Hookworm Therapy: Advancing Type 2 Diabetes treatment?

Nature Communications, in its summer edition of 2023, brought forth ground-breaking research that could potentially revolutionise the treatment and prevention of metabolic diseases, particularly type 2 diabetes. Researchers utilised live hookworm infections which resulted in significant improvements in insulin resistance among volunteers at risk of type 2 diabetes, igniting enthusiasm for a larger-scale international trial involving hookworm therapy.

When hookworms come to mind, the typical association is tiny parasitic worms that can cause illness. Nevertheless, since the 70s scientists have been investigating helminth (worm) infections as a possible strategy to address a range of ailments encompassing allergies, autoimmune diseases, and now, metabolic conditions. The theory behind this approach is rooted in the hygiene hypothesis, which suggests that the decline in parasitic worm infections, due to improved sanitation, may have contributed to rising rates of metabolic and autoimmune diseases.

Metabolic Diseases and Type 2 Diabetes: A Growing Concern

Metabolic diseases encompass a range of health conditions often characterised by inflammatory immune responses. An example of a metabolic disease is type 2 diabetes—a chronic ailment characterised by insulin resistance and elevated blood sugar levels. The prevalence of type 2 diabetes is increasing globally, with over half a billion adults already diagnosed. In the UK, more than 4.9 million individuals are presently diagnosed with diabetes, and the vast majority of them (around 90%) have type 2 diabetes. This growing health concern calls for innovative preventative approaches to reduce the burden on individuals and healthcare systems.

The Hygiene Hypothesis: Why hookworms?

In regions where parasitic worms are endemic, the prevalence of type 2 diabetes and other metabolic diseases tends to be lower. However, the introduction of deworming programs in these areas has been followed by an increase in metabolic disease rates. Interestingly, when people are ‘dewormed’, their insulin resistance tends to surge. Insulin resistance is a critical factor in regulating blood sugar levels and plays a role in the development of metabolic issues like type 2 diabetes and cardiovascular disease. However, it is crucial to acknowledge that the rise in diabetes after interventions in these areas may result from lifestyle changes, such as a reduction in exercise or increased fast food consumption. 

Figure 1: Effect of deworming on frequency of metabolic disease

Hookworms and Immune Response: The connection 

Low-grade, systemic inflammation is a well-established contributor to insulin resistance. A biased type-1 immune response can worsen insulin resistance by targeting components in the insulin-signalling pathway. Therefore, to combat insulin resistance in metabolic diseases, maintaining a balanced inflammatory response by favouring a type 2 or regulatory immune response, is essential to halt the detrimental cascade of inflammation.

Helminth infections are associated with type 2 immune responses and alterations to the gut microbiome. Studies involving worm infections in animal models have demonstrated improvements in metabolic parameters, type 2 immune responses, and changes in the gut microbiome, but no human trials have been conducted. Until now.

The study: A Pioneering Human Trial

The world-first human trial conducted at James Cook University involved experimental hookworm infection in 40 participants, all at risk for type 2 diabetes and cardiovascular disease. In a two-year, randomised, double-blinded clinical trial, 27 participants were infected with either 20 or 40 Necator americanus larvae, while 13 received placebos.

In order to induce a placebo effect, or in this instance, a nocebo effect, researchers employed chilli pepper sauce to simulate the sensation of hookworm larvae penetrating the arm. This approach is commonly referred to as a sham intervention, as it led the control group participants to believe that they had also been exposed to hookworms.

The primary aim of this phase 1 study was to confirm the safety of this innovative therapy. The study showed that adverse events were more frequent in the hookworm-treated group, mainly manifesting as gastrointestinal symptoms, but completion rates were comparable to the placebo group.

Remarkably, the study found that low hookworm infection was associated with improvements in insulin resistance and fasting blood glucose, with all but one participant opting to keep their hookworms after the trial. Notably, the consistent monitoring of dietary and physical activity habits did not reveal any discernible changes between the infected and control groups. 

Figure 2: Summary of study findings

Promising Results: The Path Ahead

The research offers a promising insight into the potential of live hookworms for improving metabolic health. While these results are encouraging, it is essential to recognize that this is just the beginning. Larger clinical trials are needed to determine the optimal dosage of hookworms and to clarify the mechanisms behind their positive effects on metabolic health. Researchers hope to uncover the specific molecules released by hookworms that suppress inflammation and improve metabolism.

In the quest to harness the power of hookworms, scientists are exploring protein-based treatments that mimic the effects of live worms, potentially providing a more palatable and controlled alternative for patients. However, many questions remain unanswered, including how hookworms precisely impact human metabolism, whether through immune system manipulation and/or weight loss.

Closing Thoughts: Are we hooked?

Before rushing to embrace hookworms as a solution for metabolic and autoimmune diseases, it's vital to remember that these results are preliminary and come with some caveats. Individual responses may vary depending on the dosage and follow-up protocols. 

This research paves the way for future investigations, offering new hope in the fight against type 2 diabetes and metabolic diseases. As the scientific community delves deeper into the potential of hookworms, we may unlock new possibilities for improved metabolic health and overall well-being.