Sweeteners Disrupt Blood Glucose Via Effects on Gut Bacteria

Liam Davenport

October 09, 2018

BERLIN — Low-calorie sweeteners appear to impair glucose uptake and control by disrupting the gut microbiome, Australian researchers have shown for the first time in findings that suggest artificial sweeteners could potentially play havoc with glucose-lowering medications in patients with diabetes.

In a study of healthy individuals presented here at the European Association for the Study of Diabetes (EASD) 2018 Annual Meeting, Richard L. Young, PhD, head of the Intestinal Nutrient Sensing Group, University of Adelaide, South Australia, and colleagues showed that a low-calorie sweetener capsule altered the gut ecosystem in favor of pathogenic bacteria compared with placebo.

Young told a press conference that "2 weeks' supplementation with sweeteners in capsules increases glucose absorption and glycemic responses to glucose, and decreases glucose-evoked increases in the incretin glucagon-like peptide 1 (GLP-1)."

He added, "I hope I've convinced you that [sweeteners] trigger changes in the gut microbiome, including its functional properties."

Asked by Medscape Medical News whether, based on their impact on GLP-1 levels, low-calorie sweeteners could affect the efficacy of diabetes medications, he said, "There's definitely the possibility that they could interact."

He pointed out that posters presented during the meeting also suggest that some of the effects of "some of the GLP-1 receptor agonists are certainly mediated through changes in the microbiome, which is an emerging phenomenology." He added: "I think that the microbiome is not often considered by clinicians as a first-pass way of understanding of mechanisms."

Approached for comment, session cochair Ellen E. Blaak, PhD, professor of physiology of fat metabolism, NUTRIM School of Nutrition and Translational Research, Maastricht University, the Netherlands, said that the results are "interesting."

She said she would like to see more long-term data; however, she added that the issue of what is used as placebo in such studies is important. "Do you take sugar sweetened beverages as the placebo?" she asked. "Then the results will be different."

Blaak also pointed out that there needs to be a balance between the beneficial effects of artificial sweeteners in moderate amounts, "which may help you to comply with lifestyle interventions," as they can help with weight control, and the potential adverse events when taken to excess, "so I think there are two sides to it."

Research in Mice Shows Sweeteners Disrupt Gut Microbiome

Young began his presentation by noting that "the vast majority [of sweeteners] are fairly recent entrants to the food chain, and the number of products that are available for low-calorie sweeteners is expanding exponentially."

He added, "Of course, they're increasingly marketed towards the health conscious sector of the market."

Previous studies have indicated, however, that a high intake of low-calorie sweeteners is associated with poorer glycemic control and that HbA1c levels increase with increasing consumption of beverages that contain them.

At last year's meeting, as reported by Medscape Medical News, Young and his team showed that sweeteners were, compared with placebo, associated with a 20% increase in 3-O-methyl-glucose absorption and a 24% increase in plasma glucose levels (P < .05 for both), again in healthy volunteers. The low-calorie sweeteners were also associated with a significant 34% reduction in GLP-1 levels versus placebo (P < .05).

And research in mice has shown that low-calorie sweetener supplementation can cause changes in the gut microbiome, as well as alter microbial carbohydrate-related metabolic pathways, increasing fecal short-chain fatty acid production, Young said.

Noting that the majority of studies in humans have been of limited duration and none have assessed glucose absorption, for the current analysis, Young said his team randomized 40 nondiabetic individuals to a low-calorie sweetener tablet containing sucralose 92 mg and acesulfame potassium 52 mg, which is equivalent to approximately 1.2 L of sweetened beverage per day, or placebo.

Participants took the tablets three times daily for 2 weeks with a standardized evening meal. Complete data were available for 16 patients assigned to placebo and 17 patients assigned to the low-calorie sweetener arm. The two groups had similar baseline patient and clinical characteristics.

Sweeteners Decrease "Good" Bacteria, Increase "Bad" Ones

Participants' gut microbiomes were assessed using stool samples collected before and after the 2-week treatment period. The team wanted to determine whether low-calorie sweetener supplementation altered the human gut microbiome in a way that predicts host glycemic changes.

Young explained, "We were able to see a number of different species emerging...In essence, we saw a loss of health-associated bacterium."

There were decreases in levels of Eubacterium cylindroides, as well as in levels of the beneficial and fermentative Bifidobacterium, Lactobacillus, and Bacteroides populations, which are correlated with augmented glucose absorption (P ≤ .001 for all). There were also reductions in levels of Butyrivibrio populations, which have been shown to be correlated with attenuated GLP-1 release (P ≤ .001).

"In contrast, we saw increases in a number of gut pathogens that are normally low or absent in health," Young said. Specifically, there was an increase in 11 opportunistic gut pathogens, including Klebsiella, Porphyromonas, and Finegoldia (P ≤ .001 for all).

"In healthy nondiabetic subjects, 2 weeks of low-calorie sweetener supplementation was sufficient to disrupt gut bacteria and increase the abundance of those which are normally absent in healthy individuals," the team summarizes.

The observed decrease in fermentative bacteria populations and changes in the pathways used by bacteria to harvest energy "predicted a deterioration in the body's ability to regulate glucose," they add.

"Our findings support the concept that such sweeteners worsen blood sugar control in healthy subjects by disrupting the regulation of glucose uptake and disposal, as well as from changes in the balance of gut bacteria. This highlights the clinical relevance of dietary low-calorie sweetener patterns to overall blood sugar control."

Young said that he and his colleagues will test the causal nature of the association between low-calorie sweetener-related changes in the microbiome and glycemic changes through "experiments in both healthy individuals and individuals with type 2 diabetes, who are particularly high consumers of this type of product."

The study was funded by the Australian National Health and Medical Research Council. The authors have reported no relevant financial relationships.

European Association for the Study of Diabetes (EASD) 2018 Annual Meeting; October 5, 2018; Berlin, Germany. Abstract 241.

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