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Artificial sweeteners and metabolic dysregulation: Lessons learned from agriculture and the laboratory

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Abstract

Escalating rates of obesity and public health messages to reduce excessive sugar intake have fuelled the consumption of artificial sweeteners in a wide range of products from breakfast cereals to snack foods and beverages. Artificial sweeteners impart a sweet taste without the associated energy and have been widely recommended by medical professionals since they are considered safe. However, associations observed in long-term prospective studies raise the concern that regular consumption of artificial sweeteners might actually contribute to development of metabolic derangements that lead to obesity, type 2 diabetes and cardiovascular disease. Obtaining mechanistic data on artificial sweetener use in humans in relation to metabolic dysfunction is difficult due to the long time frames over which dietary factors might exert their effects on health and the large number of confounding variables that need to be considered. Thus, mechanistic data from animal models can be highly useful because they permit greater experimental control. Results from animal studies in both the agricultural sector and the laboratory indicate that artificial sweeteners may not only promote food intake and weight gain but can also induce metabolic alterations in a wide range of animal species. As a result, simple substitution of artificial sweeteners for sugars in humans may not produce the intended consequences. Instead consumption of artificial sweeteners might contribute to increases in risks for obesity or its attendant negative health outcomes. As a result, it is critical that the impacts of artificial sweeteners on health and disease continue to be more thoroughly evaluated in humans.

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References

  1. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011–2012. JAMA. 2014;311:806–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet (London). 2014;384:766–81.

    Article  Google Scholar 

  3. Harnack L, Stang J, Story M. Soft drink consumption among US children and adolescents: nutritional consequences. J Am Diet Assoc. 1999;99:436–41.

    Article  CAS  PubMed  Google Scholar 

  4. Tremblay MS, Willms JD. Is the Canadian childhood obesity epidemic related to physical inactivity? Int J Obes Relat Metab Disord. 2003;27:1100–5.

    Article  CAS  PubMed  Google Scholar 

  5. Martinez Steele E, Baraldi LG, da Costa Louzada ML, Moubarac J-C, Mozaffarian D, Monteiro CA. Ultra-processed foods and added sugars in the US diet: evidence from a nationally representative cross-sectional study. BMJ Open. 2016;6:e009892.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Moubarac J-C, Martins APB, Claro RM, Levy RB, Cannon G, Monteiro CA. Consumption of ultra-processed foods and likely impact on human health. Evidence from Canada. Public Health Nutr. 2013;16:2240–8.

    Article  PubMed  Google Scholar 

  7. Poti JM, Mendez MA, Ng SW, Popkin BM. Is the degree of food processing and convenience linked with the nutritional quality of foods purchased by US households? Am J Clin Nutr US. 2015;101:1251–62.

    Article  CAS  Google Scholar 

  8. Singh GM, Micha R, Khatibzadeh S, Lim S, Ezzati M, Mozaffarian D. Estimated global, regional, and national disease burdens related to sugar-sweetened beverage consumption in 2010. Circulation. 2015;132:639–66. 2015/07/01 ed.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. United States Department of Agriculture. Dietary Guidelines for Americans, 2015–2020. 8Th Ed. 2015.

  10. International survey shows most consumers worry about extra sugar. NewHope360.com [Internet]. 2015 Apr 10.

  11. Sylvetsky AC, Welsh JA, Brown RJ, Vos MB. Low-calorie sweetener consumption is increasing in the United States. Am J Clin Nutr. 2012;96:640–6. 2012/08/03 ed.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sylvetsky A, Rother K. Trends in the consumption of low-calorie sweeteners. Physiol. Behav. [Internet]. 2016;1:1–17. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0031938416301184.

  13. Butchko HH, Stargel WW, Comer CP, Mayhew DA, Benninger C, Blackburn GL, et al. Aspartame: review of safety. Regul Toxicol Pharmacol. 2002;35:S1–93. 2002/08/16 ed.

    Article  PubMed  Google Scholar 

  14. Magnuson BA, Burdock GA, Doull J, Kroes RM, Marsh GM, Pariza MW, et al. Aspartame: a safety evaluation based on current use levels, regulations, and toxicological and epidemiological studies. Crit Rev Toxicol. 2007;37:629–727. 2007/09/11 ed.

