John Croese1, Paul Giacomin2, Severine Navarro2, Andrew Clouston3, Leisa McCann2, Annette Dougall2, Ivana Ferreira2, Atik Susianto2, Peter O'Rourke4, Mariko Howlett5, James McCarthy6, Christian Engwerda4, Dianne Jones7, Alex Loukas8. 1. Department of Gastroenterology and Hepatology, The Prince Charles Hospital, Brisbane, Australia; Center for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia. Electronic address: mcroese@bigpond.net.au. 2. Center for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia. 3. Envoi Specialist Pathologists, Brisbane, Australia. 4. QIMR Berghofer Medical Research Institute, Brisbane, Australia. 5. Royal Brisbane and Women's Hospital, Brisbane, Australia. 6. QIMR Berghofer Medical Research Institute, Brisbane, Australia; Royal Brisbane and Women's Hospital, Brisbane, Australia. 7. Logan Hospital, Brisbane, Australia. 8. Center for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia. Electronic address: alex.loukas@jcu.edu.au.
Abstract
BACKGROUND: Celiac disease (CeD) is a common gluten-sensitive autoimmune enteropathy. A gluten-free diet is an effective treatment, but compliance is demanding; hence, new treatment strategies for CeD are required. OBJECTIVE: Parasitic helminths hold promise for treating inflammatory disorders, so we examined the influence of experimental hookworm infection on the predicted outcomes of escalating gluten challenges in CeD subjects. METHODS: A 52-week study was conducted involving 12 adults with diet-managed CeD. Subjects were inoculated with 20 Necator americanus larvae, and escalating gluten challenges consumed as pasta were subsequently administered: (1) 10 to 50 mg for 12 weeks (microchallenge); (2) 25 mg daily + 1 g twice weekly for 12 weeks (GC-1g); and (3) 3 g daily (60-75 straws of spaghetti) for 2 weeks (GC-3g). Symptomatic, serologic, and histological outcomes evaluated gluten toxicity. Regulatory and inflammatory T cell populations in blood and mucosa were examined. RESULTS: Two gluten-intolerant subjects were withdrawn after microchallenge. Ten completed GC-1g, 8 of whom enrolled in and completed GC-3g. PRIMARY OUTCOMES: median villous height-to-crypt depth ratios (2.60-2.63; P = .98) did not decrease as predicted after GC-1g, and the mean IgA-tissue transglutaminase titers declined, contrary to the predicted rise after GC-3g. SECONDARY OUTCOMES: quality of life scores improved (46.3-40.6; P = .05); celiac symptom indices (24.3-24.3; P = .53), intra-epithelial lymphocyte percentages (32.5-35.0; P = .47), and Marsh scores were unchanged by gluten challenge. Intestinal T cells expressing IFNγ were reduced following hookworm infection (23.9%-11.5%; P = .04), with corresponding increases in CD4(+) Foxp3(+) regulatory T cells (0.19%-1.12%; P = .001). CONCLUSIONS: Necator americanus and gluten microchallenge promoted tolerance and stabilized or improved all tested indices of gluten toxicity in CeD subjects.
BACKGROUND:Celiac disease (CeD) is a common gluten-sensitive autoimmune enteropathy. A gluten-free diet is an effective treatment, but compliance is demanding; hence, new treatment strategies for CeD are required. OBJECTIVE: Parasitic helminths hold promise for treating inflammatory disorders, so we examined the influence of experimental hookworm infection on the predicted outcomes of escalating gluten challenges in CeD subjects. METHODS: A 52-week study was conducted involving 12 adults with diet-managed CeD. Subjects were inoculated with 20 Necator americanus larvae, and escalating gluten challenges consumed as pasta were subsequently administered: (1) 10 to 50 mg for 12 weeks (microchallenge); (2) 25 mg daily + 1 g twice weekly for 12 weeks (GC-1g); and (3) 3 g daily (60-75 straws of spaghetti) for 2 weeks (GC-3g). Symptomatic, serologic, and histological outcomes evaluated gluten toxicity. Regulatory and inflammatory T cell populations in blood and mucosa were examined. RESULTS: Two gluten-intolerant subjects were withdrawn after microchallenge. Ten completed GC-1g, 8 of whom enrolled in and completed GC-3g. PRIMARY OUTCOMES: median villous height-to-crypt depth ratios (2.60-2.63; P = .98) did not decrease as predicted after GC-1g, and the mean IgA-tissue transglutaminase titers declined, contrary to the predicted rise after GC-3g. SECONDARY OUTCOMES: quality of life scores improved (46.3-40.6; P = .05); celiac symptom indices (24.3-24.3; P = .53), intra-epithelial lymphocyte percentages (32.5-35.0; P = .47), and Marsh scores were unchanged by gluten challenge. Intestinal T cells expressing IFNγ were reduced following hookworm infection (23.9%-11.5%; P = .04), with corresponding increases in CD4(+) Foxp3(+) regulatory T cells (0.19%-1.12%; P = .001). CONCLUSIONS:Necator americanus and gluten microchallenge promoted tolerance and stabilized or improved all tested indices of gluten toxicity in CeD subjects.
Authors: Phurpa Wangchuk; Catherine Shepherd; Constantin Constantinoiu; Rachael Y M Ryan; Konstantinos A Kouremenos; Luke Becker; Linda Jones; Geraldine Buitrago; Paul Giacomin; David Wilson; Norelle Daly; Malcolm J McConville; John J Miles; Alex Loukas Journal: Infect Immun Date: 2019-03-25 Impact factor: 3.441
Authors: Laura Kivelä; Alberto Caminero; Daniel A Leffler; Maria Ines Pinto-Sanchez; Jason A Tye-Din; Katri Lindfors Journal: Nat Rev Gastroenterol Hepatol Date: 2020-11-20 Impact factor: 46.802