Artificial sweetener sucralose shown to dampen immunotherapy effectiveness
Sucralose has been shown to reduce the effectiveness of anti-PD-1 immune checkpoint inhibitor therapy by interfering with gut microbiota. However, probiotic supplements may help to counteract these effects.
Researchers from the University of Pittsburgh and UPMC Hillman Cancer Center (both PA, USA) have uncovered that sucralose – a popular artificial sweetener – hinders the effectiveness of anti-PD-1 based immune checkpoint inhibitor (ICI) immunotherapy by interfering with the gut microbiome. The team hope that this could be mitigated by incorporating probiotics into patients’ diets.
ICI immunotherapies often yield variable treatment success, with many patients unable to sustain a durable response, requiring close observation and alternative treatment plans. Identifying why some patients respond differently to treatments can help clinicians tailor treatment plans to boost treatment success. In recent years, the gut microbiome has been recognized as an important tumor-extrinsic regulator of immunotherapy response. Therefore, understanding how factors such as diet and probiotics change the gut microbiome and the consequential effects on ICI treatment response has become a focal point for immunotherapy researchers.
Artificial sweeteners, a popular constituent of many people’s diets, are proven to alter the gut microbiome. In this study, the Pittsburgh-based research team sought to identify the impacts of one popular sweetener type – sucralose – on gut microbiota and characterize subsequent effects on ICI response.
The researchers surveyed 132 patients with advanced melanoma or NSCLC who had received anti-PD-1 immunotherapy alone or in combination with chemotherapy. By using a self-reporting dietary questionnaire, the team quantified how often study participants consumed sucralose in tea, coffee and soft drinks. The results confirmed that higher levels of sucralose were associated with poorer immunotherapy efficacy across both cancer types.
To elucidate the mechanisms by which sucralose was hindering treatment effectiveness, the researchers fed varying concentrations of the sweetener to groups of tumor-bearing mice during treatment with ICIs. Consistent with the survey finding, they observed that mice fed with higher concentrations of sucralose responded less favorably to anti-PD-1 treatment than those fed with lower sucralose diets.
By analyzing blood, tumor fluid and stool samples from the mice, the researchers also found that higher sucralose consumption led to an increase in particular species of gut bacteria that deplete arginine, an amino acid essential to T-cell function and anticancer activity.
Interestingly, the negative effects of sucralose on immunotherapy could be prevented by feeding the mice supplements that restored arginine production, indicating this could be a helpful strategy for ICI patients who didn’t want to give up dietary sweeteners.
“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,” explains Abby Overacre, lead author. “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.”
In terms of next steps, the researchers are hoping to initiate a clinical trial to investigate whether citrulline supplements can mitigate the immunotherapy-dampening effects of artificial sweeteners and how other sugar substitutes impact immuno-oncology.