    Article  CAS  PubMed  Google Scholar 

  15. Swithers SE. Not-so-healthy sugar substitutes? Curr. Opin. Behav. Sci. 2016;106–10.

  16. Nowlis GH, Kessen W. Human newborns differentiate differing concentrations of sucrose and glucose. Science. 1976;191:865–6.

    Article  CAS  PubMed  Google Scholar 

  17. Ganchrow JR, Steiner JE, Canetto S. Behavioral displays to gustatory stimuli in newborn rat pups. Dev Psychobiol. 1986;19:163–74.

    Article  CAS  PubMed  Google Scholar 

  18. Nelson LF, Hazel LN, Moore AA, Maddock HM, Ashton GC, Culbertson CC, et al. Baby pigs have a sweet tooth. Iowa Farm Sci. 1953;17:3–6.

    Google Scholar 

  19. Hanson LE, Rutledge EA, JMR and EFF. Dry rations for pigs weaned at 3 weeks. Minn Agr Exp Sta Mimeo Minn Agr Exp Sta Mimeo. 1954;H-124.

  20. Lewis CJ, Catron DV, Combs GE, Ashton GC, Culbertson CC. Sugar in pig starters. J Anim Sci. 1955;14:1103–15.

    Article  Google Scholar 

  21. Sterk A, Schlegel P, Mul AJ, Ubbink-Blanksma M, Bruininx EM. Effects of sweeteners on individual feed intake characteristics and performance in group-housed weanling pigs. J Anim Sci. 2008;86:2990–7.

    Article  CAS  PubMed  Google Scholar 

  22. Ponce CH, Brown MS, Silva JS, Schlegel P, Rounds W, Hallford DM. Effects of a dietary sweetener on growth performance and health of stressed beef calves and on diet digestibility and plasma and urinary metabolite concentrations of healthy calves. J Anim Sci US. 2014;92:1630–8.

    Article  CAS  Google Scholar 

  23. Siurana A, Wall EH, Rodriguez M, Castillejos L, Ferret A, Calsamiglia S. The effect of dietary supplementation of artificial sweetener on performance of milk-fed calves. In: Shanks RD, editor. J. Anim. Sci. Vol. 92, E-Supplement 2Journal Dairy Sci. Vol. 97, E-Supplement 1. Kansas City, MO; 2014. p. 816.

  24. Soulet C. SUCRAM®, the white-gold taste enhancer from PANCOSMA. Engromix Website. 2015.

  25. Bigos A, Palkowska E, Rosolowska-Huszca D. Effect of artificial and natural sweeteners on glucose and insulin in plasma of rats. J Pre-Clin Clin Res. 2012;6:93–7.

    Google Scholar 

  26. Mitsutomi K, Masaki T, Shimasaki T, Gotoh K, Chiba S, Kakuma T, et al. Effects of a nonnutritive sweetener on body adiposity and energy metabolism in mice with diet-induced obesity. Metabolism US. 2014;63:69–78.

    Article  CAS  Google Scholar 

  27. Abou-Donia MB, El-Masry EM, Abdel-Rahman AA, McLendon RE, Schiffman SS. Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome p-450 in male rats. J Toxicol Environ Health A. 2008;71:1415–29. 2008/09/19 ed.

    Article  CAS  PubMed  Google Scholar 

  28. Suez J, Korem T, Zeevi D, Zilberman-Schapira G, Thaiss CA, Maza O, et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature. 2014;514:181–6. 2014/09/19 ed.

    CAS  PubMed  Google Scholar 

  29. Foletto KC, Melo Batista BA, Neves AM, de Matos Feijo F, Ballard CR, Marques Ribeiro MF, et al. Sweet taste of saccharin induces weight gain without increasing caloric intake, not related to insulin-resistance in Wistar rats. Appetite. 2015/11/12 ed. 2015.

  30. Feijo Fde M, Ballard CR, Foletto KC, Batista BA, Neves AM, Ribeiro MF, et al. Saccharin and aspartame, compared with sucrose, induce greater weight gain in adult Wistar rats, at similar total caloric intake levels. Appetite. 2013;60:203–7. 2012/10/24 ed.

