Cambridge researchers have shown how commonly used sweeteners and related compounds slow the growth of certain gut bacteria. One compound in particular, isosteviol, a stevia-derived diterpenoid, when combined with the antidepressant duloxetine significantly impaired two gut bacterial species associated with blood sugar regulation and gut health and altered inflammatory signaling in cultured intestinal cells.
The scientists say more research is needed to understand the real-world health impacts of this laboratory study, one of the first to assess the direct impact of sweeteners on gut bacteria, particularly when they are combined with other substances.
Sweeteners are widely used in a range of food and drinks, including soft drinks, sweets, desserts, snacks and cereals. While marketed as healthier alternatives to sugar, there is increasing evidence of associations with diseases such as type 2 diabetes, obesity and cancer.
Despite their pervasive use, there have been very few studies that look at the direct interactions between sweeteners and gut bacteria, the vast community of microorganisms that live in the digestive tract and play a crucial role in keeping our bodies healthy.
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?"
Professor Kiran Patil, MRC Toxicology Unit, University of Cambridge
"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.
In research published in Molecular Systems Biology, Dr Blasche and colleagues looked at how artificial and low-calorie sweeteners and related compounds affect the bacteria living in our gut, and how these effects change when sweeteners are consumed together with other common substances such as caffeine, flavorings, or medicines.
The researchers grew each of 25 gut bacterial species, including beneficial, neutral, and potentially harmful bacteria, in the lab. They then exposed each culture individually to 39 commercially available sweeteners and sugar substitutes, some of which are artificial, others natural, and measured how well the bacteria multiplied.
Around three-quarters of the sweeteners changed how at least one bacterial species grew. Some sweeteners slowed down or stopped the growth of certain bacteria linked to a healthy gut.
The researchers then tested the 39 sweeteners in combination with common compounds such as caffeine, vanillin (vanilla extract), advantame (an artificial sweetener) and duloxetine. They also tested 12 sweetener combinations with eight commonly used drugs to assess whether this had any impact on the gut bacteria. They found 102 interactions where sweeteners acted differently when combined with other substances. In 34 cases, combinations made the effects stronger, while in 68 cases the effects were weaker.
Most striking was the combination of isosteviol, a stevia-derived diterpenoid, and the antidepressant duloxetine. This combination strongly suppressed Roseburia intestinalis and was associated with reduced growth of Parabacteroides merdae, two gut bacteria that have been associated with maintaining a healthy digestive system. In the US in 2023, over 4.2 million patients were prescribed duloxetine.
As no gut bacterium exists alone, but rather as part of a 'community' within the gut, the researchers created a synthetic community containing all 25 bacteria. After allowing it to grow over time, they tested the community with isosteviol, duloxetine, or both, looking at which species increased or decreased and whether the overall diversity changed.
By mimicking in this simplified way what might happen in the human gut, they showed that the combination of isosteviol and duloxetine reduced microbial diversity. A diverse microbiome is generally considered important for good gut health. The isosteviol-duloxetine combination also altered which bacterial species thrived or declined.
Further analysis showed that the effect of the isosteviol-duloxetine combination on the community increased toxicity in HeLa cells and reduced secretion of the inflammatory signaling molecules IL-6 and IL-8 by cultured Caco-2 intestinal cells.
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."
The researchers stress that, as their experiments were carried out in the lab, not tested in humans, more research needs to be done before it is possible to conclude that there will be direct health effects in people.
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 programme and the UK Medical Research Council.
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Journal reference:
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