Sugar substitutes lead to long-term changes in rats

By Theresa Pablos, DrBicuspid.com contributing writer

February 7, 2020 -- Sugar substitutes, such as aspartame and stevia, may have long-lasting effects on the brain and gut. New research published in BMJ found that rats with in-utero exposure to low-calorie sweeteners had altered insulin sensitivity, gut bacteria, body weight, and even dopamine pathways.

The findings prompt some concern, as more people are consuming sugar substitutes in response to the obesity epidemic. While many sugar alternatives are considered safe to consume during pregnancy and nursing, new research is showing low-calorie sweeteners may have negative health implications.

"Consumption of low-calorie sweetener and [high-fructose and sucrose diet] by obese pregnant and lactating rats altered gut microbiota of offspring causing impaired adiposity and glucose tolerance in early life, despite no direct consumption of sweeteners by offspring," wrote the authors, led by Jodi Nettleton from the University of Calgary kinesiology department in Alberta (BMJ, January 29, 2020).

The researchers tested the link between sugar alternatives and long-term health using 60 pregnant rats and their offspring. They split the mother rats into four test groups:

  1. Obese mother rats who consumed water with aspartame during pregnancy and lactation
  2. Obese mother rats who consumed water with stevia during pregnancy and lactation
  3. Obese mother rats who consumed plain water during pregnancy and lactation
  4. Normal-weight rats who consumed plain water during pregnancy and lactation

Exposure to low-calorie sweeteners in utero and early infancy was associated with body-altering effects for both male and female rats, although the findings were generally more pronounced in male rats.

Specifically, male offspring of mothers that consumed aspartame had greater weight gain at 6 weeks and 12 weeks than offspring only exposed to water. They also had higher faster insulin and higher blood glucose levels one to two hours after birth.

Meanwhile, female offspring of mothers that consumed aspartame had greater weight gain at 12 weeks to 18 weeks than offspring exposed to water and stevia. They also had higher body weight at 6 weeks to 15 weeks.

Not only did the rats experience weight gain changes in their first few weeks of life, but many also experienced changes in their dopamine reward pathway. All rats exposed to aspartame and stevia in utero and early infancy showed altered gene expression for dopamine receptor levels. Furthermore, male rats exposed to aspartame showed changed dopamine transporter genes, and female offspring exposed to aspartame showed altered mu-opioid receptor levels.

"In our [low-calorie sweetener] offspring, altered mesolimbic gene expression did not translate into greater food intake and may not have directly contributed to the observed metabolic phenotype," the authors wrote. "However, our results suggest that long-lasting changes in [nucleus accumbens] mu-opioid receptor expression as a result of maternal diet during pregnancy/lactation may impact food preference of offspring in the absence of direct [high-fructose and sucrose diet] and [low-calorie sweetener] exposure during their lifetime."

After the researchers tested the offspring, they transplanted some of their gut bacteria into mice. Mice who received gut bacteria from offspring exposed to low-calorie sweeteners had greater body weight at seven, 10, and 14 days after the transplant than those who received bacteria from offspring exposed to plain water. Mice with low-calorie sweetener bacteria also had greater fat mass and percentage of body fat.

In addition, mice with gut bacteria from rats exposed to sugar alternatives had greater glucose values at one and a half to two hours following food consumption. The glucose values were also significantly higher at zero to 30 minutes for mice with bacteria from aspartame-exposed offspring.

"Currently, it is hypothesized that aspartame may impact gut microbiota by altering intestinal alkaline phosphatase (IAP) activity," the authors wrote. "Mice consuming aspartame have reduced IAP activity alongside glucose intolerance."

It is important to note the researchers did not include a group of mother rats that consumed pure sugar, nor could they determine whether the effects of sugar alternatives were more important during pregnancy or lactation. The researchers hope more studies are conducted on the topic.

"Future studies should examine independent effects of gestation and lactation exposure to [low-calorie sweeteners] and use a pair-fed design to isolate the effects of the obesogenic diet," the authors concluded. "This study not only supports findings that [low-calorie sweeteners] may not be metabolically inert, but that indirect exposure may also have long-lasting impact on offspring and development of central feeding circuits."


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