    Article  PubMed  Google Scholar 

  31. Swithers SE, Davidson TL. A role for sweet taste: calorie predictive relations in energy regulation by rats. Behav Neurosci. 2008;122:161–73. 2008/02/27 ed.

    Article  PubMed  Google Scholar 

  32. Swithers SE, Sample CH, Davidson TL. Adverse effects of high-intensity sweeteners on energy intake and weight control in male and obesity-prone female rats. Behav Neurosci. 2013;127:262–74. 2013/02/13 ed.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Martinez C, Gonzalez E, Garcia RS, Salas G, Constantino-Casas F, Macias L, et al. Effects on body mass of laboratory rats after ingestion of drinking water with sucrose, fructose, aspartame, and sucralose additives ~ !2009-03-31 ~ !2010-11-25 ~ !2010-08-26 ~ !. Open Obes J. [Hilversum] :; 2010. p. 116–24.

  34. Fowler SP, Williams K, Resendez RG, Hunt KJ, Hazuda HP, Stern MP. Fueling the obesity epidemic? Artificially sweetened beverage use and long-term weight gain. Obes (Silver Spring). 2008;16:1894–900. 2008/06/07 ed.

    Article  Google Scholar 

  35. Bleich SN, Wolfson JA, Vine S, Wang YC. Diet-beverage consumption and caloric intake among US adults, overall and by body weight. Am J Public Health. 2014;104:e72–8. 2014/01/18 ed.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Fowler SP, Williams K, Hazuda HP. Diet soda intake is associated with long-term increases in waist circumference in a biethnic cohort of older adults: the San Antonio Longitudinal Study of Aging. J Am Geriatr Soc. 2015;63:708–15. 2015/03/18 ed.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Swithers SE. Artificial sweeteners produce the counterintuitive effect of inducing metabolic derangements. Trends Endocrinol Metab. 2013;24:431–41. 2013/07/16 ed.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. O’Connor L, Imamura F, Lentjes MA, Khaw KT, Wareham NJ, Forouhi NG. Prospective associations and population impact of sweet beverage intake and type 2 diabetes, and effects of substitutions with alternative beverages. Diabetologia. 2015;58:1474–83. 2015/05/07 ed.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Azad MB, Sharma AK, de Souza RJ, Dolinsky VW, Becker AB, Mandhane PJ, et al. Association Between Artificially Sweetened Beverage Consumption During Pregnancy and Infant Body Mass Index. JAMA Pediatr. [Internet]. 2016; Available from: http://archpedi.jamanetwork.com/article.aspx?. doi:10.1001/jamapediatrics.2016.0301

  40. Mueller NT, Jacobs DRJ, MacLehose RF, Demerath EW, Kelly SP, Dreyfus JG, et al. Consumption of caffeinated and artificially sweetened soft drinks is associated with risk of early menarche. Am J Clin Nutr US. 2015;102:648–54.

    Article  CAS  Google Scholar 

  41. Carwile JL, Willett WC, Spiegelman D, Hertzmark E, Rich-Edwards J, Frazier AL, et al. Sugar-sweetened beverage consumption and age at menarche in a prospective study of US girls. Hum Reprod. 2015;30:675–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Charalampopoulos D, McLoughlin A, Elks CE, Ong KK. Age at menarche and risks of all-cause and cardiovascular death: a systematic review and meta-analysis. Am J Epidemiol US. 2014;180:29–40.

    Article  Google Scholar 

  43. Swithers SE. Not so sweet revenge: unanticipated consequences of high-intensity sweeteners. Behav Anal. 2015;38:1–17.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Provencher V, Polivy J, Herman CP. Perceived healthiness of food. If it’s healthy, you can eat more! Appetite. England. 2009;52:340–4.

    Google Scholar 

  45. Forwood SE, Ahern A, Hollands GJ, Fletcher PC, Marteau TM. Underestimating calorie content when healthy foods are present: an averaging effect or a reference-dependent anchoring effect? PLoS One US. 2013;8:e71475.

    Article  CAS  Google Scholar 

  46. Carels RA, Harper J, Konrad K. Qualitative perceptions and caloric estimations of healthy and unhealthy foods by behavioral weight loss participants. Appetite. 2006;46:199–206.

