A common artificial sweetener loved by millions weakens the effects of cancer treatments.
University of Pittsburgh researchers discovered that sucralose, a zero-calorie sweetener, reduced immunotherapy effectiveness in melanoma and non-small cell lung cancer patients.
Initially developed in the 1970s for people with obesity and diabetes to sweeten food while avoiding blood sugar spikes, sucralose, more commonly known as Splenda, has become ubiquitous.
It’s used in over 4,500 foods and drinks, including diet sodas and low-calorie foods. In the US, it accounts for 30 percent of the sweetener market.
Cancer patients undergoing immunotherapy, which boosts the immune system to recognize and kill cancer cells, may reach for a diet soda or sugar-free baked good, believing they’re making a healthy choice.
However, sucralose kills some good bacteria that reside in the gut while allowing harmful strains to grow, impacting the body’s ability to digest foods and break down fiber, train immune cells to fight pathogens, make vitamins like folate and B12, produce serotonin, and reduce inflammation.
Senior author Dr Diwakar Davar, an oncologist and hematologist at UPMC, said in a statement: ‘We found that sucralose impeded the effectiveness of immunotherapies across a range of cancer types, stages and treatment modalities.
‘These observations raise the possibility of designing prebiotics, such as targeted nutrient supplementation for patients who consume high levels of sucralose.’
Cancer patients on immunotherapy might choose diet drinks or sugar-free treats thinking they’re healthier options (stock)
The team used mouse models, some with lung cancer and some with melanoma, to test how sucralose altered their microbiomes, finding that the sweetener disrupted the delicate balance.
This reduced key amino acids such as arginine, which are needed to fuel immune cells. It also led to dysfunctional CD8+ T cells, critical for fighting cancer, and blunted the effects of anti-PD-1 immunotherapy, a class of cancer treatments that includes popular medicines Keytruda and Opdivo.
Lead author Dr Abby Overacre, an immunology professor at Pitt and UPMC Hillman, said: ‘When arginine levels were depleted due to sucralose-driven shifts in the microbiome, T cells couldn’t function properly.
‘As a result, immunotherapy wasn’t as effective in mice that were fed sucralose.’
To assess the relevance of these findings for humans, they questioned 132 advanced cancer patients, including 91 people with melanoma and 41 with lung cancer, about their sucralose intake, as well as 25 people at high risk of their melanoma recurring.
People reported drinking diet sodas, using the artificial sweetener in coffee and tea, and eating low-calorie snacks sweetened with it.
A high amount of sucralose was considered anything above 0.16 mg per kilogram of body weight per day. For a 155-lb person, that’s less than a single packet of Splenda.
People with melanoma and lung cancer who consumed at least that much sucralose had a 3.2 times higher risk of their cancer progressing faster, as well as less tumor shrinkage in response to immunotherapy.
Sucralose reduced immunotherapy effectiveness in various cancers regardless of type, stage, or treatment approach
People at risk of melanoma recurrence who drank or ate at least that much sucralose had a higher risk of their cancer returning after surgery and immunotherapy and fewer signs of a strong immune response to tumors.
Experiments in mice revealed that disruption to the microbiome due to sucralose was the driving force behind alterations in their cancer-fighting T cells, which were starved of the crucial amino acid arginine.
When scientists transplanted feces from sucralose-fed mice into untreated mice, the latter exhibited a similar poor immune response to immunotherapy.
But when scientists supplemented their low levels of arginine using the amino acid citrulline, commonly found in melons, pumpkins, and legumes, T cells regained their cancer-killing ability, reversed their resistance to immunotherapy, and their tumors shrank.
Their findings were published in the journal Cancer Discovery.
Dr Overacre said: ‘It’s easy to say, “Stop drinking diet soda,” but when patients are being treated for cancer, they are already dealing with enough, so asking them to drastically alter their diet may not be realistic.
‘We need to meet patients where they are. That’s why it’s so exciting that arginine supplementation could be a simple approach to counteract the negative effects of sucralose on immunotherapy.’
The researchers hope to launch a clinical trial investigating whether citrulline supplements, which boost arginine levels more than arginine itself, affect the gut microbiome and anti-tumor immune response in patients.
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