This sweetener has an unexpected impact on immunity

Brent R. Stockwell, Ph.D.
5 min readMar 20, 2023

Sucralose (Splenda) impairs T cell immunity and promotes infections and cancers, but also mitigates autoimmune diseases.

An unexpected effect of an artificial sweetener

Sugar tastes good.

Sugar is used to enhance the taste of many foods, especially desserts, such as cakes, pies, and cookies. However, sugar can have a dark side, promoting weight gain, tooth decay, diabetes, and a disease-associated microbiome.

As result, for decades, zero-calorie sugar substitutes, such as aspartame, saccharin, and sucralose, have been developed and used in diet sodas and low calories foods. While these artificial sweeteners are generally perceived as safe, a some negative health effects have been identified.

Sugar (Adobe Stock)

Recently, a new paper in Nature from Karen Vousden and colleagues found that sucralose, which is marketed as Splenda, impairs immune responses in mice:

Sucralose prevents T cells from proliferating

The authors gave mice either sucralose or saccharin in their drinking water, and the impact on a variety of immune cells determined. There was no effect on most immune cells, including neutrophils, monocytes, B cells, natural killer cells, macrophages, or dendritic cells. Thus most immune cells were unaffected.

However, sucralose ingestion did impair T cells, whereas saccharin ingestion did not.

Interestingly, the effect on T cells was not mediated by the normal sweet taste receptor through which sucralose causes its sweet taste. Sucralose induced its effect on T cells through an unexpected change in the membranes of these cells.

Sucralose specifically blocked T cell proliferation induced by the T cell receptor, not other T cell stimulation mechanisms.

In short, sucralose has a surprising and specific effect on one type of immune cells.

Artificial sweeteners
Artificial sweeteners (Adobe Stock)

Sucralose changes the properties of T cell membranes

The authors set out to determine how sucralose impairs T cell proliferation.

They found that sucralose does not affect glucose consumption or processing, insulin levels, body weight, lean or fat mass, or body weight.

However, they were able to determine that sucralose specifically impairs activation of phospholipase C gamma 1( PLCγ1) downstream of the T cell receptor.

PLCγ1 is a protein that is normally activated in T cells after T cell receptors are activated.

To determine how sucralose could impair PLCγ1 activation, the authors used a combination of fractionation and mass spectrometry imaging of T cells, and found that sucralose was mostly localized to the membranes of T cells.

Moreover, they found that accumulation of sucralose in the membrane of T cells prevents clustering of PLCγ1 proteins together, which is required for PLCγ1 and T cell activation.

T cell receptor
T cell receptor in the membrane of a T cell (Adobe Stock)

Sucralose accelerates cancer and infections by reducing T cell numbers

The authors found that the impairment of T cells caused by sucralose reduced the ability of T cells to infiltrate into tumors in mice, which is required for immune-mediated tumor suppression.

Thus, tumors in mice fed sucralose grew much larger. This is obviously concerning.

Mouse drinking diet soda
Mouse drinking diet soda with sucralose (generated with Midjourney)

The researchers also tested the effect of sucralose on infection by Listeria monocytogenes — they found that the resulting infection was more severe in mice fed sucralose, consistent with impaired T cell responses to the infection.

OK, so sucralose can make infections worse, when those infections depend on T cell responses.

Listeria monocytogenes (Adobe Stock)

Sucralose may be useful for treating autoimmune diseases

Sometimes T cells become overactivated and cause autoimmune disorders. In such a context, the authors hypothesized that sucralose could be beneficial. Indeed, they found that sucralose was helpful in ameliorating type I diabetes caused by T cell activation, as well as in colitis.

Hence, sucralose consumption could actually be beneficial for treating autoimmune diseases that involve aberrant T cell proliferation and activation.

What to do if you love sweets, but don’t want either sugar or to increase your risk of cancer and bacterial infections?

If you have a fondness for sweet foods and drinks, you may be feeling stuck between consuming sugar, with its potential deleterious effects, or artificial sweeteners such as sucralose, that could have negative effects on your T cells. What to do?

Sucralose boxing with sigar
Choosing between sugar and sucralose (Composited from Midjourney images)

The best option might be to gradually reduce your consumption of sweets, which will over time likely reduce your craving for sweet foods.

However, there may be a way to counteract the impact of sucralose on T cells. Another recent paper suggests that ferroptosis in tissues can promote T cell activation:

Ferroptosis is a type iron-dependent cell death we identified in my lab in 2012, when we coined this term.

Perhaps a diet that promotes a modest degree of T cell activation through driving a small amount of tissue ferroptosis could counteract the impact of sucralose on dampening T cell immunity.

Our recent collaboration with Peter Canoll and colleagues showed that a diet low in cysteine and methionine (which we termed a CMD diet) has such a ferroptosis-promoting effect, which was beneficial in a mouse model of brain cancer:

Thus, an interesting future avenue to explore would be whether a CMD diet would counteract the effects of sucralose and maintain T cell immunity.

In summary, if you consume many desserts and sodas with sucralose, you should think about its impact on health. And maybe don’t consume too much of it.

Pastries with sucralose
Many low calories sweets contain sucralose



Brent R. Stockwell, Ph.D.

Chair and Professor of Biological Sciences at Columbia University. Top Medium writer in Science, Creativity, Health, and Ideas