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Two gluten-intolerant subjects were withdrawn after microchallenge.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.
Key words
- Celiac disease;
- gluten;
- hookworm;
- autoimmunity;
- helminth therapy;
- desensitization;
- mucosal immunology;
- regulatory T cells;
- intra-epithelial lymphocytes
Abbreviations used
CeD, Celiac disease;
CSI, Celiac symptom index;
DG, Deamidated gluten;
GC, Gluten challenge;
GFD,Gluten-free diet;
IEL, Intra-epithelial lymphocyte;
LPL, Lamina propria lymphocyte;
NA, Necator americanus;
Treg, Regulatory T;
QOL, Quality of life;
tTG, Tissue transglutaminase;
Vh:Cd, Villous height:crypt depth
The work was funded by an Australian National Health and Medical Research Council (NHMRC) Program Grant (1037304 to A.L., C.E., and J.M.), NHMRC Overseas Biomedical Fellowship 613718 (to P.G.),NHMRC Principal Research Fellowship (1020114 to A.L.), NHMRC Senior Research Fellowship (1058685 to C.E.), NHMRC Practitioner Fellowship and Government of Queensland Health Research Fellowship(1041802 to J.M.) and a Far North Queensland Hospital Foundation Small Research Grant (P.G. and S.N.).
Disclosure of potential conflict of interest: This work was funded by an Australian National Health and Medical Research Council Program Grant (1037304). The authors declare that they have no other relevant conflicts of interest.
Corresponding authors: John Croese, MD, Gastroenterology Unit, The Prince Charles Hospital, Rode Rd, Chermside, Brisbane, QLD 4032, Australia.
Alex Loukas, PhD, Australian Institute of Tropical Health & Medicine, James Cook University, McGregor Rd, Smithfield, Cairns, QLD 4878, Australia.
