Gut microbiome, artificial sweeteners, and powering the immune system

Provocatively Subtitled: Sucralose kills cancer patients?

A new paper in a journal from the American Association of Cancer Research caught my eye the other day. Sucralose consumption has a striking impact on survival rates—melanoma patients consuming higher amounts had only a 10% response rate to checkpoint inhibitors compared to 57% in low consumers. ¹

The study looked at how a specific artificial sweetener, sucralose (Splenda is one brand name), affected patient survival and response rates to immune checkpoint inhibitors in cancer due to changes to the gut microbiome.

Let’s take a look at why sucralose matters, the role of the gut microbiome in T cell exhaustion, and the bigger picture of how the gut microbiome impacts longevity and health through immune system modulation.

What is sucralose?

Sucralose is a synthetic organochlorine sweetener that is approximately 385- to 650-fold sweeter than sucrose. It was first approved as an artificial sweetener in Canada in 1991, the US in 1998, and the EU in 2004. The Acceptable Daily Intake was set at 5 mg/kg body weight per day in the US and 15 mg/kg in the EU.

Approximately 16% of sucralose is absorbed into the body, with the rest remaining in the intestines and excreted through feces. Interestingly, the absorbed sucralose can stay in the bloodstream for over 18 hours, with animal studies showing that it can persist for up to 11 days after being consumed regularly for more than a month.

Background on sucralose and the gut microbiome:

Prior research had shown that artificial sweeteners in general, and sucralose specifically, change the composition of the gut microbiome.

For example:

• In healthy young adults, drinking sucralose-sweetened beverages daily for 10 weeks changed the gut microbiome. There was a “3-fold increase in Blautia coccoides and a 0.66-fold decrease in Lactobacillus acidophilus”.²

• A 30-day study in healthy, lean adults looked at the changes from consuming only 30% of the acceptable daily intake of sucralose. In addition to a 20% decrease in insulin sensitivity, sucralose reduced the diversity of the gut microbiome and increased fecal Curli protein, which is a marker of E. coli biofilm production.³

• The length of time that sucralose is consumed seems to matter. A short trial for 7 days showed no changes in insulin resistance or the gut microbiome.⁴

• Animal studies and studies that use a gut reactor with human samples show clear changes in the gut microbiome composition from sucralose consumption. Animal studies also link the gut microbiome changes to causing liver inflammation.⁵ ⁶⁷

Inflammation and sucralose:

What about changes to inflammatory markers? Studies also show that diet drinks cause system-wide changes to the expression of inflammatory pathway genes.

• A study in adults consuming drinks with sucralose and Ace-K (e.g. Gatorade Zero, Celsius, Diet Mountain Dew, Coke Zero in some countries) daily for 8 weeks caused gene expression changes in inflammatory cytokines and the upstream regulators of inflammation.⁸

• Monocytes are a type of white blood cell that can be categorized into three different subpopulations. A study in healthy adults showed that sucralose consumption (48mg, one-time ingestion) causes a shift in the type of monocyte subsets, unbalancing the monocyte expression. This study wasn’t designed to look at changes to the gut microbiome, but it was interesting that the change in monocyte activation occurred that quickly.

Bigger picture: Altered gut microbiome and T cell exhaustion

Circling back to the study on cancer survival and sucralose consumption.

The immune system is constantly looking for abnormal cells, including cancer cells, and T cells can then eliminate the abnormal cells. Immune checkpoints are the pathways that prevent the immune system from identifying normal “self” cells — essentially preventing autoimmune diseases. Certain types of tumors will upregulate the ligands for immune checkpoints, which partially mask the tumor and eventually cause T cell exhaustion.

Immune checkpoint inhibitors are a type of monoclonal antibody that block the inhibitory signal and promote T cells to kill off cancer cells. They have been a game changer for surviving melanoma and non-small cell lung cancer, as well as a few other kinds of cancers.

However, only a portion of cancer patients respond to immune checkpoint inhibitors.

This new study used food frequency questionnaires to determine that sucralose consumption was linked to a lower rate of response to immune checkpoint inhibitors. Then, to eliminate all the variables that come along with food questionnaires, researchers also used a mouse model of the two types of cancer to again show that sucralose reduced the response to immune checkpoint inhibitors.

