Infecting people at risk of type 2 diabetes (T2D) with hookworms is a safe and well tolerated treatment that could improve insulin resistance, results from an Australian pilot trial suggest.

Researchers, led by the Centre for Molecular Therapeutics at James Cook University in Cairns, claim to have provided the first reported controlled-trial evidence for the beneficial effect of helminth infection in metabolic disease.

They say their findings support the hypothesis that intestinal parasites can trigger Type 2 immune responses such as eosinophilia to counter the systemic low-level inflammation that is known to be promote insulin resistance.

“The results provide critical proof of principle that hookworms and/or the biological changes they invoke in their human hosts are a safe and potentially beneficial intervention for improving determinants of metabolic health and preventing the development of T2D,” they wrote in a paper on the preprint server medRxiv.

Their proof-of-concept study [link here] involved 40 participants deemed otherwise healthy adults at risk of developing T2D who were randomised to receive either 20 or 40 Necator americanus third-stage larvae (L3-20 and L3-40 respectively) or placebo.

Participants, the majority of whom were of caucasian descent (85%), were recruited between January 2018 and June 2020 for the two-year double-blinded placebo-controlled trial.

The primary outcome was the safety and the tolerability of experimental hookworm infection.

There were 20 adverse events in total, which were typically mild to moderate.

Adverse events were more frequent in hookworm-treated participants, where 44% experienced transient gastrointestinal (GI) symptoms, including bloating, nausea, vomiting, constipation, diarrhoea, epigastric upset, stomach cramps and abdominal pain.

Three of the hookworm-treated participants displayed GI symptoms that warranted early removal from the study and deworming; one trial participant had severe GI symptoms.

There were no GI-related adverse events in the placebo group.

However, only 24 out of the 40 participants completed the trial.

Fasting blood glucose (FBG) and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) values were significantly lowered in both hookworm-treated groups at one year.

Median change in HOMA-IR values in the L3-20 group was significantly different from placebo, with a reduction of 1.1 units from baseline value at one year and 1.4 units at 18 months, whereas the L3-40 group had “less dramatic” improvements, the team said.

Meanwhile, median FBG levels were significantly reduced from baseline levels after six months in both the L3-20 (5.2 mmol/L to 4.5mmol/L) and L3-40 groups (5.3mmol/L to 4.3mmol/L), with similar significant reductions in the L3-40 group at 12 months.

In contrast, median FBG levels for the placebo group did not significantly deviate.

In secondary metabolic outcomes, hookworm infection did not appear to improve blood lipid profiles and there were only modest reductions in body mass and BMI.

“Until now, a potential supportive role for worms in metabolic health has relied on animal studies and human cross-sectional or deworming studies that could not infer causality,” the researchers said in their paper.

“Infection with low doses of hookworms caused significantly reduced measures of glucose homeostasis (lowered HOMA-IR and fasting blood glucose) compared to pre-infection and placebo treatment, which was associated with modest body mass reductions.

“Diet and physical activity changes could not explain these improvements.”

However, the researchers noted that the small sample size limited their ability to make firm conclusions and further exploration of the benefits of hookworms was warranted.

All hookworm-treated participants who completed the study except one opted to retain their worms, with the sole individual who dewormed doing so in preparation for a medical procedure, the researchers said.

Interest in a possible role of hookworms in insulin resistance had stemmed from proponents of the hygiene hypothesis, who had noted the increasing prevalence of inflammatory and metabolic disorders in populations with a low prevalence of helminth infections.

“It follows that maintaining the systemic and adipose-specific inflammatory balance in favour of a Type 2 or regulatory immune response is a rational approach to limiting the inflammatory cascade and preventing the ensuing insulin resistance seen in metabolic disease,” the researchers wrote.