Aspartame, sucralose, acesulfame potassium and saccharin. They are among the most widely consumed artificial non-nutritive sweeteners (NNS, Non-Nutritive Sweeteners) with meaningful effects on systemic inflammation, accompanied by a noticeable rise in inflammatory biomarkers. These are the latest findings from a meta-analysis conducted by Italian researchers, published in Nutrients.
The Non-Nutritive Sweeteners
The non-nutritive artificial sweeteners are increasingly present in the typical diet, viewed as noncaloric sugar substitutes. Yet, the latest evidence from literature studies conducted on animal models shows that the use of ultraprocessed industrial foods, often rich in sweeteners and increasingly common at the table, may act as a trigger for inflammatory, metabolic, and neoplastic diseases.
Consumption of NNS, especially when prolonged, could have significant effects on common inflammatory biomarkers, such as C-reactive protein, interleukin-6 and interleukin-1β, and tumor necrosis factor alpha. This is particularly important given that chronic low-grade inflammation is a recognized factor in the development and pathogenesis of metabolic disorders, including obesity, insulin resistance, cardiovascular disease, and type 2 diabetes.
Moreover, recent studies clarify a possible link between the sweeteners, the microbiota, and immunity, where NNS would exert a pro-inflammatory effect on the microbiota, promoting dysbiosis. This, in turn, could alter metabolic signaling pathways and immune responses, exacerbating intestinal inflammation, thus increasing the risk of non-communicable diseases.
These findings come from a broad review of 37 animal studies available in the literature through May 2025, selected from major search engines such as PubMed, Web of Science, and Scopus. Of the studies considered, 17 addressed aspartame, 16 sucralose, 5 acesulfame potassium, and 4 saccharin.
Early Findings
The exposure to aspartame has shown a significant rise in pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, in various tissues such as plasma, colon, liver, adipose tissue, and in specific brain regions, including the prefrontal cortex and hippocampus. It also appears linked to oxidative stress and neuroendocrine dysregulation, marked by elevated circulating corticosterone and lipid peroxidation, neuroinflammation, and microglial activation.
Regarding the inflammatory dynamics and mechanisms, aspartame engages activation of the transcription factor NF-κB and the NLRP3 inflammasome in tissues such as the brain, lung, and liver. Finally, there is evidence of a negative impact on inflammatory bowel disease and systemic inflammation, even at daily intake levels considered acceptable.
Evidence on Sucralose
This sweetener is thought to cause damage to the intestinal barrier, resulting in endotoxemia. This condition compromises barrier integrity. This outcome would translate into increased circulating lipopolysaccharide (LPS) and reduced levels of occludin and secretory IgA. With prolonged intake, sucralose would promote a decrease in microbial diversity, a generally harmful change, favoring an increase in pro-inflammatory microbial gene profiles, which are found, for example, in metabolic and inflammatory diseases.
Finally, systemic inflammatory effects extending to the gut have been observed, with increases in IL-6, TNF-α, and circulating LPS, a causal factor in neuroinflammation, associated with histopathological changes observed in the liver, kidneys, pancreas, and the urinary bladder.
Other Findings
Acesulfame potassium, or Ace-K, has an effect predominantly on the gut, with studies suggesting increased inflammation of the intestinal mucosa similar to those seen in inflammatory bowel diseases and an increase in permeability. Meanwhile, saccharin shows inconclusive data—some studies indicating attenuation of colitis, while others show inflammatory effects in the liver, such as increased iNOS and TNF-α, potentially mediated by alterations in the gut microbiota.
These results, however, are dose-dependent: for aspartame, significant effects are observed at doses starting around 17 mg/kg with greater increases in TNF-α, IL-6, IL-1β, and NF-κB at high-dose consumption (60 mg/kg) compared with a lower dose (30 mg/kg). For Ace-K, significant cytokine elevations were found only at higher exposure levels, especially with chronic or long-term intake.
For aspartame, some studies that used shorter exposure durations or lower doses did not detect significant changes in inflammatory markers. Finally, maternal or long-term exposure to aspartame was associated with altered T-helper cytokine profiles in offspring. Further large-scale, well-designed randomized clinical trials will be needed to confirm the pro-inflammatory effects of artificial sweeteners, paying attention to the causal role of the gut microbiota, based on current evidence suggesting that NNS consumption is linked to gut dysbiosis, which in turn affects metabolic signaling pathways and immune responses.
Moreover, given the difficulty in estimating the exact daily intake of NNS and given that amounts are not clearly listed on food labels, further public health research and monitoring are needed to track and limit exposure, particularly among children who are more likely to approach or exceed the acceptable daily intake. It is also crucial to improve the quality and completeness of reporting in preclinical studies, especially regarding randomization, blinding, exclusion criteria, and animal welfare practices, to enhance reproducibility and reliability of future research.
Source: Raoul P.C., Romano M., Galli F.S. et al. Impact of Artificial Sweeteners on Inflammation Markers: A Systematic Review of Animal Studies. Nutrients, 2025, 17(20), 3251. DOI: https://doi.org/10.3390/nu17203251
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