The strongest effect appeared when researchers combined isosteviol, a sweetener used by the food and beverage industry, with the antidepressant duloxetine. Together, the two compounds sharply reduced the growth of two important bacterial species associated with digestive health, blood sugar regulation, and immune function.

The scientists caution that the experiments were conducted in a laboratory rather than in people. More research will therefore be needed to determine whether the bacterial changes lead to meaningful 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, growing evidence has linked sweetener consumption with conditions including 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 might explain the connections.

One possible factor is the gut microbiome, the enormous community of bacteria and other microorganisms living in the digestive system. These microbes help break down food, produce useful compounds, train the immune system, and influence metabolism. Changes in the number or balance of these organisms may affect health throughout the 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 from population studies. While these studies have indicated involvement of the microbiome in mediating the effect of sweeteners, it's 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 ever take sweeteners by themselves -- we take them with drinks, in snacks, or even in medication to mask bitterness," added Dr. Sonja Blasche, a lead author of the study, also the MRC Toxicology Unit.

Testing 39 Sweeteners Against Gut Bacteria

For the study, published in Molecular Systems Biology, Dr. Blasche and her colleagues investigated how artificial and low-calorie sweeteners influence gut bacteria. They also examined whether those effects change when sweeteners are mixed with substances commonly encountered in foods, drinks, and medicines.

The team grew 25 bacterial species 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 both 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 halted 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 living there.

More Than 100 Unexpected Interactions

People rarely consume a sweetener in isolation. It may appear alongside caffeine in a beverage, flavoring in a dessert, or an active ingredient in a medication.

To recreate some of that complexity, the researchers paired the sweeteners with substances including caffeine, vanillin (vanilla extract), advantame (an artificial sweetener), and eight commonly used drugs.

The team identified more than 100 cases in which a sweetener's effect 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 partly on what else is consumed at the same time.

Antidepressant Combination Stood Out

The most dramatic result involved 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 US 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.

Gut Microbial Diversity Declined

The combination of isosteviol and duloxetine reduced microbial diversity within the synthetic community. Greater diversity is generally considered a feature of a resilient and healthy gut microbiome, although the ideal microbial composition can vary between individuals.

The combination also changed the community's internal balance by allowing some bacterial species to flourish while others declined.

Additional experiments suggested that these changes increased toxicity toward certain host cells. They also disrupted the activity of other cells involved in inflammation and immune responses.

These results raise the possibility that interactions between sweeteners, medications, and microbes could influence more than digestion alone. 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 medication and food additives. These common combinations could have unintended effects on our gut microbiome."

Human Studies Are Still Needed

The researchers emphasize that the findings should not be interpreted as proof that sweeteners or the tested combinations cause harm in people.

The experiments involved bacteria and cell models under controlled laboratory conditions. In the human digestive system, sweeteners may be absorbed, chemically altered, diluted, or broken down before reaching particular microbes. Diet, genetics, medication use, and the existing composition 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 effects on health.

Professor Patil, the study's senior author, added: "Our study suggests that artificial sweeteners don't just pass through the body passively -- they can interact with gut microbes, and these effects can be amplified or altered by other substances like medications. These findings can help guide new studies towards understanding how sweeteners might influence health in unexpected ways."

The research was funded by the European Union's Horizon 2020 program and the UK Medical Research Council.