Experimental hookworm infection and gluten microchallenge promote tolerance in celiac disease

J Allergy Clin Immunol. 2015 Feb;135(2):508-16. doi: 10.1016/j.jaci.2014.07.022. Epub 2014 Sep 20.


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Results: Two gluten-intolerant subjects were withdrawn after microchallenge.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.

Keywords: Celiac disease; autoimmunity; desensitization; gluten; helminth therapy; hookworm; intra-epithelial lymphocytes; mucosal immunology; regulatory T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Ancylostomatoidea / immunology*
  • Animals
  • Celiac Disease / complications
  • Celiac Disease / diagnosis
  • Celiac Disease / immunology*
  • Celiac Disease / therapy
  • Duodenum / immunology
  • Duodenum / parasitology
  • Duodenum / pathology
  • Female
  • Glutens / administration & dosage
  • Glutens / immunology*
  • Hookworm Infections / complications
  • Hookworm Infections / immunology*
  • Humans
  • Immune Tolerance*
  • Immunophenotyping
  • Male
  • Middle Aged
  • Necator americanus / immunology
  • Patient Outcome Assessment
  • Surveys and Questionnaires
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism


  • Glutens