The sugar substitute sucralose makes immunotherapy less effective

Patients with certain types of cancers who consume sucralose, found in the artificial sweetener Splenda, respond worse to immunotherapy compared with those who don’t, researchers report July 30 in Cancer Discovery. But supplementing diets with the amino acid arginine might mitigate these effects, they say.

The findings add to a growing body of research showing that the gut microbiome — the vast community of microbes living in our digestive system — plays a crucial role in how well cancer treatments work. In this case, sucralose appears to disrupt beneficial gut bacteria that help support immune function, including T cells, the mainstay of our immune system.

“What’s new in this study is that sucralose is promoting a microbiome that has few of the beneficial bacteria and more of the not so useful ones,” says Magdalena Plebanski, an immunologist at RMIT University in Melbourne, Australia, who wasn’t part of the study. “[And that] sucralose could potentially be negatively affecting T cells directly.”

Previous research suggested that sucralose affects immunotherapy, but the underlying mechanism had not been clear. To investigate further, immunologist Abby Overacre and colleagues examined the gut microbiome in mice that were fed sucralose at levels equivalent to what humans might consume.

“Artificial sweeteners reduced [gut microbiome] diversity, and along with that, reduced overall levels of arginine,” says Overacre, of the University of Pittsburgh. “Arginine is very important for immune cell function, especially in cancer.”

The mice had been bred to have the same types of cancers as the human patients. Those fed sucralose showed reduced responsiveness to immunotherapy, but mice given regular table sugar responded just fine, Overacre says.

To see how this translated to humans, the researchers surveyed 132 patients with advanced melanoma or non-small cell lung cancer who were receiving anti-PD1 therapy, a kind of immunotherapy that targets a pathway used by cancer cells to evade the immune system. Patients filled out detailed questionnaires about their diets, including the consumption of artificial sweeteners.

Even small amounts of sucralose appeared to have an adverse effect on immunotherapy response.

“[We] identified a cutoff of approximately 0.07 milligrams per kilogram of body weight that segregated patients who did poorly compared to patients who didn’t,” says medical oncologist Diwakar Davar of the University of Pittsburgh, another of the study’s authors. He notes that this level is well below the U.S. Food and Drug Administration’s recommended daily limit for sucralose consumption — 5 milligrams per kilogram, or about 22 cans of diet Mountain Dew for a 70-kilogram male.

Despite the small quantities involved, Overacre advises patients undergoing immunotherapy not to panic by “throwing away everything in your kitchen.” Adding an arginine or citrulline supplement, which boosts arginine, is easy, she says.

Clinical oncology pharmacist Andrew Ruplin is a bit more measured noting that patients should discuss the implications of these findings with their oncologists to make appropriate decisions about supplementation.

The “data joins a growing body of evidence that the benefits and risks of immunotherapy may be altered by individual patient behaviors that were completely unknown to us previously,” says Ruplin of the Fred Hutchinson Cancer Center in Seattle, but he would like to see additional prospective human trials, with larger numbers of patients and different cancers included before implementing the findings in treatment.

The researchers hope to launch clinical trials to investigate whether supplements can improve both the gut microbiome and antitumor immune response in patients. They also want to look at the impact of other sugar substitutes on immunotherapy.