How much of an impact did sucralose make (in humans)? For melanoma, people consuming less than 0.16mg/kg/day of sucralose had a response rate of 57% to the immune checkpoint inhibitors. Those with higher consumption of >0.16 mg/kg/day had a response rate of 10%. For context, a diet Mountain Dew has 27 mg of sucralose, and Celsius has 100 mg. So the “high” group would be consuming about the equivalent of a half a Diet Mountain Dew per day.

Not responding, in these types of cancers, is not good… not good at all.

Screenshot showing progression free survival (PFS) related to sucralose intake for patients on immune checkpoint inhibitors

In mice with tumors, the researchers were then able to control the variables and determine that sucralose changed the gut microbiome composition. To confirm the causal role of the gut microbiome change, the researchers created germ-free mice with tumors and did fecal transplants from the non-responder mice who had been consuming sucralose and saw the same results.

The researchers also did metabolomics and pathway analysis to figure out what was different. The change in the microbiome also changed how arginine, an amino acid, was used by bacteria, vs. being absorbed. It also changed the amino acid transporter, SLC7A3, which is responsible for arginine uptake. Adding arginine or citrulline (arginine precursor) reversed the negative effects on the immune checkpoint inhibitors!

Thus, sucralose —> gut microbiome changes, transporter changes —> low arginine.

What is arginine?
Arginine is synthesized in the body from citrulline and glutamate. It can then be used in nitric oxide synthesis — which is the focus of most studies on supplemental arginine or citrulline for the benefits related to blood pressure and immune function. Arginine can also be converted to creatine in a multistep process that involves a methyl group.

Arginine is also a key amino acid needed for T cells to function. Other studies have shown arginine to be important in cytotoxic T cell function in fighting cancer.

Active T cells need arginine: Inactive T cells don’t have a high nutrient requirement, but when T cells are activated, they use a large amount of glucose, amino acids, and fatty acids. An important study in 2016 showed that l-arginine levels are the key to the metabolic activity of T cells, and higher l-arginine levels promote T cell survival.⁹

Longevity, balance, and gut health

Zooming out to the 30,000-foot view…

The gut microbiome plays multiple roles: it consumes nutrients, but it also produces vitamins and short-chain fatty acids that the body needs.¹⁰

The recent study on the 116-year-old supercentenarian woman showed that one of the biggest factors for her longevity was that her microbiome contained high levels of bifidobacteria. (Additionally, she had very few deleterious genetic variants.) I wrote about the study here.

The cancer treatment study shows the unexpected, and likely tragic, consequences of changing the gut microbiome with sucralose. However, the artificial sweetener isn’t the only thing that changes the gut microbiome composition. Another new study from Estonia looked at the microbiome of 2,500 people to see the long-term effects of antibiotics on the microbiome. What they discovered using electronic health records data is that, in addition to antibiotics, other medications, including beta-blockers, benzodiazepines, glucocorticoids, and proton pump inhibitors, also have detectable effects on the microbiome composition up to several years after use.¹¹

The connection between the gut microbiome and T cells is more than just the need for arginine in activated T cells. The composition of the gut microbiome is involved in T cell maturation, the differentiation into Th1, Th2, and Treg cells, and the activation of T cells.¹² T cells are also integral to maintaining the integrity of the gut mucosal layer.

Practical takeaways:
If you want to add more arginine-rich foods to your diet, the Cleveland Clinic suggests including more meat, fish, nuts, seeds, and legumes.

L-arginine is also readily available as a supplement* and inexpensive in powder form. Doses in studies range from 2 - 30 grams per day, with a small percentage of participants reporting intestinal symptoms at high doses. Arginine is often taken for high blood pressure and can reduce blood pressure, so if you already have hypotension, this may not be a good option for you.

Alternatively, citrulline is the precursor that the body converts to arginine in the kidneys. Studies point to supplemental citrulline being a little more efficient than supplemental arginine for increasing systemic arginine levels. Citrulline is also readily available as a supplement.

As always, talk to your doctor and pharmacist if you have any questions about supplements, especially if you are on prescription medications.

Let me conclude with this:
It seems like there are always unintended consequences. I can’t help but think that these study participants with cancer were opting for sugar-free options to avoid sugar, thinking they were doing the right thing. But in the end, the artificial sweetener affected the microbiome, which then limited the arginine needed by the T cells that were fighting the cancer.

1. Morder, Kristin M., et al. “Sucralose Consumption Ablates Cancer Immunotherapy Response through Microbiome Disruption.” Cancer Discovery, Oct. 2025, pp. OF1–20. DOI.org (Crossref), https://doi.org/10.1158/2159-8290.CD-25-0247.

