SummaryIntestinal helminths are potent regulators of their host’s immune system and can ameliorate inflammatory diseases such as allergic asthma. In the present study we have assessed whether this anti-inflammatory activity was purely intrinsic to helminths, or whether it also involved crosstalk with the local microbiota. We report that chronic infection with the murine helminth Heligmosomoides polygyrus bakeri (Hpb) altered the intestinal habitat, allowing increased short chain fatty acid (SCFA) production. Transfer of the Hpb-modified microbiota alone was sufficient to mediate protection against allergic asthma. The helminth-induced anti-inflammatory cytokine secretion and regulatory T cell suppressor activity that mediated the protection required the G protein-coupled receptor (GPR)-41. A similar alteration in the metabolic potential of intestinal bacterial communities was observed with diverse parasitic and host species, suggesting that this represents an evolutionary conserved mechanism of host-microbe-helminth interactions.
Hookworms are soil-transmitted nematode parasites that can reside for many years in the small intestine of their human hosts; Necator americanus is the predominant infecting species. Adult worms feed on the blood of a host and can cause iron deficiency anaemia, especially in high-risk populations (children and women of childbearing age). Almost 500 million people in developing tropical countries are infected, and simulation models estimate that hookworm infection is responsible for >4 million disability-adjusted life years lost annually. Humans mount an immune response to hookworms, but it is mostly unsuccessful at removing adult worms from the bowel. Accordingly, the host switches to an immune-tolerant state that enables hookworms to reside in the gut for many years. Although anthelmintic drugs are available and widely used, their efficacy varies and the drugs do not prevent reinfection. Thus, other control strategies aimed at improving water quality, sanitation and hygiene are needed. In addition, efforts are underway to develop a human hookworm vaccine through public-private partnerships. However, hookworms could also be a resource; as hookworms have the capability to regulate the host's inflammation, researchers are experimentally infecting patients to treat some inflammatory diseases as an approach to discover new anti-inflammatory molecules. This area of endeavour might well yield new biotherapeutics for autoimmune and allergic diseases.
Background and AimsThe association between hygiene and prevalence of autoimmune disease has been
attributed in part to enteric helminth infection. A pilot study of
experimental infection with the hookworm Necator americanus
was undertaken among a group of otherwise healthy people with celiac disease
to test the potential of the helminth to suppress the immunopathology
induced by gluten.MethodsIn a 21-week, double-blinded, placebo-controlled study, we explored the
effects of N. americanus infection in 20 healthy,
helminth-naïve adults with celiac disease well controlled by diet.
Staged cutaneous inoculations with 10 and 5 infective 3rd stage
hookworm larvae or placebo were performed at week-0 and -12 respectively. At
week-20, a five day oral wheat challenge equivalent to 16 grams of gluten
per day was undertaken. Primary outcomes included duodenal Marsh score and
quantification of the immunodominant α-gliadin peptide (QE65)-specific
systemic interferon-γ-producing cells by ELISpot pre- and post-wheat
challenge.ResultsEnteric colonisation with hookworm established in all 10 cases, resulting in
transiently painful enteritis in 5. Chronic infection was asymptomatic, with
no effect on hemoglobin levels. Although some duodenal eosinophilia was
apparent, hookworm-infected mucosa retained a healthy appearance. In both
groups, wheat challenge caused deterioration in both primary and several
secondary outcomes.ConclusionsExperimental N. americanus infection proved to be safe and
enabled testing its effect on a range of measures of the human autoimmune
response. Infection imposed no obvious benefit on pathology.Trial RegistrationClinicalTrials.gov NCT00671138
The interactions between gastrointestinal parasitic helminths and commensal bacteria are likely to play a pivotal role in the establishment of host-parasite cross-talk, ultimately shaping the development of the intestinal immune system. However, little information is available on the impact of infections by gastrointestinal helminths on the bacterial communities inhabiting the human gut. We used 16S rRNA gene amplification and pyrosequencing to characterize, for the first time to our knowledge, the differences in composition and relative abundance of fecal microbial communities in human subjects prior to and following experimental infection with the blood-feeding intestinal hookworm, Necator americanus. Our data show that, although hookworm infection leads to a minor increase in microbial species richness, no detectable effect is observed on community structure, diversity or relative abundance of individual bacterial species.
The intestinal microbiota plays a critical role in the development of the immune system. Recent investigations have highlighted the potential of helminth therapy for treating a range of inflammatory disorders, including celiac disease (CeD); however, the mechanisms by which helminths modulate the immune response of the human host and ameliorate CeD pathology are unknown. In this study, we investigated the potential role of alterations in the human gut microbiota in helminth-mediated suppression of an inflammatory disease. We assessed the qualitative and quantitative changes in the microbiota of human volunteers with CeD prior to and following infection with human hookworms, and following challenge with escalating doses of dietary gluten. Experimental hookworm infection of the trial subjects resulted in maintenance of the composition of the intestinal flora, even after a moderate gluten challenge. Notably, we observed a significant increase in microbial species richness over the course of the trial, which could represent a potential mechanism by which hookworms can regulate gluten-induced inflammation and maintain intestinal immune homeostasis.
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