tolerance via a vaccine.
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Affiliation(s)
- James Haridy
- a Department of Gastroenterology and Hepatology , Monash University, Eastern Health Clinical School , Melbourne , Australia
| | - Diana Lewis
- a Department of Gastroenterology and Hepatology , Monash University, Eastern Health Clinical School , Melbourne , Australia
| | - Evan D Newnham
- a Department of Gastroenterology and Hepatology , Monash University, Eastern Health Clinical School , Melbourne , Australia
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36
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Roestenberg M, Mo A, Kremsner PG, Yazdanbakhsh M. Controlled human infections: A report from the controlled human infection models workshop, Leiden University Medical Centre 4-6 May 2016. Vaccine 2017; 35:7070-7076. [PMID: 29162320 DOI: 10.1016/j.vaccine.2017.10.092] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Revised: 10/30/2017] [Accepted: 10/31/2017] [Indexed: 10/18/2022]
Abstract
The principle of deliberately infecting humans with infectious agents in a controlled setting, so-called controlled human infections (CHI), is not novel. Many CHI models have a long history and were established decades ago such as the intentional exposure to yellow fever and dengue performed in the 1900's (Reed, 1902) [2]. In these times bioethics and scientific reasoning were in their infancy. Nowadays, clinical trials are highly regulated and CHI are executed worldwide. Controlled human malaria infections and influenza infections are the two most frequently practiced. Others are experiencing a revival or are being carefully developed. Because CHI models test the efficacy of promising vaccine or drug candidates early in clinical development, they offer the potential to decrease the number of failing phase 2 and 3 trials, reducing risks for patients and saving costs and efforts. In addition, CHI models provide unprecedented opportunities to dissect the physiological, immunological and metabolic changes that occur upon infection. However, it is clear that controlled infections require careful deliberation of safety, ethics, quarantine, scientific output and the production of infectious material. An independent international workshop was hosted by the Leiden University Medical Centre in The Netherlands, bringing together clinical investigators, basic scientists, regulators, funders and policy makers from 22 different countries to discuss the opportunities and challenges in CHI. The aim of the workshop was to discuss CHI as a tool to advance science, drug and vaccine development, share the challenges of establishing a CHI model with specific focus on neglected tropical diseases and the possibilities to transfer models to endemic sites. Noticeably, among the 128 participants were clinical investigators from ten different countries in Sub-Saharan Africa. An important dimension of the meeting was to give the floor to young established clinicians and scientists to voice their perspective on the future of CHI models.
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Affiliation(s)
| | - Annie Mo
- Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA
| | - Peter G Kremsner
- Universitätsklinikum Tübingen, Germany and Centre de Recherches Médicales de Lambaréné, Gabon
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37
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Gordon CA, Kurscheid J, Jones MK, Gray DJ, McManus DP. Soil-Transmitted Helminths in Tropical Australia and Asia. Trop Med Infect Dis 2017; 2:E56. [PMID: 30270913 PMCID: PMC6082059 DOI: 10.3390/tropicalmed2040056] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Revised: 10/16/2017] [Accepted: 10/17/2017] [Indexed: 12/21/2022] Open
Abstract
Soil-transmitted helminths (STH) infect 2 billion people worldwide including significant numbers in South-East Asia (SEA). In Australia, STH are of less concern; however, indigenous communities are endemic for STH, including Strongyloides stercoralis, as well as for serious clinical infections due to other helminths such as Toxocara spp. The zoonotic hookworm Ancylostoma ceylanicum is also present in Australia and SEA, and may contribute to human infections particularly among pet owners. High human immigration rates to Australia from SEA, which is highly endemic for STH Strongyloides and Toxocara, has resulted in a high prevalence of these helminthic infections in immigrant communities, particularly since such individuals are not screened for worm infections upon entry. In this review, we consider the current state of STH infections in Australia and SEA.
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Affiliation(s)
- Catherine A Gordon
- QIMR Berghofer Medical Research Institute, Molecular Parasitology Laboratory, Queensland 4006, Australia.
| | - Johanna Kurscheid
- Australian National University, Department of Global Health, Research School of Population Health, Australian Capital Territory 2601, Australia.
| | - Malcolm K Jones
- School of Veterinary Science, University of Queensland, Brisbane, QLD 4067, Australia.
| | - Darren J Gray
- Australian National University, Department of Global Health, Research School of Population Health, Australian Capital Territory 2601, Australia.
| | - Donald P McManus
- QIMR Berghofer Medical Research Institute, Molecular Parasitology Laboratory, Queensland 4006, Australia.
