Scientists Infected People With Hookworms To Improve Their Metabolic Health

A world-first human trial has revealed that inoculation with live hookworms resulted in modest improvements in insulin resistance in a small study of 40 participants at risk for type 2 diabetes. The research is published in Nature Communications.

Parasitic worms and metabolic disease

Type 2 diabetes is a chronic condition characterized by resistance to the glucose-controlling hormone insulin and high blood sugar levels. There is a pressing need to develop new therapies for the condition as cases are on the rise globally, predisposing millions of people to further health complications such as heart disease or stroke.

Interestingly, metabolic and inflammatory diseases are less prevalent in areas where infection with parasitic worms is endemic, and cases of inflammatory and metabolic diseases have been growing in developed countries where there have been efforts to eliminate infections by parasitic worms.

However, there is currently no solid clinical evidence for the role of worms in protecting against metabolic disease: “Metabolic diseases are characterized by inflammatory immune responses, and previous studies have suggested that hookworms release proteins into their host to control the immune system and safeguard their survival,” said the study’s lead author Dr. Doris Pierce, a lecturer in oral biosciences at James Cook University (JCU).

To address this, Pierce and colleagues recruited 40 participants – all at risk of type 2 diabetes – into their 2-year clinical trial to infect them with either the parasitic hookworm Necator americanus or a placebo to assess the potential therapeutic benefits.

Modest improvements in metabolic health markers

All participants received regular health checks during the randomized, double-blinded trial in which 27 participants were inoculated with N. americanus eggs (larvae). Of these, 14 participants received 20 larvae and 13 received 40 larvae, while an additional 13 participants received a placebo.

The main aim of the study was to monitor the safety and side effects of inoculation, while also measuring other outcomes such as insulin resistance, fasting blood glucose (FBG) and body mass.

“The trial delivered some considerable metabolic benefits to the hookworm-treated recipients, particularly those infected with 20 larvae,” said Pierce.

Participants infected with 20 hookworms showed reduced levels of insulin resistance, measured by the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). HOMA-IR dropped from 3 units before the trial to just 1.8 units within 12 months – a statistically significant difference and a return to the healthy range.

Median FBG levels in the 40-larvae group were significantly reduced compared to placebo at both 6 and 12 months, though there was no significant difference in FBG in the 20-larvae group compared to placebo at any time point. There were no statistically significant differences in body mass or body mass index (BMI) in either of the two worm groups compared to placebo – however, the 20-worm group did show small but statistically significant reductions in body mass and BMI compared to pre-study levels at both 18 and 24 months.

Side effects were reported by 44% of the worm recipients, which were mostly mild to moderate, such as bloating, nausea, constipation, diarrhea and stomach cramps. Most resolved without medical intervention. Three individuals experienced side effects classified as severe and were given deworming treatments. Two recovered while one participant’s symptoms persisted, suggesting they were unrelated to the study.

After two years, participants could elect to stay in the trial for a further 12 months or take a deworming medication. Of those that completed the trial, all but one of the infected participants – who was preparing for a medical procedure – decided to continue.

Further studies required to draw firm conclusions

Overall, the study “suggests that experimental infection with low hookworm doses is safe and is associated with improvements in glucose homeostasis in people with metabolic syndrome and at risk of type 2 diabetes,” the authors write in the paper.

Of note, the authors explained that small sample sizes likely limited the ability to draw firm conclusions from the research. According to Dr. Paul Giacomin, senior author of the study and senior research fellow at JCU, the findings warrant follow-up studies on a larger scale: “This early-phase JCU clinical trial provides proof of concept that infection with live hookworms is safe and appears to lead to some improvements in people’s metabolic health, which will hopefully be confirmed by larger clinical trials in [the] future,” Giacomin said.

“Also, if we can learn more about what hookworms release into the body to influence metabolism, we may be able to design protein-based treatments that mimic the effect of the live worm,” he added.

Reference: Pierce DR, McDonald M, Merone L, et al. Effect of experimental hookworm infection on insulin resistance in people at risk of type 2 diabetes. Nat Commun. 2023;14(1):4503. doi: 10.1038/s41467-023-40263-4

This article is a rework of a press release issued by James Cook University. Material has been edited for length and content.