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Sucralose Consumption Ablates Cancer Immunotherapy Response through Microbiome Disruption
Kristin M Morder1,2, Madison Nguyen1, Drew N Wilfahrt1,2
1UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.
Abstract:
Gut microbiota composition is directly associated with response to immunotherapies in cancer. The impact of diet on the gut microbiota and downstream immune responses to cancer remains unclear. In this study, we show that consumption of a common nonnutritive sweetener, sucralose, modifies microbiome composition, restricts T-cell metabolism and function, and limits immunotherapy response in preclinical models of cancer and patients with advanced cancer treated with anti-PD-1-based immune checkpoint inhibitors. Sucralose consumption is associated with a reduction in microbiota-accessible arginine, and amino acid supplementation or fecal microbiome transfer from anti-PD-1 responder mice completely restores T-cell function and immunotherapy response. Overall, sucralose consumption destabilizes the gut microbiota, resulting in compromised T-cell function and ablated immune checkpoint inhibitor response in cancer.
Significance:
This study highlights an unappreciated role of sucralose in reducing immunotherapy efficacy in both mouse models and samples from patients with cancer through shifts in the microbiome and arginine degradation that lead to T-cell exhaustion. T-cell function and immunotherapy responses are restored through amino acid supplementation. See related commentary by Chandra et al., p. 2196.
Insights
Dietary sucralose impacts gut microbes, hindering cancer immunotherapy effectiveness. Restoring gut health via amino acids or fecal transplants can reverse these negative effects, improving T cell function and treatment response.
Area of Science:
- Oncology
- Immunology
- Microbiome Research
Background:
- Gut microbiota composition influences cancer immunotherapy response.
- The impact of diet, specifically non-nutritive sweeteners, on this relationship is not well understood.
Purpose of the Study:
- To investigate how sucralose consumption affects gut microbiota.
- To determine the downstream effects on T cell function and immunotherapy efficacy in cancer.
- To identify potential interventions to restore immunotherapy response.
Main Methods:
- Preclinical cancer models and advanced cancer patients treated with anti-PD-1 immune checkpoint inhibitors (ICIs).
- Analysis of microbiome composition and T cell metabolism.
- Intervention studies involving amino acid supplementation and fecal microbiome transfer (FMT).
Main Results:
- Sucralose consumption altered gut microbiota composition.
- Sucralose intake restricted T cell metabolism and function, leading to reduced ICI response.
- A reduction in microbiota-accessible arginine was observed with sucralose.
- Amino acid supplementation or FMT from responders restored T cell function and immunotherapy response.
Conclusions:
- Sucralose destabilizes the gut microbiota, compromising T cell function.
- Sucralose consumption significantly ablates anti-PD-1 immune checkpoint inhibitor response in cancer.
- Targeting gut microbiota and metabolic pathways presents a strategy to enhance cancer immunotherapy.
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