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38
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Sipahi AM, Baptista DM. Helminths as an alternative therapy for intestinal diseases. World J Gastroenterol 2017; 23:6009-6015. [PMID: 28970717 PMCID: PMC5597493 DOI: 10.3748/wjg.v23.i33.6009] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2017] [Revised: 07/05/2017] [Accepted: 08/08/2017] [Indexed: 02/06/2023] Open
Abstract
Animal models and clinical studies have shown that helminth infections exert immunomodulatory activity, altering intestinal permeability and providing a potential beneficial action on autoimmune and inflammatory disorders in human beings, such as inflammatory bowel disease (IBD) and celiac disease. This is consistent with the theory that intestinal microbiota is responsible for shaping human immunological responses. With the arrival of the immunobiologic era and the use of antibodies, we propose a distinctive pathway for treating patients with IBD and celiac disease. We have some evidence about the safety and tolerability of helminth use, but evidence about their impact on disease activity is lacking. Using worms to treat diseases could be a possible way to lower treatment costs, since the era of immunobiologic agents is responsible for a significant rise in expenses. Some questions remain to be investigated regarding the use of helminths in intestinal disease, such as the importance of the specific species of helminths used, appropriate dosing regimens, optimal timing of treatment, the role of host genetics, diet, environment, and the elucidation of the exact mechanisms of action. One promising approach is the use of helminth-derived anti-inflammatory molecules as drugs. Yet there are still many challenges with this method, especially with regard to safety. Studies on intestinal permeability point to Strongyloides stercoralis as a useful nematode for these purposes.
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Affiliation(s)
- Aytan Miranda Sipahi
- LIM 07-Laboratory of Experimental Clinical Gastroenterology, Department of Gastroenterology and Hepatology, Clínicas Hospital of University of São Paulo-HCFMUSP and, School of Medicine at the University of São Paulo, São Paulo 04023-062, Brazil
| | - Daniel Machado Baptista
- LIM 07-Laboratory of Experimental Clinical Gastroenterology, Department of Gastroenterology and Hepatology, Clínicas Hospital of University of São Paulo-HCFMUSP and, School of Medicine at the University of São Paulo, São Paulo 04023-062, Brazil
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Liu Y, Ye Q, Liu YL, Kang J, Chen Y, Dong WG. Schistosoma japonicum attenuates dextran sodium sulfate-induced colitis in mice via reduction of endoplasmic reticulum stress. World J Gastroenterol 2017; 23:5700-5712. [PMID: 28883695 PMCID: PMC5569284 DOI: 10.3748/wjg.v23.i31.5700] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 03/30/2017] [Accepted: 04/21/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To elucidate the impact of Schistosoma (S.) japonicum infection on inflammatory bowel disease by studying the effects of exposure to S. japonicum cercariae on dextran sodium sulfate (DSS)-induced colitis.
METHODS Infection was percutaneously established with 20 ± 2 cercariae of S. japonicum, and colitis was induced by administration of 3% DSS at 4 wk post infection. Weight change, colon length, histological score (HS) and disease activity index (DAI) were evaluated. Inflammatory cytokines, such as IL-2, IL-10 and IFN-γ, were tested by a cytometric bead array and real-time quantitative polymerase chain reaction (RT-PCR). Protein and mRNA levels of IRE1α, IRE1β, GRP78, CHOP, P65, P-P65, P-IκBα and IκBα in colon tissues were examined by Western blot and RT-PCR, respectively. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling positive cells, cleaved-caspase 3 expression and Bcl2/Bax were investigated to assess the apoptosis in colon tissues.
RESULTS Mice infected with S. japonicum cercariae were less susceptible to DSS. Mice infected with S. japonicum cercariae and treated with DSS showed decreased weight loss, longer colon, and lower HS and DAI compared with mice treated with DSS alone. A substantial decrease in Th1/Th2/Th17 response was observed after infection with S. japonicum. Endoplasmic reticulum (ER) stress and the nuclear factor-kappa B (NF-κB) pathway were reduced in mice infected with S. japonicum cercariae and treated with DSS, along with ameliorated celluar apoptosis, in contrast to mice treated with DSS alone.
