The impact of perinatal low-calorie sweetener exposure on the development of neural systems involved in metabolic regulation

By Dr. Sanchari Sinha Dutta, Ph.D.Reviewed by Danielle Ellis, B.Sc.Apr 6 2023

A study published in the Journal of Clinical Investigation Insight reveals that consumption of low-calorie sweeteners during pregnancy can affect the metabolism and neural development of the offspring. The study identifies a gut microbial-host co-metabolite as a potential causative factor mediating these changes.

Background

The prevalence of obesity and diabetes is increasing drastically worldwide. This could be due to a significant increase in refined sugar consumption, particularly in sugar-sweetened beverages.

As a healthier alternative, people are choosing low-calorie sweeteners that provide a sweet taste without excessive calorie intake. However, evidence claims that low-calorie sweeteners can lead to weight gain and glucose intolerance.

Besides affecting adult metabolism, exposure to low-calorie sweeteners during pregnancy is known to cause adversities in infants, including body weight gain, insulin resistance, development of sweet taste preference, and alteration of gut microbiota composition.

In the current study, scientists have investigated how exposure to low-calorie sweeteners during pregnancy may impact the metabolism and neural development of the offspring.

In addition to investigating possible metabolic abnormalities, they have specifically focused on developing hypothalamic melanocortin and autonomic circuits, as these neural pathways are associated with regulating energy expenditure and glucose homeostasis.  

Study design

The study was conducted on adult female mice exposed to two commonly used low-calorie sweeteners, namely aspartame and rebaudioside A, during pregnancy and lactation periods.

The doses of both sweeteners were kept well within the daily admissible intake limit in humans.

Important observations

The exposure to low-calorie sweeteners during pregnancy and lactation induced certain changes in adult female mice. The mice exposed to rebaudioside A showed a redistribution of body composition, including a reduction in fat mass and an induction in lean mass. The mice exposed to aspartame showed increased insulin levels in the blood.   

However, no effects of low-calorie sweetener exposure were observed on body weight, food intake, glucose tolerance, leptin level, and size and percentage of pancreatic beta cell mass in adult female mice.

Impact of low-calorie sweetener exposure in offspring

The effect of in utero low-calorie sweetener exposure was observed in adult male offspring (14-week-old) but not in female offspring.

The male offspring exhibited increased fat mass, reduced lean mass, and glucose intolerance compared to non-exposed control offspring.  

A long-term impact of in utero low-calorie sweetener exposure on gut microbiota composition and diversity was observed in the adult offspring. Specifically, an increased abundance of Enterobacteriaceae family was observed in the offspring gut microbiota. However, no significant alteration in the gut microbiota was observed in exposed dams.

Regarding neural development, in utero exposure to low-calorie sweeteners caused rewiring of the hypothalamic melanocortin circuits in the paraventricular nucleus of the hypothalamus and disruption of the parasympathetic innervation of pancreatic islets in male offspring.  

The study conducted an untargeted metabolomic analysis of maternal milk and offspring blood samples. In both samples, considerable changes in metabolite profiles due to low-calorie sweetener exposure were observed.

In maternal milk samples, rebaudioside A and aspartame exposure caused differential regulation of 151 and 92 metabolites, respectively. Similarly, in offspring blood samples, rebaudioside A and aspartame exposure caused differential regulation of 9 and 35 metabolites, respectively.     

Among all samples, the only commonly changed metabolite was phenylacetylglycine, a co-metabolite of gut microbiota and host. This metabolite is also a potential marker of cardiovascular disease. An upregulated expression of this metabolite was observed in low-calorie sweetener-exposed milk and blood samples.   

These observations were further confirmed by treating the mice with phenylacetylglycine during pregnancy and lactations. The findings revealed that phenylacetylglycine treatment causes similar metabolic and neurodevelopmental changes as observed in the offspring upon in utero low-calorie sweetener exposure.

Study significance

The study reveals that in utero exposure to low-calorie sweeteners can induce significant metabolic and neurodevelopmental changes in offspring. Moreover, the study identifies a gut microbial-host co-metabolite phenylacetylglycine as a potential mediator of low-calorie sweetener-related changes.