Aspartame triggers genetic changes tied to glioblastoma severity

By Dr. Liji Thomas, MDReviewed by Lauren HardakerJul 8 2025

Despite no visible tumor growth, new research finds that the artificial sweetener aspartame reshapes gut bacteria and upregulates cancer-linked genes in glioblastoma.

Study: Metagenomics and transcriptomics analysis of aspartame’s impact on gut microbiota and glioblastoma progression in a mouse model. Image credit: Pheelings media/Shutterstock.com

Aspartame is a commonly used artificial sweetener. It was first recommended to reduce total caloric intake, but it was later suspected of having potentially damaging health effects. A recent study published in Scientific Reports indicates that its use is associated with molecular changes linked to a poorer prognosis in glioblastoma multiforme (GBM) cases.

Introduction

Aspartame dates back to the 1960s. It is widely used in low-sugar drinks and chewing gum, as well as in some cough syrups and chewable vitamins. However, the joint report by the International Agency for Research on Cancer (IARC) and the Joint FAO (Food and Agriculture Organization of the United Nations)/WHO (World Health Organization) Expert Committee on Food Additives (JECFA), has declared it as possibly carcinogenic to humans, setting its acceptable daily intake at 0-40 mg/kg and recommending further study.

GBM is a leading killer among primary brain cancers, being both the most aggressive tumor and the most likely to cause death. It grows rapidly and is intractable to conventional cancer treatments. It also potently suppresses the immune response in its tumor microenvironment.

Aspartame may not be as safe an alternative to sugar as previously thought. Several studies have suggested that its intake increases the risk of multiple cancers, of the gut, the brain, the reproductive system, and the blood, among others. Its consumption is also linked to the development of headaches. However, some research has shown conflicting findings, and more studies are needed to clarify the risk.

Food additives such as aspartame may affect memory, perhaps by cooperating with others. Earlier studies failed to link high aspartame levels from diet drinks to blood cancer or glioma risk. However, aspartame can directly impact the gut microbiome and thus mediate glioblastoma risk via the gut-brain axis.

This axis affects immunity and metabolic pathways in the tumor's immediate microenvironment. For instance, the gut microbiota mainly produces short-chain fatty acids (SCFA) like butyrate and other molecules like tryptophan, which are cell activators in their own right. They stimulate cell receptors and initiate metabolic pathways within the cell.

The converse also occurs, with the tumor microenvironment signaling and changing the gut microbiome via the microbial community inhabiting the tumor. These microbes promote tumor development by facilitating genomic instability, suppressing immune recognition of tumor antigens, and aberrant metabolic pathways.

For instance, bacterial DNA is found within GBM tumors. Its effect on gene expression and regulation within the developing tumor remains unclear. However, tumor microbiota will likely present novel therapeutic and diagnostic targets for cancer management.

Another area of interest is the impact of epigenetic modifications, especially N6-methyladenosine modification, in messenger RNA (mRNA). This is intimately connected with metabolism and with the gut microbiota, again suggesting a mediator of the connection between glioma progression and the gut.

About the study

The current study's authors explored the possibility that aspartame could worsen the prognosis in GBM. They used advanced tools to analyze the metagenomics and transcriptomics of a GBM mouse model.

Gliomas were induced using cancerous cells transplanted into healthy mice. These were then exposed to aspartame in drinking water, with an aspartame-free control group. The aim was to understand better how aspartame affects the tumor prognosis via the gut microbiome.

Study results

The results indicate that tumor growth remained unchanged despite aspartame consumption. However, the gut microbiome underwent a significant change. The abundance of bacteria belonging to the Rikenellaceae family was reduced.

Essential genes in the N6-methyladenosine-regulated pathway were expressed at higher levels in the aspartame-exposed mice. These included cyclin-dependent kinase inhibitor 1A (CDKN1A), MYC (myelocytomatosis) oncogene, and transforming growth factor-β (TGFB1).

The increased expression of TGFB1, a known marker of adverse prognosis in glioblastoma, may indicate an unfavorable molecular profile in aspartame-exposed tumors. Although tumor size did not increase, aspartame may influence gene expression patterns associated with more aggressive disease. This elevated expression could be due to changes in RNA methylation along the N6-methyladenosine pathway. However, more research is needed to confirm these effects in humans.

Conclusion

For the first time, this study showed that the gut microbiome is affected by the presence of aspartame, both in composition and abundance. This is in keeping with earlier findings showing that volatile fatty acids like acetic and propionic acid impact the gut microbes, especially Rikenellaceae. This family is connected to multiple metabolic health disorders, such as non-alcoholic fatty liver disease and Parkinson’s disease.

Though there was no evidence that the tumor grew faster when the mice were exposed to aspartame, the changes in the gut microbiome were noticeable, primarily the reduction in Rikenellaceae. This could alter tumor progression via its eventual impact on the gut-brain axis.

Aspartame intake also increased methylation in the N6-methyladenosine pathway and upregulated associated genes. This suggests that this pathway plays a key role in gene regulation, especially of genes implicated in cancer progression like MYC, CDKN1A, and TGFB1. These reflected N6-methyladenosine peaks, indicating that these genes may represent potential targets influenced by aspartame-related epigenetic changes.

“These insights open new avenues for GBM treatment strategies, including gene-targeted therapies and microbial-based interventions, among others.”

However, the study had limitations. It involved a small sample size, used only female mice, and did not explore the impact of aspartame metabolites or the intratumoral microbiome. These factors may be necessary to clarify the precise mechanisms involved in future research. In addition, as a preclinical study conducted in mice, the findings cannot yet be directly generalized to human health outcomes.

Future studies will explore the role played by aspartame metabolites and the microbiome within the tumor in mediating this compound's effects.

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