CONCLUSION Exposure to S. japonicum attenuated inflammatory response in a DSS-induced colitis model. In addition to the Th1/Th2/Th17 pathway and NF-κB pathway, ER stress was shown to be involved in mitigating inflammation and decreasing apoptosis. Thus, ER stress is a new aspect in elucidating the relationship between helminth infection and inflammatory bowel disease (IBD), which may offer new therapeutic methods for IBD.
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Affiliation(s)
- Ya Liu
- Department of Gastroenterology, Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Qing Ye
- Department of Hospital Infection, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Yu-Lan Liu
- Departments of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Jian Kang
- Department of Gastroenterology, Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Yan Chen
- Department of Gastroenterology, Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Wei-Guo Dong
- Department of Gastroenterology, Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
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40
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Varyani F, Fleming JO, Maizels RM. Helminths in the gastrointestinal tract as modulators of immunity and pathology. Am J Physiol Gastrointest Liver Physiol 2017; 312:G537-G549. [PMID: 28302598 PMCID: PMC5495915 DOI: 10.1152/ajpgi.00024.2017] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 03/06/2017] [Accepted: 03/12/2017] [Indexed: 01/31/2023]
Abstract
Helminth parasites are highly prevalent in many low- and middle-income countries, in which inflammatory bowel disease and other immunopathologies are less frequent than in the developed world. Many of the most common helminths establish themselves in the gastrointestinal tract and can exert counter-inflammatory influences on the host immune system. For these reasons, interest has arisen as to how parasites may ameliorate intestinal inflammation and whether these organisms, or products they release, could offer future therapies for immune disorders. In this review, we discuss interactions between helminth parasites and the mucosal immune system, as well as the progress being made toward identifying mechanisms and molecular mediators through which it may be possible to attenuate pathology in the intestinal tract.
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Affiliation(s)
- Fumi Varyani
- 1Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom; ,2Edinburgh Clinical Academic Track, Western General Hospital, University of Edinburgh, Edinburgh, United Kingdom; and
| | - John O. Fleming
- 3Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
| | - Rick M. Maizels
- 1Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom;
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41
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Smallwood TB, Giacomin PR, Loukas A, Mulvenna JP, Clark RJ, Miles JJ. Helminth Immunomodulation in Autoimmune Disease. Front Immunol 2017; 8:453. [PMID: 28484453 PMCID: PMC5401880 DOI: 10.3389/fimmu.2017.00453] [Citation(s) in RCA: 159] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 04/03/2017] [Indexed: 12/26/2022] Open
Abstract
Helminths have evolved to become experts at subverting immune surveillance. Through potent and persistent immune tempering, helminths can remain undetected in human tissues for decades. Redirecting the immunomodulating "talents" of helminths to treat inflammatory human diseases is receiving intensive interest. Here, we review therapies using live parasitic worms, worm secretions, and worm-derived synthetic molecules to treat autoimmune disease. We review helminth therapy in both mouse models and clinical trials and discuss what is known on mechanisms of action. We also highlight current progress in characterizing promising new immunomodulatory molecules found in excretory/secretory products of helminths and their potential use as immunotherapies for acute and chronic inflammatory diseases.
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Affiliation(s)
- Taylor B Smallwood
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia
| | - Paul R Giacomin
- Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia
| | - Alex Loukas
- Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia
| | - Jason P Mulvenna
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia.,Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia.,QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Richard J Clark
- School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia
| | - John J Miles
- Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia.,QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.,School of Medicine, The University of Queensland, Brisbane, QLD, Australia
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42
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Briggs N, Weatherhead J, Sastry KJ, Hotez PJ. The Hygiene Hypothesis and Its Inconvenient Truths about Helminth Infections. PLoS Negl Trop Dis 2016; 10:e0004944. [PMID: 27632204 PMCID: PMC5025185 DOI: 10.1371/journal.pntd.0004944] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Current iterations of the hygiene hypothesis suggest an adaptive role for helminth parasites in shaping the proper maturation of the immune system. However, aspects of this hypothesis are based on assumptions that may not fully account for realities about human helminth infections. Such realities include evidence of causal associations between helminth infections and asthma or inflammatory bowel disease as well as the fact that helminth infections remain widespread in the United States, especially among populations at greatest risk for inflammatory and autoimmune diseases.