    Article  PubMed  Google Scholar 

  47. Chernev A. The dieter’s paradox. J Consum Psychol Elsevier. 2011;21:178–83.

    Article  Google Scholar 

  48. Macdiarmid J, Blundell J. Assessing dietary intake: who, what and why of under-reporting. Nutr Res Rev. 1998;11:231–53.

    Article  CAS  PubMed  Google Scholar 

  49. Duca FA, Bauer PV, Hamr SC, Lam TK. Glucoregulatory relevance of small intestinal nutrient sensing in physiology, bariatric surgery, and pharmacology. Cell Metab. 2015;22:367–80.

    Article  CAS  PubMed  Google Scholar 

  50. Nelson G, Hoon MA, Chandrashekar J, Zhang Y, Ryba NJ, Zuker CS. Mammalian sweet taste receptors. Cell. 2001;106:381–90.

    Article  CAS  PubMed  Google Scholar 

  51. Tellez LA, Han W, Zhang X, Ferreira TL, Perez IO, Shammah-Lagnado SJ, et al. Separate circuitries encode the hedonic and nutritional values of sugar. Nat Neurosci US. 2016;19:465–70.

    Article  CAS  Google Scholar 

  52. Swithers SE, Laboy AF, Clark K, Cooper S, Davidson TL. Experience with the high-intensity sweetener saccharin impairs glucose homeostasis and GLP-1 release in rats. Behav Brain Res. 2012;233:1–14. 2012/05/09 ed.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bryant C, Mclaughlin J. Low calorie sweeteners: evidence remains lacking for effects on human gut function. Physiol Behav. 2016. doi:10.1016/j.physbeh.2016.04.026.

    PubMed  Google Scholar 

  54. Sato S, Hokari R, Kurihara C, Sato H, Narimatsu K, Hozumi H, et al. Dietary lipids and sweeteners regulate glucagon-like peptide-2 secretion. Am J Physiol Gastrointest Liver Physiol. 2013;304:G708–14.

    Article  CAS  PubMed  Google Scholar 

  55. Moran AW, Al-Rammahi M, Zhang C, Bravo D, Calsamiglia S, Shirazi-Beechey SP. Sweet taste receptor expression in ruminant intestine and its activation by artificial sweeteners to regulate glucose absorption. J Dairy Sci. 2014;97:4955–72.

    Article  CAS  PubMed  Google Scholar 

  56. Jang HJ, Kokrashvili Z, Theodorakis MJ, Carlson OD, Kim BJ, Zhou J, et al. Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1. Proc Natl Acad Sci U S A. 2007;104:15069–74. 2007/08/29 ed.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Pepino MY. Metabolic effects of non-nutritive sweeteners. Physiol. Behav. [Internet]. 2015;152:450–5. Available from: http://www.sciencedirect.com/science/article/pii/S0031938415003728.

  58. Gorboulev V, Schurmann A, Vallon V, Kipp H, Jaschke A, Klessen D, et al. Na(+)-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes. 2012;61:187–96.

  59. Palmnas MS, Cowan TE, Bomhof MR, Su J, Reimer RA, Vogel HJ, et al. Low-dose aspartame consumption differentially affects gut microbiota-host metabolic interactions in the diet-induced obese rat. PLoS One. 2014;9:e109841. 2014/10/15 ed.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Wisen O, Johansson C. Gastrointestinal function in obesity: motility, secretion, and absorption following a liquid test meal. Metabolism. 1992;41:390–5.

    Article  CAS  PubMed  Google Scholar 

  61. Nguyen NQ, Debreceni TL, Bambrick JE, Chia B, Wishart J, Deane AM, et al. Accelerated intestinal glucose absorption in morbidly obese humans: relationship to glucose transporters, incretin hormones, and glycemia. J Clin Endocrinol Metab. 2015;100:968–76.

    Article  CAS  PubMed  Google Scholar 

  62. Pepino MY, Tiemann CD, Patterson BW, Wice BM. S. K. Sucralose affects glycemic and hormonal responses to an oral glucose load. Diabetes Care. 2013;36:2530–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI, et al. Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A. 2005;102:11070–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci U S A. 2004;101:15718–23. 2004/10/27 ed.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Nettleton JE, Reimer RA, Shearer J. Reshaping the gut microbiota: impact of low calorie sweeteners and the link to insulin resistance? Physiol. Behav. [Internet]. 2016; Available from: http://linkinghub.elsevier.com/retrieve/pii/S0031938416301640.

