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

Study: Maternal low-calorie sweeteners consumption rewires hypothalamic melanocortin circuits via a gut microbial co-metabolite pathway. Image Credit: Towfiqu ahamed barbhuiya/Shutterstock

Background

The prevalence of obesity and diabetes is increasing drastically worldwide. This may very well be because of a big increase in refined sugar consumption, particularly in sugar-sweetened beverages.

As a healthier alternative, individuals are selecting low-calorie sweeteners that provide a sweet taste without excessive calorie intake. Nevertheless, evidence claims that low-calorie sweeteners can result in weight gain and glucose intolerance.

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

In the present study, scientists have investigated how exposure to low-calorie sweeteners while pregnant may impact the metabolism and neural development of the offspring.

Along with investigating possible metabolic abnormalities, they’ve specifically focused on developing hypothalamic melanocortin and autonomic circuits, as these neural pathways are related to regulating energy expenditure and glucose homeostasis.  

Study design

The study was conducted on adult female mice exposed to 2 commonly used low-calorie sweeteners, namely aspartame and rebaudioside A, while pregnant and lactation periods.

The doses of each sweeteners were kept well throughout the day by day admissible intake limit in humans.

Necessary observations

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

Nevertheless, 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 descendant.

The male offspring exhibited increased fat mass, reduced lean mass, and glucose intolerance in comparison with non-exposed control offspring.  

A protracted-term impact of in utero low-calorie sweetener exposure on gut microbiota composition and variety was observed within the adult offspring. Specifically, an increased abundance of Enterobacteriaceae family was observed within the offspring gut microbiota. Nevertheless, no significant alteration within 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 within the paraventricular nucleus of the hypothalamus and disruption of the parasympathetic innervation of pancreatic islets in male offspring.  

The study conducted an untargeted metabolomic evaluation of maternal milk and offspring blood samples. In each samples, considerable changes in metabolite profiles because of 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.     

Amongst all samples, the one commonly modified metabolite was phenylacetylglycine, a co-metabolite of gut microbiota and host. This metabolite can be a possible marker of heart problems. 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 while pregnant and lactations. The findings revealed that phenylacetylglycine treatment causes similar metabolic and neurodevelopmental changes as observed within 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. Furthermore, the study identifies a gut microbial-host co-metabolite phenylacetylglycine as a possible mediator of low-calorie sweetener-related changes.