Background
Since 1980, numbers of obese or overweight adults and children have grown exponentially worldwide to a current estimate of 2.1 billion people, thus establishing obesity as a pandemic and the fourth leading cause of death worldwide in 2017 [
1]. Specifically, abdominal obesity has been highlighted as the central factor in metabolic syndrome (MetS), a cluster of physiological, metabolic, and biochemical risk factors including abdominal obesity, insulin resistance, hypertension, and dyslipidaemia, as it appears to precede all other factors [
2]. Presence of MetS significantly increases the risk of developing several life-threatening diseases such as cancer, cardiovascular disease (CVD), and Type 2 diabetes mellitus (T2DM) [
2]. With almost one quarter of the world’s population affected, the prevalence of MetS in adults in rural Australia alone is 35.8%, and numbers in the Asia-Pacific region are growing disproportionately [
3], likely due to rapid socio-economic development and adoption of the Western diet and sedentary lifestyle [
4]. Associated with MetS, the escalating emergence of non-communicable diseases such as CVD and T2DM constitutes a significant public health crisis for the affected regions [
3].
Central and visceral obesity observed in MetS are a strong predictor for the development of T2DM, as they promote chronic inflammation and subsequent insulin resistance [
5]. Worldwide numbers of patients with T2DM are on the rise, and currently 8.8% of adults are living with the disease, equating to 425 million people (
http://www.diabetesatlas.org). Although the causative mechanisms are not exhaustively understood, chronic inflammation is increasingly accepted as strongly implicated in the pathogenesis of T2DM as excess calorie intake and sedentary behaviour are in the development of obesity [
6]. Vascular dysfunction resulting from chronic inflammation enhances the risk of diabetic complications such as myocardial infarction, peripheral arterial disease, and diabetic nephropathy and retinopathy [
7].
Interestingly, increasing incidence and prevalence of inflammatory diseases such as T2DM, inflammatory bowel disease, and asthma in developed countries offset the successful reduction in parasite-related diseases following helminth eradication efforts [
8]. In 1989, the lower prevalence of inflammatory diseases in transitioning or low-middle income countries with higher incidences of helminth infections [
9] led to development of the “Hygiene Hypothesis” and generated suggestions of a potential role for symbiotic parasites in the prevention and management of certain inflammatory diseases [
10]. Data from cross-sectional and animal studies further corroborate this inverse relationship between helminths and inflammatory diseases. A cross-sectional study in Northern Australia unearthed an inverse relationship between infection with
Strongyloides stercoralis and T2DM, indicating a possible protective relationship [
11]. A recent meta-analysis also confirmed a potential protective nature of helminth infection against T2DM [
10] with another study indicating an inverse relationship between helminth infection and CVD risk factors such as dyslipidaemia [
10]. Further supporting this notion, a recent study in a helminth-endemic region of Indonesia showed that anthelminthic drug treatment of people with an active helminth infection significantly raised HOMA-IR values and insulin resistance, suggesting that the removal of worms was causally associated with worsened glycaemic control [
12]. Findings from animal studies confirm the suggestion of a possible protective effect of helminth infections against T2DM and MetS via processes of immunomodulation [
9], where helminth infections may dampen pro-inflammatory immune responses and skew towards a type 2 immune response [
9]. A further study also demonstrated that infection with doses of 20 human hookworm
Necator americanus (
Na) is safe, well tolerated, and associated with Th2 and concomitant regulatory T cell responses [
13,
14], identifying
Na as a potentially effective treatment for inflammation associated with MetS and T2DM. Additionally, helminth infections may also modulate immune responses indirectly via their effect on the composition of the intestinal microbiota [
15]. For example, infection of mice with gastrointestinal helminths was able to prevent colonisation with the pro-inflammatory bacterium
Bacteroides vulgatus by inducing a Th2 and regulatory immune response that promoted the expansion of protective
Clostridiales strains [
16]. Finally, a recent review of helminths and T2DM concluded that chronic helminth infections influence the development of metabolic diseases and that these effects can be long lasting; however, human studies to date have been cross-sectional and cannot infer causality [
17]. The authors called for controlled human helminth infection trials to better understand how these can modulate the immune and metabolic response.
Herein we describe a randomised, double-blind, placebo-controlled Phase 1b safety and tolerability trial that will assess the effect of inoculation with 20 or 40 infective stage three larvae (L3) of
Na on body fat composition, inflammation and immune response, in otherwise healthy women and men aged 18–50 with central obesity and features of MetS over 24 months (Table
1).
