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Zani, F., Blagih, J., Gruber, T. et al. The dietary sweetener sucralose is a negative modulator of T cell-mediated responses. Nature 615, 705–711 (2023). https://doi.org/10.1038/s41586-023-05801-6
Sucralose is a general purpose sweetener that can be found in a variety of foods including baked goods, beverages, chewing gum, gelatins, and frozen dairy desserts. It is considered calorie free and is about 600 times sweeter than sucrose (the main constituent of white sugar). The maximum acceptable daily intake (ADI) of sucralose for humans has been established as 15 mg per kg (body weight) by the European Food Safety Authority (EFSA) or 5 mg per kg (body weight) by the US Food and Drug Administration (FDA).
Since previous reports have suggested that high doses of sucralose can have either pro-inflammatory or anti-inflammatory activities, this study decided to test a possible effect of sucralose on the immune system. They did so by conducting experiments on mice whose consumption of sucralose over 10 weeks was near the equivalent of the ADI recommended by either EFSA (at the 0.72 mg ml−1 dose) or FDA (at the 0.17 mg ml−1 dose). The plasma (a main constituent of blood) concentration in the mice being used reached around 1 μM at the highest dose of sucralose, consistent with the levels that can be achieved in humans.
The focus of the study, within the immune system, was T-cells, which are a type of white blood cell that develop from stem cells in bone marrow, help protect the body from infection and may help fight cancer. First, the study tested the effect of sucralose on T-cell proliferation (rapid growth). During illness and stress, the immune system can suffer a considerable loss of T cells. The remaining T cells undergo vigorous compensatory expansion, known as homeostatic proliferation, to reconstitute the immune system. They found that certain types of T-cells, known as CD8+ and CD4+ T cells, showed reduced homeostatic proliferation in sucralose-treated mice at both the EFSA and FDA dose. However, it did not affect the cells’ viability (ability to work properly).
Differentiation is a process by which a less specialised cell undergoes maturation to become more distinct in form and function. T-cell differentiation and the functioning of their effectors (cells that performs a specific function in response to a stimulus) have a critical role in determining T-cell responses. The study found that both these functions significantly decreased in the presence of sucralose but not with the other sweeteners, suggesting that high sucralose exposure decreases T-cell proliferation and differentiation.
T-cells are activated by calcium signalling in response to stimuli such as an invasion by foreign bacteria or viruses. Through further experiments, this study found that sucralose led to a defect in the release of intracellular (within cells) calcium stores, which may be the cause of a mitigated T-cell response. However, they found that sucralose did not impede calcium signalling in other immune cell types such as B-cells or dendritic cells. It is possible that the membrane composition of T cells makes them particularly sensitive to sucralose and it remains to be determined whether sucralose affects other cell types, including other immune cells, in conditions not tested in this study.
To investigate the effect of sucralose on the human immune system, since tests so far had been on mice, the effects of sucralose on human tumours were examined and similar results were found: the activity of T-cells against these tumours was diminished in the presence of sucralose.
In further tests, they also found that the removal of sucralose resulted in the recovery of the normal proliferation rate in T-cells, suggesting that the response to sucralose is reversible.
In conclusion, this study revealed an unexpected role for high doses of sucralose in modulating immunity by affecting T-cell proliferation, differentiation and effector function. It should be noted that although the doses of sucralose used in this study are clearly higher than those resulting from normal human dietary consumption of sucralose-sweetened drinks and foods, they are relevant to the ADI recommendation when adjusted for mice. The findings do not provide evidence that normal sucralose intake is immuno-suppressive, but they do demonstrate that at high (but achievable) doses, sucralose has an unexpected effect on T-cell functions. The study was corroborated by previous works, however, further experiments are necessary to determine the precise mechanistic details of how sucralose affects T-cell signalling. Although the results support a direct effect of sucralose on T-cell signalling, the possibility that sucralose may also affect T-cells through additional mechanisms, such as epigenetic changes (changes in the expression of genes due to environmental stimuli) in response to long-term sucralose exposure cannot be excluded. This study was useful as it added to the evidence that sucralose is not an inert molecule and may affect human health. This work could pave the way for treatment with doses of sucralose for various conditions arising from unrestrained T-cell activity, such as autoimmune disorders.
Summarised by Radhika Jain
Works Cited
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