Randomized, Placebo Controlled Trial of Experimental Hookworm Infection for Improving Gluten Tolerance in Celiac Disease

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.

Experimental human hookworm infection: a narrative historical review

“…americanus infected individuals produce higher levels of the regulatory cytokine IL-10 and impaired production of pro-inflammatory IFN γ , IL-5 and IL-3 [ 56 ]. Use of hookworm infection as a novel therapeutic in inflammatory bowel disease [ 57 ], coeliac disease [ 50 , 53 , 54 , 58 ], allergic airway reactivity [ 46 ], asthma [ 45 ], and multiple sclerosis [ 44 ] has been published, with further clinical trials registered for metabolic disease [ 59 ], ulcerative colitis “Hookworm therapy for maintenance in ulcerative colitis: A placebo-controlled pilot study investigating the feasibility and efficacy of hookworm inoculation in patients with ulcerative colitis currently in remission” [ 60 ], and cancer therapeutics “Hookworm Therapy for young people at high risk for colorectal cancer”[ 61 ].…”

“…While this suggests that the gastrointestinal symptoms may be dose related, the occurrence of severe symptoms is not strictly dose related, with 2 participants reported to require termination of infection after application of just 10 larvae [ 45 , 46 ]. In a phase 1b randomised controlled trial investigating therapeutic hookworm infection for coeliac disease, 2 participants experienced severe gastrointestinal symptoms requiring termination of infection after inoculation with 20 larvae, while those receiving 40 larvae reported only mild and tolerable symptoms [ 50 ]. Albendazole is effective at eliminating the intestinal stages of infection and gastrointestinal symptoms resolve within 24 to 48 hours of treatment.…”

“…Historically, hookworm ova were obtained by dissection of female worms (presumably recovered from faeces after anthelmintic drug treatment) [ 26 , 35 ], from the faeces of infected patients [ 27 , 41 , 42 , 82 ], from laboratory hamsters [ 45 – 47 ] and, most commonly, from infected volunteer donors [ 29 , 32 , 48 , 50 – 54 , 57 , 58 , 62 , 63 , 72 , 79 ].…”

“…Larvae are produced by mixing hookworm eggs with charcoal or vermiculite, using various modifications of the Harada–Mori method [ 51 – 53 , 83 ]. Although some authors have reported pretreatment of faeces with antifungal and antibacterial agents prior to culture [ 50 – 52 ], the role of antimicrobials at this stage has not been established. The addition of charcoal would be expected to inactivate antibiotic present in the preparation [ 84 ], and the development of hookworm larvae has been shown to be dependent on the presence of intestinal bacterial flora [ 3 ].…”

Parasitic helminth infections in humans modulate Trefoil Factor levels in a manner dependent on the species of parasite and age of the host

“…In adults, hookworm infections have been linked with a generalized immunosuppression that may lead to reduced vaccine efficacy [9,10]. N. americanus experimental infections engage host immunoregulatory pathways driven by cytokines like interleukin 10 (IL-10) and transforming growth factor beta (TGF-β) [11], which could partially explain the ameliorative effect of hookworm infections in the context of autoinflammatory diseases, like celiac disease [12]. Whether such immunosuppression is due to host derived suppressive molecules and/or parasite derived factors released within the excretory secretory products remains unclear.…”