Common sweeteners can do so much more to our bodies than just replacing sugar. Scientists at the University of Cambridge have discovered that many widely used sweeteners can directly interfere with the growth of gut bacteria, and their effects can become even more pronounced when combined with medications or other everyday substances.
In laboratory experiments involving 39 sweeteners and 25 species of gut bacteria, researchers found that about three-quarters of the sweeteners altered the growth of at least one bacterial species. Some slowed or completely stopped the growth of microbes associated with a healthy digestive system.
One combination particularly stood out. When the sweetener isosteviol was combined with the antidepressant duloxetine, it strongly suppressed two important gut bacteria involved in maintaining digestive health and regulating blood sugar. The combination also disrupted the balance of a simulated gut microbiome and produced changes that could have implications for inflammation and immune responses.
The results, published in Molecular systems biologyraise new questions about how sugar substitutes interact with the body. However, the researchers emphasize that their experiments were conducted in the laboratory and not on humans, and that additional studies are needed to determine whether these effects have real health consequences.
Are artificial sweeteners really safe for gut bacteria?
Sweeteners have become a familiar ingredient in modern diets. They appear in everything from soft drinks and candies to desserts, packaged snacks and breakfast cereals, often providing sweetness with fewer calories than traditional sugar.
These ingredients are often touted as healthier alternatives to sugar. Yet a growing body of research has identified associations between sweetener consumption and health problems such as type 2 diabetes, obesity and cancer. Such associations do not necessarily mean that sweeteners cause these illnesses, and scientists are still working to understand the biological mechanisms that could explain these findings.
One area of particular interest is the gut microbiome, the enormous collection of bacteria and other microorganisms that inhabit the digestive tract. These microscopic residents help break down food, produce useful compounds, support the immune system, and contribute to metabolic health.
Although sweeteners are consumed around the world, surprisingly little research has directly examined how they affect individual gut bacteria. Most previous research has relied on animal experiments or studies comparing dietary habits and health outcomes in large groups of people.
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. Although these studies have indicated the involvement of the microbiome in mediating the effect of sweeteners, it is unclear how sweeteners act in the body – is it through direct interactions with our gut bacteria?
Another challenge is that people rarely consume sweeteners themselves. They are usually mixed with other ingredients and these combinations can change their behavior.
“The answer to this question is further complicated by the fact that we rarely take sweeteners alone – we take them with drinks, in snacks or even in medicines to mask bitterness,” added Dr Sonja Blasche, lead author of the study, also from the MRC Toxicology Unit.
Scientists test 39 sweeteners
To study these interactions, Blasche and his colleagues designed a series of laboratory experiments examining artificial and naturally occurring low-calorie sweeteners.
The team cultured 25 different species of gut bacteria, including microorganisms considered beneficial, neutral or potentially harmful. Each species was grown separately so that researchers could measure its response to specific sweeteners without interference from other bacteria.
They then exposed these bacterial cultures to 39 commercially available sweeteners and checked whether the microorganisms continued to multiply normally.
The results revealed a surprisingly widespread effect. About three out of four sweeteners alter the growth of at least one bacterial species.
In some cases, bacterial populations grew more slowly. In others, growth has stopped completely. Several affected species are associated with maintaining a healthy intestinal environment, suggesting that certain sweeteners may directly influence the microorganisms that contribute to digestive health.
However, the effects were not uniform. Different sweeteners influenced different bacteria, showing that these substances cannot necessarily be treated as a single group when evaluating their biological activity.
More than 100 unexpected interactions with everyday substances
The researchers then explored a question that previous studies had largely overlooked: What happens when sweeteners are combined with other ingredients or medications?
To find out, they tested sweeteners as well as several commonly encountered substances, including caffeine, vanillin (vanilla extract), advantame (an artificial sweetener), and eight widely used medications.
The combinations produced more than 100 cases in which the effect of one sweetener on bacterial growth changed in the presence of another substance.
In 34 cases, the combinations intensified the effects on the bacteria. In 68 other cases, the effects lessened.
These results suggest that how a sweetener influences gut microbes may depend not only on the sweetener itself, but also on what comes with it.
A compound that has a relatively modest effect when tested alone might behave differently when combined with a beverage ingredient, food additive, or drug.
A combination of sweetener and antidepressant stands out
Of all the combinations studied, one produced particularly striking results.
Researchers found that isosteviol, a sweetener used in the food and beverage industry, strongly inhibited two important gut bacteria when combined with the antidepressant duloxetine.
The species affected were Intestinal roseburia And Parabacteroides merdaeboth associated with important functions of the digestive system, including processes related to gut health and blood sugar regulation.
Duloxetine is a widely prescribed medication. In the United States alone, more than 4.2 million patients received a prescription for this drug in 2023.
Lab results suggest that certain sweeteners and medications may interact in ways that significantly alter the growth of particular gut microbes.
However, this does not establish that people taking duloxetine experience these effects or that taking isosteviol along with the drug is harmful. Understanding whether the same interactions occur in the human body will require additional research.
The combination also disrupted gut microbiome diversity
Studying individual bacterial species has provided valuable information, but the human gut is much more complicated than a collection of isolated microbes.
Inside the digestive system, bacteria coexist in large interconnected communities. Different species compete for nutrients, exchange chemical compounds and influence each other.
To better approximate this environment, the researchers created a simplified artificial intestinal community containing the 25 bacterial species from their initial experiments.
After allowing the community to grow, they introduced different combinations of sweeteners and drugs. They then tracked changes in bacterial populations and measured the overall diversity of the microbial community.
Microbial diversity refers to the variety of microorganisms present and how they are distributed within a community. A diverse gut microbiome is generally considered important for maintaining digestive health and supporting the stability of the gut environment.
The results showed that the combination of isosteviol and duloxetine reduced bacterial diversity and changed the relative abundance of different species.
In other words, the combination did more than hit a few bacteria individually. This changed the composition of the broader microbial community.
Additional experiments revealed another potentially important effect. The bacterial community exposed to the combination of isosteviol and duloxetine showed increased toxicity towards certain host cells and altered the behavior of other cells involved in inflammation and immune responses.
These observations suggest that interactions between sweeteners, drugs, and gut bacteria could have consequences beyond just bacterial growth, although it is unclear whether similar effects occur in humans.
Scientists Question Common Assumption About Sweeteners
The findings raise questions about the widely held assumption that low-calorie sweeteners have little direct biological activity.
A substance described as metabolically neutral is generally considered to have limited effects on the body’s metabolic processes. The new experiments suggest that, at least under laboratory conditions, some sweeteners can interact directly with gut microorganisms.
Dr Blasche said: “Sweeteners are often marketed as being metabolically neutral, but our study challenges this idea. We found that they can directly affect gut bacteria, especially when mixed with other compounds such as medications and food additives. These common combinations could have unintended effects on our gut microbiome.
The results also highlight why examining individual food ingredients in isolation cannot provide a complete picture of their behavior.
A typical meal or drink contains several compounds, and people may also take medications that interact with these substances. The Cambridge experiments demonstrate that such combinations can sometimes produce…
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