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31 July 2023

A JCU world-first human trial into the safety and efficacy of using live hookworms to treat metabolic disorders, including heightened insulin resistance – a precursor to Type 2 diabetes – has yielded promising results, sparking interest in staging an international, larger-scale trial.

Results of the study, conducted by AITHM PhD researcher and recent PhD graduate Dr Doris Pierce, indicated that hookworm infection was safe and well-tolerated, and had a beneficial impact on metabolism, inducing a clinically significant reduction in insulin resistance levels in most trial participants.

Dr Pierce recruited 40 people – all with early warning signs of metabolic diseases – to take part in the two-year clinical trial, which concluded in early 2022. The participants, from Cairns and Townsville, ranged in age from 27 to 50.  Seventy-five per cent were women.

Participants were inoculated with either 20 or 40 infectious larvae of the human hookworm species Necator Americanus or a placebo. The trial was double-blinded, so neither the participants nor the researchers knew who was receiving which treatment.

After two years, participants were offered a deworming medication or could elect to stay in the trial for a further 12 months. All but one of the infected participants, who dewormed before undergoing a planned medical procedure, decided to keep their worms.

“Metabolic diseases are characterised by inflammatory immune responses and an altered gut microbiome. Previous studies with animal models have indicated that hookworms induce an anti-inflammatory response in their host to safeguard their own survival,” said Dr Pierce.

Successful efforts to eradicate parasitic worms in developed countries are now linked to increases in human inflammatory and metabolic diseases, including Type 2 diabetes.

All participants in the JCU trial received regular clinical health checks for safety purposes. Blood and faecal samples were collected to monitor any alterations to their immune response and gut microbiome composition. Participant mood and mental well-being were evaluated by the Patient Health Questionnaire-9 (PHQ-9), which assesses the degree of depression.

Sixteen of the 40 participants left during the trial, mostly due to changes in personal circumstances, such as job-related relocations away from the trial sites. Only three opted out due to hookworm-related gastrointestinal discomfort, which was remedied as soon as they were dewormed. All the remaining participants completed the full three-year trial with no serious adverse health consequences.

In fact, the trial delivered some considerable metabolic benefits to the hookworm recipients, particularly those infected with 20 larvae.

Participants recruited for the trial had a Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) level greater than 2.12 units or two other indicators of metabolic syndrome, a cluster of risk factors, including high blood sugar, elevated blood pressure, and abnormal blood lipids, which significantly increase the risk of developing cancer and cardiovascular disease, as well as Type 2 diabetes.

Strikingly, participants infected with 20 hookworms experienced a HOMA-IR level drop from their pre-trial level of 3.0 units to just 1.8 units within 12 months, restoring their level of insulin resistance to a normal, healthy range. The improvements in insulin resistance were not as marked in the people who received 40 hookworms, but their HOMA-IR levels still dropped from 2.4 to 2.0.

“These lowered HOMA-IR values indicated that people were experiencing considerable improvements in insulin sensitivity – results that were both clinically and statistically significant,” observed Dr Pierce.

People who received the placebo treatment had their HOMA-IR values increase from 2.2 to 2.9 during the same period, providing compelling evidence that the improvements were indeed due to the hookworm treatment.

Worm-treated recipients had elevated levels of cytokines, small proteins which play a crucial role in stimulating the immune response of white blood cells such as eosinophils and basophils, which were also present at higher levels. These findings were supported by earlier studies that linked this type of immune activity to the presence of parasites and improvements in insulin resistance.

The Patient Health Questionnaire-9 indicated that, overall, trial participants were in a positive mood, which improved a little during the study. However, worm recipients tended to report feeling better, mood-wise, than those in the placebo group.

“That was an interesting observation as well, given that much of the trial took place during the first waves of the COVID-19 pandemic. I think that to see any improvement in mood was remarkable in itself,” said Dr Pierce.

She has now embarked on the next phase of her study, investigating samples provided by trial participants to record any changes in their gut microbiome health.

“Are some species of bacteria more or less common in the microbiome of people with insulin resistance and obesity? And does hookworm infection help redress any such imbalances?”

Dr Pierce’s PhD supervisor, AITHM Senior Research Fellow and immunologist, Dr Paul Giacomin, said the trial results warranted follow-up studies on a larger scale, which could be conducted at multiple test sites in Australia and overseas.

“The JCU trial provides sufficient proof of concept that infection with live hookworms is safe and appears to have some sort of beneficial effects on people’s metabolic health, which will hopefully be confirmed by future clinical trials designed to confirm efficacy and explore how hookworms influence metabolism,” he said.

“A wider, international trial will also allow us to gain a better understanding of the differential effects of hookworm infection on people of different ages, genders, races, and genetic backgrounds.”

In the meantime, JCU is already working with collaborators to standardise the production of hookworms suitable for advanced clinical trials.

Further trials may also identify specific worm proteins that influence human metabolism and/or immune and microbiome pathways utilised by worms, both of which could facilitate the eventual development of treatments that do not rely on live worm infection,” he said.

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