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Affiliation(s)
- Neima Briggs
- Department of Immunology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America
- The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, United States of America
- Sabin Vaccine Institute and Texas Children’s Hospital Center for Vaccine Development, Departments of Pediatrics and Molecular Virology and Microbiology, National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
| | - Jill Weatherhead
- Sabin Vaccine Institute and Texas Children’s Hospital Center for Vaccine Development, Departments of Pediatrics and Molecular Virology and Microbiology, National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
| | - K. Jagannadha Sastry
- Department of Immunology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America
- The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas, United States of America
| | - Peter J. Hotez
- Sabin Vaccine Institute and Texas Children’s Hospital Center for Vaccine Development, Departments of Pediatrics and Molecular Virology and Microbiology, National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America
- James A Baker III Institute for Public Policy, Rice University, Houston, Texas, United States of America
- Department of Biology, Baylor University, Waco, Texas, United States of America
- Scowcroft Institute of International Affairs, Bush School of Government and Public Service, Texas A&M University, College Station, Texas, United States of America
- * E-mail:
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43
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Current Status of Celiac Disease Drug Development. Am J Gastroenterol 2016; 111:779-86. [PMID: 27021196 DOI: 10.1038/ajg.2016.105] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 02/02/2016] [Indexed: 02/08/2023]
Abstract
Celiac disease (CeD) is one of the most common immune-mediated diseases. Symptoms and disease activity are incompletely controlled by the gluten-free diet, which is currently the only available therapy. Although no therapies are yet approved, there is a growing field of candidates and an improving understanding of the regulatory pathway. In this review, we briefly discuss the epidemiology, pathophysiology, and current treatment paradigm for CeD. We also review the major classes of therapies being considered for CeD and discuss extensively what is known and can be surmised regarding the regulatory pathway for approval of a CeD therapeutic. The coming years will see an increasing number and diversity of potential therapies entering clinical trials and hopefully the first approved agents targeting this significant unmet medical need. Although biomarkers including histology and serology will always be important in therapeutic clinical trials, they currently lack the necessary evidence linking them to improved patient outcomes required for use as primary outcomes for drug approval. For this reason, patient-reported outcomes will likely be primary end points in Phase III CeD trials for the foreseeable future.
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44
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Giacomin P, Croese J, Krause L, Loukas A, Cantacessi C. Suppression of inflammation by helminths: a role for the gut microbiota? Philos Trans R Soc Lond B Biol Sci 2016; 370:rstb.2014.0296. [PMID: 26150662 PMCID: PMC4528494 DOI: 10.1098/rstb.2014.0296] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Multiple recent investigations have highlighted the promise of helminth-based therapies for the treatment of inflammatory disorders of the intestinal tract of humans, including inflammatory bowel disease and coeliac disease. However, the mechanisms by which helminths regulate immune responses, leading to the amelioration of symptoms of chronic inflammation are unknown. Given the pivotal roles of the intestinal microbiota in the pathogenesis of these disorders, it has been hypothesized that helminth-induced modifications of the gut commensal flora may be responsible for the therapeutic properties of gastrointestinal parasites. In this article, we review recent progress in the elucidation of host-parasite-microbiota interactions in both animal models of chronic inflammation and humans, and provide a working hypothesis of the role of the gut microbiota in helminth-induced suppression of inflammation.
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Affiliation(s)
- Paul Giacomin
- Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Smithfield 4878, Australia
| | - John Croese
- Department of Gastroenterology and Hepatology, The Prince Charles Hospital, Brisbane 4007, Australia
| | - Lutz Krause
- Translational Research Institute, University of Queensland Diamantina Institute, Woolloongabba, Australia
| | - Alex Loukas
- Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Smithfield 4878, Australia
| | - Cinzia Cantacessi
- Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK
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45
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McCarville JL, Caminero A, Verdu EF. Pharmacological approaches in celiac disease. Curr Opin Pharmacol 2015; 25:7-12. [DOI: 10.1016/j.coph.2015.09.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Accepted: 09/09/2015] [Indexed: 02/07/2023]
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46
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Abstract
Autoimmune and chronic inflammatory organic diseases represent a "postindustrial revolution epidemics," and their frequency has increased dramatically in the last century. Today, it is assumed that the increase in hygiene standards reduced the interactions with helminth parasites that coevolved with the immune system and are crucial for its proper functioning. Several helminths have been proposed and tested in the search of the ideal therapeutic. In this review, the authors summarize the translational and clinical studies and review the caveats and possible solutions for the optimization of helminth therapies.
