Exploring the Long-Term Effect of Artificial Sweeteners on Metabolic Health

Abstract

Artificial sweeteners (ASs) are widely used as low-calorie sugar substitutes for managing conditions like diabetes and obesity, but recent evidence suggests their health effects may be more complex than previously understood. High consumption has been associated with increased risks of metabolic disorders, cardiovascular diseases, certain cancers, and, somewhat paradoxically, weight gain, adverse pregnancy outcomes, and potential risks for individuals with low seizure thresholds. Studies, including the Women's Health Initiative, have linked artificially sweetened beverages to an elevated risk of stroke, coronary heart disease, and mortality, independent of established risk factors. Concerns extend to gut health, where ASs like saccharin have been linked to inflammatory bowel diseases, gut microbiota disruption, increased intestinal permeability, and dysbiosis, leading to metabolic disturbances such as impaired glucose tolerance, insulin resistance, and heightened systemic inflammation. These disruptions reduce the production of short-chain fatty acids crucial for insulin sensitivity, further contributing to the development of metabolic disorders like type 2 diabetes mellitus. Given these potential health risks, this review underscores the need for cautious use, informed consumer choices, and stringent regulatory oversight, while emphasizing the necessity for further research to elucidate long-term health effects and develop strategies to mitigate these risks.

Keywords: artificial sweeteners; dysbiosis; health risks; metabolic; obesity; type 2 diabetes.

Figure 1. Types of ASs

ASs: artificial sweeteners This image was illustrated by the author Meenatchi M

Figure 2. Gut microbiota dysbiosis induced by ASs, depicting how ASs like saccharin, aspartame, sucralose, acesulfame-K, and stevia impact gut microbiota, leading to microbial dysbiosis. This dysbiosis, characterized by reduced Bifidobacterium and increased Proteobacteria, lowers SCFA production and results in dyslipidemia, inflammation, glucose intolerance, and altered insulin sensitivity. These physiological changes heighten the risk of obesity, T2DM, metabolic syndrome, and hypertension

LDL: low-density lipoprotein; HDL: high-density lipoprotein; NNS: nonnutritive sweeteners; ASs: artificial sweeteners; T2DM: type 2 diabetes mellitus; SCFA: short-chain fatty acid This image was illustrated by the author Meenatchi M

Figure 3. Impact of dysbiosis on health, showing ASs can disrupt gut microbiota, leading to an imbalance that increases harmful bacteria and impairs gut barrier function. This can result in systemic inflammation, potentially worsening conditions like IBD, promoting weight gain and obesity, and increasing the risk of T2DM by impairing insulin sensitivity and disrupting glucose metabolism

IBD: inflammatory bowel disease; SCFA: short-chain fatty acid; T2DM: type 2 diabetes mellitus; ASs: artificial sweeteners This image was illustrated by the author Meenatchi M

Figure 4. Impact of ASs on gut health and inflammation, depicting how ASs like saccharin, sucralose, and aspartame can alter gut microbiota, increasing proinflammatory bacteria and reducing beneficial ones. This imbalance (dysbiosis) leads to "leaky gut syndrome," allowing toxins into the bloodstream and triggering inflammation through the NF-κB pathway. The resulting systemic inflammation can worsen IBD and cause glucose intolerance, further contributing to IBD pathology

ASs: artificial sweeteners; NF-kB: nuclear factor kappa B; IBD: inflammatory bowel disease This image was illustrated by the author Meenatchi M

Figure 5. Effects of ASs on obesity and gut health. ASs can alter gut microbiota, leading to dysbiosis, reduced SCFA production, and increased gut permeability. This imbalance raises systemic inflammation, disrupts hunger and satiety hormones (GLP-1 and PYY), and contributes to overeating and obesity

ASs: artificial sweeteners; SCFA: short-chain fatty acid; GLP-1: glucagon-like peptide-1; PYY: peptide tyrosine tyrosine This image was illustrated by the author Meenatchi M

Figure 6. Impact of nonnutritive sweeteners on gut microbiota and diabetes development, depicting how ASs disrupt gut microbiota, leading to dysbiosis. This imbalance reduces short-chain fatty acids, lowering insulin sensitivity and causing insulin resistance, which can lead to glucose intolerance and diabetes. Dysbiosis also increases LPS, triggering systemic inflammation, impaired insulin signaling, and further disrupting glucose metabolism, thereby increasing the risk of diabetes

ASs: artificial sweeteners; LPS: lipopolysaccharides This image was illustrated by the author Meenatchi M