The Personalized Microbiome-driven Effects of Non-nutritive Sweeteners on Human Glucose Tolerance
By: Tien Vo
There has been speculation about the effects of non-nutritive sweeteners on human glucose tolerance. Researchers have also identified these sugar substitutes to be microbiome-driven. Non-nutritive sweeteners are not uncommon in the United States. They have been a standard product in the human diet. NNS is considered a food additive that provides a sweet taste similar to sugar while containing significantly less food than sugar-based sweeteners, making it a zero-calorie or low-calorie sweetener (Sugar substitute, 2019). These artificial sweeteners are commercially available in various forms, such as powders, packets, and pills.
These sweeteners are known to be fundamental ingredients in diet-related goods. Some common sugar substitutes are saccharin, sucralose, stevia, and aspartame. Structurally, saccharin is an amide. It is an artificial sweetening agent with the chemical structure of C₇H₅NO₃S (Saccharin, n.d.). Sucralose, on the other hand, has a structure of C₁₂H₁₉Cl₃O₈ (Sucralose, n.d.). Stevia powder is formatted as C₄₄H₇₀O₂₃ (Stevia Powder, n.d.) As for aspartame, its chemical structure is C₁₄H₁₈N₂O₅ (Aspartame, n.d.). All of these sweet alternatives are typically found in drinks and diet-related food items.
The term “microbiome” has been used in many ways. In more simplistic terms, a microbiome is a community of microorganisms that live in a particular environment. Microorganisms can be considered bacteria, fungi, or viruses. The human microbiome contains these little microorganisms that live on or in a certain part of the human body. They can be found in our gastrointestinal tract or skin.
Glucose is known to be the main sugar found in our blood. This simple sugar is the most abundant monosaccharide and is your body’s predominant source of energy. Glucose tolerance is the body’s ability to put away high amounts of glucose. A glucose intolerance would entail a person’s inability to dispose of glucose. Understanding your body’s way of using glucose is important. It is incredibly helpful in aiding diabetics, people who are insulin resistant, and those who have hypoglycemia.
Studies have been conducted to comprehend the relationship between the human microbiome and glucose tolerance. Some research has illustrated how the microbiome is causally linked to elevated glycemic response (Suez, 2022). Gut microbiota has been shown to aid in the control and prevention of blood sugar metabolism disorders. They can target multiple pathways within the human body, such as through the intestine, liver, and pancreas. Researchers have found that these pathways can tip the scales in favor of improving our gut health, insulin resistance, and glycemic control. The microbes in our bodies can also influence and alter host blood glucose; however, blood glucose levels can also affect the microbiota and host response to specific bacteria.
Sugar substitutes and glucose tolerance have also been found to correlate with one another. NNS has been discovered to alter stool and oral microbiomes, along with metabolomes. Saccharin and sucralose can significantly impair glycemic responses in healthy adults (Suez, 2022). Human non-nutritive consumption can induce microbiome-dependent glycemic alterations which could ultimately cause health-related problems in the long run.
Some randomized-controlled trials have concluded that non-nutritive sweeteners can have no beneficial or damaging effects. Others suggest that these NNS can contribute to diabetes and obesity. Within the study of the effects of non-nutritive sweeteners on glucose tolerance, both sucralose and saccharin supplementation impairs glycemic responses in strictly non-NNS-consuming healthy volunteers (Suez, 2022). Saccharin and sucralose significantly raised glycemic response during exposure compared with glucose vehicle and NSC. Short-term consumption of sucralose and saccharin in doses can harm the glycemic reactions in healthy individuals.
Stool samples were collected at various times throughout the study to determine if there were any changes in the gut microbiome with the artificial sweeteners. Each of the four non-nutritive sweeteners had a considerable result on the microbiome function. None of these microbial features differed between the glucose or the NSC groups. A significant effect on the microbiome composition was observed in the sucralose and saccharin groups (Suez, 2022). Therefore, the sweeteners that affected the bacterial diversity the most were saccharin and sucralose.