2. Méndez-García, Lucía A., et al. “Ten-Week Sucralose Consumption Induces Gut Dysbiosis and Altered Glucose and Insulin Levels in Healthy Young Adults.” Microorganisms, vol. 10, no. 2, Feb. 2022, p. 434. PubMed Central, https://doi.org/10.3390/microorganisms10020434. https://pmc.ncbi.nlm.nih.gov/articles/PMC8880058/

3. Romo-Romo, Alonso, et al. “Sucralose Consumption Modifies Glucose Homeostasis, Gut Microbiota, Curli Protein, and Related Metabolites in Healthy Individuals: A Randomized Placebo-Controlled, Triple-Blind Trial.” Clinical Nutrition ESPEN, vol. 69, Oct. 2025, pp. 733–44. PubMed, https://doi.org/10.1016/j.clnesp.2025.08.029. https://pubmed.ncbi.nlm.nih.gov/40907790/

4. Thomson, Pamela, et al. “Short-Term Impact of Sucralose Consumption on the Metabolic Response and Gut Microbiome of Healthy Adults.” British Journal of Nutrition, vol. 122, no. 8, Oct. 2019, pp. 856–62. Cambridge University Press, https://doi.org/10.1017/S0007114519001570.

5. Bian, Xiaoming, et al. “Gut Microbiome Response to Sucralose and Its Potential Role in Inducing Liver Inflammation in Mice.” Frontiers in Physiology, vol. 8, 2017, p. 487. PubMed, https://doi.org/10.3389/fphys.2017.00487. https://pubmed.ncbi.nlm.nih.gov/28790923/

6. Gerasimidis, Konstantinos, et al. “The Impact of Food Additives, Artificial Sweeteners and Domestic Hygiene Products on the Human Gut Microbiome and Its Fibre Fermentation Capacity.” European Journal of Nutrition, vol. 59, no. 7, Oct. 2020, pp. 3213–30. PubMed, https://doi.org/10.1007/s00394-019-02161-8. https://pubmed.ncbi.nlm.nih.gov/31853641/

7. Zheng, Zibin, et al. “Low Dose of Sucralose Alter Gut Microbiome in Mice.” Frontiers in Nutrition, vol. 9, 2022, p. 848392. PubMed, https://doi.org/10.3389/fnut.2022.848392 .https://pubmed.ncbi.nlm.nih.gov/35284433/

8. Sylvetsky, Allison C., et al. “Consumption of Diet Soda Sweetened with Sucralose and Acesulfame‐Potassium Alters Inflammatory Transcriptome Pathways in Females with Overweight and Obesity.” Molecular Nutrition & Food Research, vol. 64, no. 11, Jun. 2020, p. 1901166. DOI.org (Crossref), https://doi.org/10.1002/mnfr.201901166. https://onlinelibrary.wiley.com/doi/abs/10.1002/mnfr.201901166

9. Geiger, Roger, et al. “L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-Tumor Activity.” Cell, vol. 167, no. 3, Oct. 2016, pp. 829-842.e13. PubMed Central, https://doi.org/10.1016/j.cell.2016.09.031. https://pmc.ncbi.nlm.nih.gov/articles/PMC5075284/

10. Korver, Douglas R. “Intestinal Nutrition: Role of Vitamins and Biofactors and Gaps of Knowledge.” Poultry Science, vol. 101, no. 4, Dec. 2021, p. 101665. PubMed Central, https://doi.org/10.1016/j.psj.2021.101665. https://pmc.ncbi.nlm.nih.gov/articles/PMC8850792/

11. Aasmets, Oliver, et al. “A Hidden Confounder for Microbiome Studies: Medications Used Years before Sample Collection.” mSystems, Sep. 2025, p. e0054125. PubMed, https://doi.org/10.1128/msystems.00541-25. https://pubmed.ncbi.nlm.nih.gov/40910778/

12. Shim, Ju A, et al. “The Role of Gut Microbiota in T Cell Immunity and Immune Mediated Disorders.” International Journal of Biological Sciences, vol. 19, no. 4, Feb. 2023, pp. 1178–91. PubMed Central, https://doi.org/10.7150/ijbs.79430. https://pmc.ncbi.nlm.nih.gov/articles/PMC10008692/

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