The observation that experimental helminth infection can be associated with immunomodulation and suppression of inflammatory diseases at distal tissue sites, has been used as rationale for trialing helminths such as Necator americanus for the treatment of inflammatory disorders in humans. However, the lack of sufficient knowledge of the immunological interplay between human host and parasite in a controlled infection setting limits ongoing clinical intervention studies. In this one-year longitudinal study, healthy volunteers were recruited and infected with N. americanus. Changes in immune responses, microbiome, plasma metabolome and gut physiology were examined over the course of the one-year period. All participants were successfully infected as confirmed by detectable eggs in the feces and adult worms visualized in the intestine. In general, individual variation in immune cells, serum cytokines, fecal microbiome and plasma metabolites were greater than changes induced by the infection. Nevertheless, eosinophils, serum IL-5, and fecal eosinophil degranulation markers transiently increased in the acute phase of infection. In addition, while we observed stability in microbial community composition through the course of infection, we found a difference in the microbial community composition of participants with moderate gastrointestinal symptoms. No significant changes were observed in gut physiology measured using SmartpillTM, except for a decrease in small bowel pH. Untargeted plasma metabolomics analysis of participant plasma over the course of infection revealed enrichment in tryptophan metabolism following infection which was associated with increased CTLA-4 expression on regulatory T cells (TREGS), CRTH2+ T helper 2 cells (TH2) and CCR6+ T helper 9 cells (TH9). In conclusion, hookworm infection is well tolerated and represents an innovative platform for investigating immunomodulatory properties of hookworm infection in a therapeutic clinical setting.

Background Human hookworm has been proposed as a treatment for ulcerative colitis (UC). This pilot study assessed the feasibility of a full-scale randomized control trial examining hookworm to maintain clinical remission in patients with UC. Methods Twenty patients with UC in disease remission (Simple Clinical Colitis Activity Index [SCCAI] ≤4 and fecal calprotectin (fCal) <100 ug/g) and only on 5-aminosalicylate received 30 hookworm larvae or placebo. Participants stopped 5-aminosalicylate after 12 weeks. Participants were monitored for up to 52 weeks and exited the study if they had a UC flare (SCCAI ≥5 and fCal ≥200 µg/g). The primary outcome was difference in rates of clinical remission at week 52. Differences were assessed for quality of life (QoL) and feasibility aspects including recruitment, safety, effectiveness of blinding, and viability of the hookworm infection. Results At 52 weeks, 4 of 10 (40%) participants in the hookworm group and 5 of 10 (50%) participants in the placebo group had maintained clinical remission (odds ratio, 0.67; 95% CI, 0.11-3.92). Median time to flare in the hookworm group was 231 days (interquartile range [IQR], 98-365) and 259 days for placebo (IQR, 132-365). Blinding was quite successful in the placebo group (Bang’s blinding index 0.22; 95% CI, −0.21 to 1) but less successful in the hookworm group (0.70; 95% CI, 0.37-1.0). Almost all participants in the hookworm group had detectable eggs in their faeces (90%; 95% CI, 0.60-0.98), and all participants in this group developed eosinophilia (peak eosinophilia 4.35 × 10^9/L; IQR, 2.80-6.68). Adverse events experienced were generally mild, and there was no significant difference in QoL. Conclusions A full-scale randomized control trial examining hookworm therapy as a maintenance treatment in patients with UC appears feasible.

The observation that experimental helminth infection can be associated with immunomodulation and suppression of inflammatory diseases at distal tissue sites, has been used as rationale for trialing helminths such as Necator americanus for the treatment of inflammatory disorders in humans. However, the lack of sufficient knowledge of the immunological interplay between human host and parasite in a controlled infection setting limits ongoing clinical intervention studies. In this one-year longitudinal study, healthy volunteers were recruited and infected with N. americanus. Changes in immune responses, microbiome, plasma metabolome and gut physiology were examined over the course of the one-year period. All participants were successfully infected as confirmed by detectable eggs in the feces and adult worms visualized in the intestine. In general, individual variation in immune cells, serum cytokines, fecal microbiome and plasma metabolites were greater than changes induced by the infection. Nevertheless, eosinophils, serum IL-5, and fecal eosinophil degranulation markers transiently increased in the acute phase of infection. In addition, while we observed stability in microbial community composition through the course of infection, we found a difference in the microbial community composition of participants with moderate gastrointestinal symptoms. No significant changes were observed in gut physiology measured using SmartpillTM, except for a decrease in small bowel pH. Untargeted plasma metabolomics analysis of participant plasma over the course of infection revealed enrichment in tryptophan metabolism following infection which was associated with increased CTLA-4 expression on regulatory T cells (TREGS), CRTH2+ T helper 2 cells (TH2) and CCR6+ T helper 9 cells (TH9). In conclusion, hookworm infection is well tolerated and represents an innovative platform for investigating immunomodulatory properties of hookworm infection in a therapeutic clinical setting.