The metabolic pathways that increased the most for sucralose were alanine, aspartate, and glutamate metabolism. These are a part of amino acid metabolism. Biosynthesis and the TCA cycle pathways are also associated with the impact of sucralose on glycemic control. Most of the microbial features of the sucralose group had multiple top loadings related to purine metabolism as well. Metabolic pathways that were the most decreased were related to purine metabolism. Uric acid and plasma levels of pseudouridine were also significantly reduced during sucralose supplementation.
Many of the pathways positively correlated to saccharin were involved with UMP biosynthesis. Top loadings for the saccharin group included pathways related to glycolysis and glucose degradation (Suez, 2022). Those that negatively correlated were related to glycolysis metabolism and glycan degradation. Untargeted plasma metabolomics of the saccharin responders detected high levels of saccharin during consumption.
The TCA cycle and pyruvate metabolism significantly increased during exposure to stevia. Several of the top loadings in the stevia group also corresponded with fatty acid biosynthesis. Whereas, L-rhamnose biosynthesis decreased when encountering stevia. L-rhamnose is critical for the viability and virulence of many human pathogenic bacteria (van der Beek, 2019). In the aspartame group, high top loadings correlated with polyamine metabolism. Fatty acid degradation and biosynthesis decreased when exposed to aspartame. All of these results suggest that supplementation with NNS can impact the functional potential of the gut microbiome.
The collection of fecal material and its transplantation into germ-free mice gave insight into NNS-modulated microbiomes with glucose tolerance. These mice grew in a completely sterile environment. Thus, making the mice have no gut microbiome of their own. The mice relied on what the researchers supplied to establish a normal and functioning gut microbiome.
The glucose tolerance in each sweetener group significantly increased. For the saccharin and sucralose groups, the mice that were the strongest responders had a significantly higher glycemic response than those that received the baseline sample. Stevia and aspartame had elevated glycemic responses as well. No significant effects on glycemic response were observed with bottom responders from any of the treatments (Suez, 2022), which suggests that a personalized microbiome-mediated occurrence had an impact on the response of the NNS exposure in these groups.
The effects of non-nutritive sweeteners on human metabolism and their microbiomes reveal that they can induce individual-specific, microbiome-dependent changes to glycemic responses. The changes in the gut microbiome on its own are enough to cause alterations in glucose metabolism. Ingesting artificial sweeteners can also adjust your glucose tolerance. I would recommend using stevia or aspartame. They had the least negative impact on the participants and the mice compared to saccharin and sucralose. I would avoid consuming sucralose and saccharin. They are both poorly absorbed, and their bioavailability is inadequate throughout the body.
References
PubChem (2019). Aspartame. Nih.gov, https://pubchem.ncbi.nlm.nih.gov/compound/134601.
PubChem (n.d.). Saccharin. pubchem.ncbi.nlm.nih.gov., https://pubchem.ncbi.nlm.nih.gov/compound/5143.
PubChem (n.d.). Stevia Powder. pubchem.ncbi.nlm.nih.gov., https://pubchem.ncbi.nlm.nih.gov/compound/Stevia-Powder#:~:text=Stevia%20Powder%20%7C%20C44H70O23%20%2D%20PubChem.
PubChem (n.d.). Sucralose. pubchem.ncbi.nlm.nih.gov., https://pubchem.ncbi.nlm.nih.gov/compound/71485.
Suez, J., Cohen, Y., Valdés-Mas, R., Mor, U., Dori-Bachash, M., Federici, S., Zmora, N., Leshem, A., Heinemann, M., Linevsky, R. et al. (2022). Personalized microbiome-driven effects of non-nutritive sweeteners on human glucose tolerance. Cell, [online] pp.S0092-8674(22)009199. doi:10.1016/j.cell.2022.07.016.
van der Beek, S.L. et al. (2019). Streptococcal DTDP-l-rhamnose biosynthesis enzymes: Functional characterization and lead compound identification. Molecular microbiology, U.S. National Library of Medicine. Available at: https://pubmed.ncbi.nlm.nih.gov/30600561/#:~:text=Biosynthesis%20of%20the%20nucleotide%20sugar,Streptococcus%20mutans%20and%20Mycobacterium%20tuberculosis. (Accessed: December 11, 2022).Wikipedia Contributors (2019). Sugar substitute, https://en.wikipedia.org/wiki/Sugar_substitute.