  66. Karlsson FH, Fak F, Nookaew I, Tremaroli V, Fagerberg B, Petranovic D, et al. Symptomatic atherosclerosis is associated with an altered gut metagenome. Nat Commun. 2012;3:1245. 2012/12/06 ed.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Tremaroli V, Backhed F. Functional interactions between the gut microbiota and host metabolism. Nature. 2012;489:242–9. 2012/09/14 ed.

    Article  CAS  PubMed  Google Scholar 

  68. Daly K, Darby AC, Hall N, Nau A, Bravo D, Shirazi-Beechey SP. Dietary supplementation with lactose or artificial sweetener enhances swine gut Lactobacillus population abundance. Br J Nutr. 2014;111 Suppl:S30–5.

  69. Daly K, Darby AC, Hall N, Wilkinson MC, Pongchaikul P, Bravo D, et al. Bacterial sensing underlies artificial sweetener-induced growth of gut Lactobacillus. Env Microbiol 2015.

  70. Rettig S, Tenewitz J, Ahearn G, Coughlin C. Sucralose causes a concentration dependent metabolic inhibition of the gut flora Bacteroides, B. fragilis and B. uniformis not observed in the Firmicutes, E. faecalis and C. sordellii (1118.1). FASEB J. 2014;28:1118.1.

  71. Anderson RL, Kirkland JJ. The effect of sodium saccharin in the diet on caecal microflora. Food Cosmet Toxicol. 1980;18:353–5.

    Article  CAS  PubMed  Google Scholar 

  72. Frankenfeld CL, Sikaroodi M, Lamb E, Shoemaker S, Gillevet PM. High-intensity sweetener consumption and gut microbiome content and predicted gene function in a cross-sectional study of adults in the United States. Ann Epidemiol. 2015.

  73. Konstantinov SR, Favier CF, Zhu WY, Williams BA, Klus J, Souffrant W-B, et al. Microbial diversity studies of the porcine gastrointestinal ecosystem during weaning transition. Anim Res. 2004;53:317–24.

    Article  CAS  Google Scholar 

  74. O’Toole PW, Jeffery IB. Gut microbiota and aging. Science. 2015;350:1214–5.

    Article  PubMed  Google Scholar 

  75. Frankenfeld CL, Sikaroodi M, Lamb E, Shoemaker S, Gillevet PM. High-intensity sweetener consumption and gut microbiome content and predicted gene function in a cross-sectional study of adults in the United States. Ann Epidemiol. 2015;25:736–42. e4.

    Article  PubMed  Google Scholar 

  76. Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut microbiota. Nature. 2012;489:220–30. 2012/09/14 ed.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Martínez I, Stegen JC, Maldonado-Gómez MX, Eren AM, Siba PM, Greenhill AR, et al. The gut microbiota of rural papua new guineans: composition, diversity patterns, and ecological processes. Cell Rep. 2015;11:527–38.

    Article  PubMed  Google Scholar 

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Acknowledgments

Supported by funds from Purdue University and NIH grant NHLBI 1R21HL126052 (SES) and by the Natural Sciences and Engineering Research Council of Canada (NSERC, JS).

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Correspondence to Susan E. Swithers.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed and all procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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SES has received research grants from the National Institutes of Health; speaker honoraria from the American Academy of Pediatrics, the Society for Behavioral Neuroendocrinology, the National Institute of Diabetes and Digestive and Kidney Diseases, Association for Behavioral Analysis International; and travel reimbursement for speaking from the Association for Chemoreception Sciences, Florida Academy of Nutrition and Dietetics, Sugar Reduction Summit, and the Mortimer D. Sackler, M.D. Winter Conference on Developmental Psychobiology. JS has received research grants from the The Natural Sciences and Engineering Research Council of Canada. They have no other conflicts to declare.

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Shearer, J., Swithers, S.E. Artificial sweeteners and metabolic dysregulation: Lessons learned from agriculture and the laboratory. Rev Endocr Metab Disord 17, 179–186 (2016). https://doi.org/10.1007/s11154-016-9372-1

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