Sucralose, a common artificial sweetener, may be preventing the body from responding to cancer immunotherapy, a new study out of the University of Pittsburgh finds.

The results come as the U.S. Department of Health and Human Services turns its attention toward ultraprocessed foods, with efforts to ban artificial food dyes and sweeteners. The Make America Healthy Again Report, released in May by the White House, spotlights artificial sweeteners such as aspartame and sucralose as ubiquitous and concerning for a variety of reasons — including their role in compromising the integrity of the microbiome and the success of cancer treatments.

Inside the body's digestive tract, the microbiome houses trillions of bacteria and around 5,000 different bacterial species. While it has many roles — including helping to digest food — it's also a key contributor to a person's immune function. The microbiome is home to 80% of the body's immune cells, per the Cleveland Clinic.

Scientists are starting to learn more about just how critical a healthy microbiome is — and what leads to an unhealthy one. Sucralose, it turns out, is one culprit.

"It's been shown very recently that these artificial sweeteners can actually greatly impact your gut microbiome, and that they're actually not inert," said Abby Overacre, assistant professor in the University of Pittsburgh's immunology department and first author on the new Pitt paper.

Previous studies on sucralose's impact on the gut found that the artificial sweetener can disrupt bacteria diversity and lead to a state of disarray and inflammation. One small study published in the journal Microorganisms in 2022 found that healthy people who consumed sucralose for 10 weeks showed signs of altered glucose and insulin function compared to a control group.

Researchers at Pitt partnered with a clinical team at UPMC Hillman Cancer Center to learn more about how sucralose was interfering with the microbiome, potentially altering cancer treatment outcomes in both mice and humans.

In a series of experiments, they induced either colorectal cancer or melanoma in mice and spiked their water with either sucralose or regular sugar. The dose was equivalent to three sugar packets.

Common energy and hydration drinks, like Celsius, Bang Energy and Gatorade Zero, would "blow that amount out of the water," she added.

They then treated the mice with a type of cancer therapy called a checkpoint inhibitor. In many cancers, the body's T cells, a type of immune cell, become exhausted trying to fight the cancer. Tumor cells can also send signals allowing them to evade detection by the immune system. Checkpoint inhibitors cut the brakes on T cells to enable them to keep fighting cancer.

After giving the mice the checkpoint inhibitor treatment, scientists measured improvement. They found that mice drinking regular sugar water improved, whereas mice drinking the sucralose water succumbed to their cancer. Specifically, researchers learned that the mice's T cells were dysregulated in the presence of sucralose.

These results were corroborated by human clients who were being treated at UPMC Hillman Cancer Center. Patients with melanoma and patients with non-small cell lung cancer who had been on a certain type of cancer immunotherapy were given a dietary history questionnaire so researchers could learn about their sucralose consumption.

They discovered that patients who reported higher sucralose consumption were linked to worse immunotherapy outcomes, as well as a greater risk of disease progression over time. The same findings did not pan out for other artificial sweeteners, such as aspartame.

Francesca Gazzaniga, assistant professor of pathology at Massachusetts General Hospital and Harvard Medical School specializing in the microbiome's role in cancer immunotherapy, said the researchers did well in investigating the impact of sucralose on immune responses.

"It's adding to this growing literature that the microbiome can impact the immune response," said Gazzaniga, who was not involved in the study.

The researchers didn't stop there, though. In a quest to understand how sucralose was interacting with the microbiome to lead to these outcomes, they studied stool samples.

It turned out that an amino acid called arginine plays an important role in the dance within the microbiome. When evaluating the stool samples from the mice who drank the sucralose water, they saw signs of arginine degradation.

Arginine helps the body create proteins, which is vital to developing new cells and repairing tissue. The amino acid can be found in meat, nuts, dairy and fish, and is sometimes used to treat conditions such as migraines and heart failure.

Additionally, mice who hadn't drank the sucralose water underwent a fecal microbiota transplant with a stool sample from the sucralose mice — and they ended up performing just as poorly as the sucralose mice in their immunotherapy outcomes.

Instead of convincing patients to change their lifestyles and stop using sucralose-filled Splenda and other products, or laboring over how they might develop a new cancer treatment to address this, researchers discovered a simple solution: They added arginine back into the mice's water bottles. T cell function was restored, and the mice who were suffering from failed immunotherapy due to sucralose began to get better.

The findings could hint at potential future treatment outcomes from human cancer patients, after further study.

"There's so much money going toward new drugs, and what we are showing is they don't always work," said Diwakar Davar, associate professor of medicine at the University of Pittsburgh, a medical oncologist and hematologist at UPMC Hillman Cancer Center and senior author on the paper. "Giving someone arginine to fix your sucralose addiction is a lot cheaper than giving someone a new cancer drug."

Davar's team at UPMC Hillman is planning another study with Overacre and her team at Pitt. The beauty of collaboration, said Overacre, is that while her lab can examine more closely the effects of different artificial sweeteners on mice, Davar can follow up with human patients and track their outcomes over time.

Gazzaniga, of Harvard and Mass General, said it's an exciting day in her field when a new study comes out, because it helps everyone understand how they can improve patient outcomes for those with cancer.

"With what's known now, I think we all can agree that the microbiome impacts the response to cancer immunotherapy," she said. "It would be really great if we can figure out the best way to take advantage of that and help people."

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