Commonly used sweeteners can directly interfere with the growth of bacteria that help maintain a healthy gut, according to laboratory research from the University of Cambridge.
The strongest effect appeared when the researchers combined isosteviol, a sweetener used by the food and beverage industry, with the antidepressant duloxetine. Together, the two compounds dramatically reduced the growth of two important bacterial species associated with digestive health, blood sugar regulation, and immune function.
Scientists warn that the experiments were carried out in a laboratory and not on people. Therefore, more research will be needed to determine whether bacterial changes lead to significant health effects under real-world conditions.
Sweeteners may not be biologically inactive
Sweeteners are found in countless everyday products, including soft drinks, candy, desserts, breakfast cereals, snacks, and some medications. They are commonly promoted as alternatives that provide sweetness with less sugar or fewer calories.
However, there is increasing evidence linking sweetener consumption to diseases such as type 2 diabetes, obesity and cancer. These associations do not prove that sweeteners directly cause those diseases, and researchers are still working to understand the biological processes that could explain the connections.
One possible factor is the gut microbiome, the huge community of bacteria and other microorganisms that live in the digestive system. These microbes help break down food, produce useful compounds, train the immune system and influence metabolism. Changes in the amount or balance of these organisms can affect the health of the entire body.
Despite the widespread use of sweeteners, relatively little research has examined whether they directly affect individual gut bacteria.
Professor Kiran Patil from the Medical Research Council (MRC) Toxicology Unit at the University of Cambridge said: “Most of what we know about the potential impact of sweeteners on our health comes from animal research or population studies. While these studies have indicated the involvement of the microbiome in mediating the effect of sweeteners, it is difficult to know how sweeteners act in the body: is it through direct interactions with our gut bacteria?”
“Answering this is further complicated by the fact that we rarely drink sweeteners alone: we take them with drinks, in snacks or even in medicines to mask the bitterness,” added Dr Sonja Blasche, lead author of the study, also from the MRC Toxicology Unit.
Test of 39 sweeteners against intestinal bacteria
For the study, published in Molecular Systems Biology, Dr. Blasche and her colleagues investigated how low-calorie and artificial sweeteners influence gut bacteria. They also examined whether those effects change when the sweeteners are mixed with substances commonly found in foods, beverages and medications.
The team grew 25 species of bacteria separately in the laboratory. The selection included bacteria considered beneficial, neutral or potentially harmful.
Each species was then exposed to 39 commercially used sweeteners, including natural and artificial varieties. The researchers monitored how quickly each bacterial culture multiplied and whether its growth slowed or stopped.
About three-quarters of the sweeteners affected the growth of at least one bacterial species. Several reduced or completely stopped the growth of bacteria associated with a healthy digestive system.
These findings suggest that some sweeteners are not simply inactive substances that pass through the digestive tract without interacting with the organisms that live there.
More than 100 unexpected interactions
People rarely consume a sweetener in isolation. It may appear alongside caffeine in a beverage, a flavoring in a dessert, or an active ingredient in a medication.
To recreate some of that complexity, the researchers combined the sweeteners with substances such as caffeine, vanillin (vanilla extract), advantame (an artificial sweetener) and eight commonly used drugs.
The team identified more than 100 cases in which the effect of one sweetener changed when another compound was present. The combined effects became stronger in 34 cases and weaker in 68 cases.
This means that the impact of a particular sweetener may depend in part on what else is consumed at the same time.
The combination of antidepressants stood out
The most dramatic result was isosteviol and duloxetine, an antidepressant prescribed to treat depression, anxiety and certain types of chronic pain.
When used together, the compounds strongly suppressed Roseburia intestinalis and Parabacteroides merdae. Both species are considered important members of the gut microbiome and have been linked to digestive health and metabolic regulation.
Duloxetine is widely used. More than 4.2 million patients in the U.S. received prescriptions for the drug in 2023.
Studying bacteria one species at a time can reveal direct effects, but the human gut is a crowded ecosystem in which microbes constantly interact. To better reflect those conditions, the scientists constructed a simplified microbial community containing all 25 bacterial species.
They allowed the community to develop and then exposed it to different combinations of sweeteners and drugs. The team tracked which species became more abundant, which declined, and whether the community retained its overall variety.
Decreased intestinal microbial diversity
The combination of isosteviol and duloxetine reduced microbial diversity within the synthetic community. Greater diversity is generally considered a characteristic of a resilient and healthy gut microbiome, although the ideal microbial composition may vary between individuals.
The combination also changed the internal balance of the community by allowing some bacterial species to flourish while others declined.
Additional experiments suggested that these changes increased toxicity toward certain host cells. They also altered the activity of other cells involved in inflammation and immune responses.
These results raise the possibility that interactions between sweeteners, drugs, and microbes may influence more than just digestion. However, the simplified laboratory system cannot fully reproduce the complexity of the human body.
Dr Blasche said: “Sweeteners are often marketed as metabolically neutral, but our study challenges this idea. We found that they can directly affect gut bacteria, particularly when mixed with other compounds such as medications and food additives. These common combinations could have unwanted effects on our gut microbiome.”
Human studies still needed
The researchers emphasize that the findings should not be interpreted as evidence that the sweeteners or combinations tested cause harm to people.
The experiments involved bacteria and cell models under controlled laboratory conditions. In the human digestive system, sweeteners can be absorbed, chemically altered, diluted or broken down before reaching specific microbes. Diet, genetics, medication use, and the existing makeup of a person’s microbiome could also change the outcome.
Future studies will need to determine whether similar interactions occur in humans, what doses would be required, and whether any microbial changes produce measurable health effects.
Professor Patil, lead author of the study, added: “Our study suggests that artificial sweeteners not only pass passively through the body, but can interact with gut microbes, and these effects can be amplified or altered by other substances such as medications. These findings may help guide further studies towards understanding how sweeteners can influence health in unexpected ways.”
The research was funded by the European Union’s Horizon 2020 program and the UK Medical Research Council.