Table 1World Health Organisation Trial Registration Data Set
Primary registry and trial identifying number | |
Date of registration in primary registry | 05/06/2017 |
Secondary identifying numbers | N/A |
Source(s) of monetary or material support | Far North Queensland Hospital Foundation, Australian Institue of Tropical Health and Medicine |
Primary sponsor | James Cook University |
Secondary sponsor(s) | None |
Contact for public queries | Prof Robyn McDermott robyn.mcdermott@jcu.edu.au |
Contact for scientific queries | Prof Robyn McDermott, Australian Institute of Tropical Health and Medicine, Cairns, Australia |
Public title | Safety and tolerability of experimental hookworm infection in humans with metabolic disease |
Scientific title | Safety and tolerability of experimental hookworm infection in humans with metabolic disease: Proof of Concept (Phase 1b) clinical trial |
Countries of recruitment | Australia |
Health condition(s) or problem(s) studied | Diabetes, Infection |
Intervention(s) | Active comparator: 20 or 40 larvae of the human hookworm Necator americanus (20 L3, 40 L3) over 24 months. |
| Placebo comparator: Tabasco sauce solution |
Key inclusion and exclusion criteria | Ages eligible for study: 18–50 years; Sexes eligible for study: both; Accepts healthy volunteers: no |
| Inclusion criteria: Healthy adults 18–50 years, with central obesity (WC > 90 cm for females and > 102 cm for males) and increased insulin resistance as assessed via abnormal homeostatic model assessment of insulin resistance (HOMA-IR), i.e. HOMA-IR > 2.12 or at least two other features of MetS: elevated blood pressure > 135/85 mmHg, dyslipidaemia, or abnormal liver function test suggesting fatty liver disease. Have provided written informed consent and are willing to comply with all Protocol scheduled visits. If of childbearing potential, must be willing to use the acceptable methods of contraception. |
| Exclusion criteria: Pregnancy, established chronic disease (CVD, diabetes, cancer, renal, gut disorder), history of substance abuse or current substance abuse, major allergies, known immunodeficiency disorder, asthma, taking prescribed medications or nutritional supplements likely to interfere with study outcomes, inability to provide informed consent. |
Study type | Interventional |
| Allocation: block randomised; intervention model: parallel assignment; Masking: double-blind, sealed envelopes and containers |
| Primary purpose: prevention |
| Phase 1 |
Date of first enrolment | March 2018 |
Target sample size | 45 |
Recruitment status | Recruiting |
Primary outcome(s) | Safety of experimental inoculation with 20 L3, defined by (a) Number of reported adverse events (AEs), relative to placebo cohort, (b) Assessment of general health and (c) Successful completion of 24-month trial. Adverse reactions: including but not limited to abdominal pain, rash, fever, weight loss, fatigue, nausea (mild, moderate or severe as assessed by trial doctor). |
Key secondary outcome(s) | Changes in insulin sensitivity from blood pathology taken at each participant contact point during the 24-month trial; Change in BMI measured by any alteration in weight (kg) and height (cm); Change in waist circumference (cm) Change in bacterial richness of microbiome measure by shotgun assay of faecal sample |
Hypotheses are that experimental infection with the human hookworm
Na
1.will be well-tolerated and safe in this cohort of otherwise healthy but obese women and men.
2.will induce a biased Type 2 and regulatory immune response with concomitant suppression of systemic, pro-inflammatory Type 1 responses.
3.will stabilise or improve determinants of metabolic disease.
4.will modify the composition of the gut microbiota.
Discussion
To our knowledge, this is the first study to examine the long-term safety/tolerability of experimental inoculation with different doses of the hookworm Na in human subjects with central adiposity and signs of MetS. With safety of helminth therapy as the primary outcome, this study will also allow observation and quantification of the longer-term effects of helminth therapy on metabolic disease progression, providing a foundation for future research into dose-controlled helminth-based therapies.
The steeply rising cost of healthcare associated with overweight and obesity-induced metabolic diseases, including T2DM, in Australia [
31] and increasing cases of obesity and T2DM in children of obese or overweight mothers [
32] urgently calls for new approaches in preventing disease progression. Several compelling lines of evidence from animal models and human studies point to a potential role for helminths in significantly reducing the impact of obesity on disease progression. Pathways may involve skewing the immune response to a Th2 or regulatory (anti-inflammatory) response as well as alteration of the gut microbiota with helminth infection. We are pioneering the safe delivery of experimental
Na infection in human trials and are, thus, uniquely placed to undertake a world-first proof-of-principle trial to determine the safety and effectiveness of
Na infection in limiting the inflammatory and metabolic cascades that are associated with obesity and T2DM.
Recent research has highlighted the complex interplay between the organisms that comprise our intestinal microbiota (commensal bacteria), macrobiota (helminths), and the host mucosal immune response. Consequently, the absence of either micro- or macrobiota may disturb homeostasis in the host and predispose the immune system to a more pro-inflammatory response [
33]. Helminths can directly influence the immune regulatory function via secretion of various products and indirectly via alteration of the microbiota [
33]. In turn, alteration of the microbiota can also promote or depress helminth presence in the host [
33]. Critically, these interactions are fundamental in shaping the health and homeostasis of the immune system; however, the mechanisms involved remain poorly understood. The present trial will offer a rare opportunity to examine the nature, kinetics, and interactions of parasite-induced changes in systemic immune responses, in composition of the gut microbiota, and in metabolic status within the carefully controlled context of a hookworm challenge trial. The findings will provide valuable information regarding the potential mechanisms by which hookworms, potentially via alterations in the microbiota, may positively influence metabolic health.
While live worm therapy is unlikely to be a widely acceptable therapy in T2DM prevention for the general public, discovering novel immune-regulatory, worm-secreted molecules may attract investment from pharma for other inflammatory conditions. Hence, this trial will be fundamental for providing the rationale for future endeavours to identify hookworm-secreted factors that could be tested as therapeutics that are more amenable to wider populations and have commercial potential.
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