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Affiliation(s)
- Irina Leonardi
- Division of Gastroenterology and Hepatology, University Hospital Zürich, Zurich, Switzerland
| | - Isabelle Frey
- Division of Gastroenterology and Hepatology, University Hospital Zürich, Zurich, Switzerland
| | - Gerhard Rogler
- Division of Gastroenterology and Hepatology, University Hospital Zürich, Zurich, Switzerland; Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
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47
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Loke P, Lim YAL. Helminths and the microbiota: parts of the hygiene hypothesis. Parasite Immunol 2015; 37:314-23. [PMID: 25869420 DOI: 10.1111/pim.12193] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Accepted: 03/18/2015] [Indexed: 12/12/2022]
Abstract
In modern societies, diseases that are driven by dysregulated immune responses are increasing at an alarming pace, such as inflammatory bowel diseases and diabetes. There is an urgent need to understand these epidemiological trends, which are likely to be driven by the changing environment of the last few decades. There are complex interactions between human genetic factors and this changing environment that is leading to the increasing prevalence of metabolic and inflammatory diseases. Alterations to human gut bacterial communities (the microbiota) and lowered prevalence of helminth infections are potential environmental factors contributing to immune dysregulation. Helminths have co-evolved with the gut microbiota and their mammalian hosts. This three-way interaction is beginning to be characterized, and the knowledge gained may enable the design of new therapeutic strategies to treat metabolic and inflammatory diseases. However, these complex interactions need to be carefully investigated in the context of host genetic backgrounds to identify optimal treatment strategies. The complex nature of these interactions raises the possibility that only with highly personalized treatment, with knowledge of individual genetic and microbiota communities, will therapeutic interventions be successful for a majority of the individuals suffering from these complex diseases of immune dysregulation.
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Affiliation(s)
- P Loke
- Department of Microbiology, New York University School of Medicine, New York, NY, USA
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48
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Giacomin P, Zakrzewski M, Croese J, Su X, Sotillo J, McCann L, Navarro S, Mitreva M, Krause L, Loukas A, Cantacessi C. Experimental hookworm infection and escalating gluten challenges are associated with increased microbial richness in celiac subjects. Sci Rep 2015; 5:13797. [PMID: 26381211 PMCID: PMC4585380 DOI: 10.1038/srep13797] [Citation(s) in RCA: 76] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Accepted: 08/04/2015] [Indexed: 02/08/2023] Open
Abstract
The intestinal microbiota plays a critical role in the development of the immune system. Recent investigations have highlighted the potential of helminth therapy for treating a range of inflammatory disorders, including celiac disease (CeD); however, the mechanisms by which helminths modulate the immune response of the human host and ameliorate CeD pathology are unknown. In this study, we investigated the potential role of alterations in the human gut microbiota in helminth-mediated suppression of an inflammatory disease. We assessed the qualitative and quantitative changes in the microbiota of human volunteers with CeD prior to and following infection with human hookworms, and following challenge with escalating doses of dietary gluten. Experimental hookworm infection of the trial subjects resulted in maintenance of the composition of the intestinal flora, even after a moderate gluten challenge. Notably, we observed a significant increase in microbial species richness over the course of the trial, which could represent a potential mechanism by which hookworms can regulate gluten-induced inflammation and maintain intestinal immune homeostasis.
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Affiliation(s)
- Paul Giacomin
- Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia
| | - Martha Zakrzewski
- Bioinformatics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - John Croese
- Prince Charles Hospital, Brisbane, QLD, Australia
| | - Xiaopei Su
- Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Javier Sotillo
- Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia
| | - Leisa McCann
- Prince Charles Hospital, Brisbane, QLD, Australia
| | - Severine Navarro
- Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia
| | - Makedonka Mitreva
- The Genome Institute, and.,Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Lutz Krause
- Bioinformatics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, QLD, Australia
| | - Alex Loukas
- Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia
| | - Cinzia Cantacessi
- Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia.,Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom
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49
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Versini M, Jeandel PY, Bashi T, Bizzaro G, Blank M, Shoenfeld Y. Unraveling the Hygiene Hypothesis of helminthes and autoimmunity: origins, pathophysiology, and clinical applications. BMC Med 2015; 13:81. [PMID: 25879741 PMCID: PMC4396177 DOI: 10.1186/s12916-015-0306-7] [Citation(s) in RCA: 116] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 03/02/2015] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND The Hygiene Hypothesis (HH) attributes the dramatic increase in autoimmune and allergic diseases observed in recent decades in Western countries to the reduced exposure to diverse immunoregulatory infectious agents. This theory has since largely been supported by strong epidemiological and experimental evidence. DISCUSSION The analysis of these data along with the evolution of the Western world's microbiome enable us to obtain greater insight into microorganisms involved in the HH, as well as their regulatory mechanisms on the immune system. Helminthes and their derivatives were shown to have a protective role. Helminthes' broad immunomodulatory properties have already begun to be exploited in clinical trials of autoimmune diseases, including inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and type-1 diabetes. SUMMARY In this review, we will dissect the microbial actors thought to be involved in the HH as well as their immunomodulatory mechanisms as emphasized by experimental studies, with a particular attention on parasites. Thereafter, we will review the early clinical trials using helminthes' derivatives focusing on autoimmune diseases.
