Invited Commentary on: “Pharmacokinetics of Sucralose and Acesulfame-Potassium in Breast Milk Following Ingestion of Diet Soda” by Rother et al on page 466.
Breast milk is a nutritive soup unique to each individual mother and her infant. It varies from day to day, and its composition is influenced by the diet and the metabolism of the nursing mother. Pharmacologists, immunologists, endocrinologists, and toxicologists have all demonstrated the permeation of both potentially beneficial and noxious substances such as drugs and their metabolites, peptide fragments, hormones, and the environmental contaminants, bisphenols, and phthalates into breast milk. In this issue of the journal Rother et al (1) extend earlier work where they showed the presence of the non-nutritive sweeteners (NNS)—sucralose and acesulfame-K in breast milk, with a pharmacodynamics study in nursing mothers. They found that the NNS were present in the breast milk of all subjects in physiologically significant amounts, and based on their previous work, at concentrations well above the taste thresholds (2). Why is this important?
NNS or non-caloric artificial sweeteners (NCAS) are ubiquitous in the modern diet. They are consumed by millions worldwide to attempt to curb weight gain, by virtue of their sweet taste with low caloric intake. Sucralose—Splenda and acesulfame-K—the 2 swee teners studied are chemically synthesized sweeteners approximately 500 and 200 times as sweet as sugar, respectively. These substances are often used in combination, as in Diet Rite Cola, which was consumed by the subjects in the Rother study. Sucralose has been used in the United States since 1998 and Ace-K since 1988; both have been approved by the FDA as an NNS in food for more than 10 years. Despite the approval by the FDA and European Food Safety Authority, concerns, admittedly largely unproven, persist about their safety. Rother et al's initial detection study and this pharmacokinetic study are important additions to the safety literature as they delineate for the first time exposure in breast-feeding infants.
The concerns about NNS are 3-fold. First, that they may adversely alter taste preferences. Second, that the ultimate effect may be contrary to what is intended and their ingestion may increase food consumption. Third, that they may adversely alter the gut bacterial microbiome and its metabolites. All of these concerns are magnified with early exposure in life. The evidence to support these concerns is either inductive or based on experimental models and emerging human data. Concerns about individual NNS may not be generalizable to others and in turn there are likely to be different responses in individuals.
ALTERED TASTE PREFERENCES
Taste preferences are established early in life. Any pediatrician who has tried to introduce an elemental formula after 6 months of age knows how difficult this compared to early exposure. Taste may be determined either by peripheral stimulation of the G-protein–coupled sweet receptor (3), by a possible opioid mediated pathway, or by direct hypothalamic stimulation. Support for peripheral stimulation comes from the studies showing reduction of pain in infants by high concentration sucrose to nociceptive stimuli such as heel prick and vaccination. Reduction of discomfort may thus program the infant to seek sweet tastes. There is some evidence that young animals have reduced expression of an efflux transporter P-glycoprotein, which may enhance the transport of sucralose into the nutrient sensing areas of the hypothalamus. This could alter taste perception adversely early in life. Ace-K acceptance may be altered by variation in the TAS2R31 bitter taste receptor gene. Rodent studies have shown that suckled progeny of dams exposed to NNS had altered adult taste perception (4). If NNS do alter taste perception, the mechanisms for each NNS may vary.
The evidence for altered satiety is somewhat weaker. The most compelling evidence comes from an Australian study of Drosophila, which showed that adding sucralose to the diet promoted hyperactivity, insomnia, glucose intolerance, enhanced sweet taste perception, and a sustained increase in food and calories consumed (5). This was reversible when sucralose ceased and controlled through a highly conserved pathway NPF/NPY pathway. The amount of sucralose used was, however, far in excess of human consumption at 2.5% of intake. There are no similar studies in man but equivalent doses of sucralose Ace-K and aspartame to sucrose and fructose did not stimulate GLP1 release nor reduce ghrelin and peptide YY release, while sucrose and fructose did (6). The carbohydrate sugars increased satiety and fullness while the NNS substances did not. In the latter study, 0.3% saccharin sweetened yogurt compared with glucose sweetened yogurt increased energy intake, weight gain, and adiposity. Again, this intake of saccharin is far in excess of what would be expected in humans, let alone passive consumption by breast-feeding babies. Therefore, while evocative, studies of supraphysiological intake of NNS in fruit flies and rodents do not make for a compelling case for alteration of satiety.
ALTERATION OF THE MICROBIOME
The gut microbiome changes rapidly during infancy, and infant feeding is a major determinant of these changes. The microbial composition of the mother's breast milk makes a substantial contribution to that of the breast-feeding infant's gut microbiome during the first month of life (7). In a landmark study Suez et al (8) demonstrated that NNS alters gut microbial communities, leading to glucose intolerance in both mice and humans. Feeding mice high concentrations of saccharin, sucralose, and aspartame resulted in an overrepresentation of taxa similar to those seen in type 2 diabetes (9). Fecal microbiome transplant to germ-free mice from NNS-fed mice transferred the glucose tolerance, so establishing causality. In the following pilot study in humans, short-term saccharin consumption at the upper limit of the acceptable daily intake led to glucose intolerance and altered intestinal microbiota in some subjects (8). Fecal microbiome transplant from these 4 NNS “responders” transferred the glucose intolerance. The mechanisms that contribute to this apparent metabolic response to NNS in some people are unclear, but certainly larger randomized trials are warranted. Bacteria do have the ability to metabolize sucralose and sucralose has been shown to have a bacteriostatic effect on some bacteria. Notably other NNS can alter the gut microbiome and impair glucose tolerance in humans and, in the case of aspartame, in doses that are compatible with human intake (10).
The evidence for harm from ingestion of NNS at normal daily doses is therefore uncertain. Studies such as those by Rother, however, provide food for thought. If we consume food additives we should not blindly accept they are safe and caution is required especially so in the case of the human infant, an innocent bystander.
1. Rother KI, Sylvetsky AC, Walter PJ, et al. Pharmacokinetics of sucralose and acesulfame-potassium in breast milk following ingestion of diet soda. J Pediatr Gastroenterol Nutr
2. Sylvetsky AC, Gardner AL, Bauman V, et al. Non-nutritive sweeteners in breast milk. J Toxicol Environ Health A
3. Palmer RK. The pharmacology and signalling of bitter, sweet and umami taste sensing. Mol Interv
4. Zhang GH, Chen ML, Liu SS, et al. Effects of mother's dietary exposure to acesulfame-K in pregnancy or lactation on the adult offspring's sweet preference. Chem Senses
5. Wang Q-P, Lin YR, Zhang L, et al. Sucralose promotes food intake through NPY and a neuronal fasting response. Cell Metab
6. Steinert RE, Frey F, Töpfer A, et al. Effect of carbohydrate sugars and artificial sweeteners on appetite and the secretion of gastrointestinal peptides. Br J Nutr
7. Pannaraj PS, Cerini JM, Yang S, et al. Association between breast milk bacterial communities and establishment and development of the infant gut microbiome. JAMA Pediatr
8. Suez J, Korem T, Zeevi D, et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature
9. Qin J, Li Y, Cai Z, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature
10. Palmnäs MS, Cowan TE, Bomhof MR, et al. Low-dose aspartame consumption differentially affects gut microbiota-host metabolic interactions in the diet-induced obese rat. PLoS One