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Affiliation(s)
- Mathilde Versini
- The Zabludowicz Center for Autoimmune Diseases, Chaim Sheba Medical Center, Tel-Hashomer, 52621, Israel.
- Department of Internal Medicine, Archet-1 Hospital, University of Nice-Sophia-Antipolis, 151 Route de Saint Antoine de Ginestière, 06202, Nice, France.
| | - Pierre-Yves Jeandel
- Department of Internal Medicine, Archet-1 Hospital, University of Nice-Sophia-Antipolis, 151 Route de Saint Antoine de Ginestière, 06202, Nice, France.
| | - Tomer Bashi
- The Zabludowicz Center for Autoimmune Diseases, Chaim Sheba Medical Center, Tel-Hashomer, 52621, Israel.
| | - Giorgia Bizzaro
- The Zabludowicz Center for Autoimmune Diseases, Chaim Sheba Medical Center, Tel-Hashomer, 52621, Israel.
| | - Miri Blank
- The Zabludowicz Center for Autoimmune Diseases, Chaim Sheba Medical Center, Tel-Hashomer, 52621, Israel.
| | - Yehuda Shoenfeld
- The Zabludowicz Center for Autoimmune Diseases, Chaim Sheba Medical Center, Tel-Hashomer, 52621, Israel.
- The Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
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50
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Ludvigsson JF, Card T, Ciclitira PJ, Swift GL, Nasr I, Sanders DS, Ciacci C. Support for patients with celiac disease: A literature review. United European Gastroenterol J 2015; 3:146-59. [PMID: 25922674 PMCID: PMC4406900 DOI: 10.1177/2050640614562599] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Accepted: 11/01/2014] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Celiac disease (CD) is a lifelong disorder. Patients are at increased risk of complications and comorbidity. OBJECTIVES We conducted a review of the literature on patient support and information in CD and aim to issue recommendations about patient information with regards to CD. METHODS DATA SOURCE We searched PubMed for English-language articles published between 1900 and June 2014, containing terms related to costs, economics of CD, or education and CD. STUDY SELECTION Papers deemed relevant by any of the participating authors were included in the study. DATA SYNTHESIS No quantitative synthesis of data was performed. Instead we formulated a consensus view of the information that should be offered to all patients with CD. RESULTS There are few randomized clinical trials examining the effect of patient support in CD. Patients and their families receive information from many sources. It is important that health care personnel guide the patient through the plethora of facts and comments on the Internet. An understanding of CD is likely to improve dietary adherence. Patients should be educated about current knowledge about risk factors for CD, as well as the increased risk of complications. Patients should also be advised to avoid other health hazards, such as smoking. Many patients are eager to learn about future non-dietary treatments of CD. This review also comments on novel therapies but it is important to stress that no such treatment is available at present. CONCLUSION Based on mostly observational data, we suggest that patient support and information should be an integral part of the management of CD, and is likely to affect the outcome of CD.
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Affiliation(s)
- Jonas F Ludvigsson
- Department of Pediatrics, Örebro University Hospital, Örebro, Sweden
- Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Tim Card
- Division of Epidemiology and Public Health, University of Nottingham, Nottingham City Hospital, Nottingham, UK
| | - Paul J Ciclitira
- Division of Nutritional Sciences, King’s College London, The Rayne Institute London, London, UK
| | - Gillian L Swift
- Department of Gastroenterology, Cardiff and Vale University Health Board, Cardiff, UK
| | - Ikram Nasr
- Division of Nutritional Sciences, King’s College London, The Rayne Institute London, London, UK
| | - David S Sanders
- Regional GI and Liver Unit, Royal Hallamshire Hospital, Sheffield, UK
| | - Carolina Ciacci
- Department of Medicine and Surgery, Gastroenterology, University of Salerno, Salerno, Italy
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