Assessing the in vivo data on low/no-calorie sweeteners and the gut microbiota

Food and Chemical Toxicology

Volumn 124, Issue , 2019, Pages 385-399

  Lobach, Alexandra R ^a   Roberts, Ashley ^a   Rowland, Ian R ^b  

^a Intertek Scientific and Regulatory Consultancy   (Canada)

^b UNIVERSITY OF READING   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ACESULFAME; ASPARTAME; CYCLAMATE SODIUM; LOW NO CALORIE SWEETENER; NEOTAME; REBAUDIOSIDE A; SACCHARIN; STEVIOL; SUCRALOSE; SWEETENING AGENT; UNCLASSIFIED DRUG;

ADVERSE OUTCOME; CHEMICAL STRUCTURE; FOOD COMPOSITION; FOOD INTAKE; FOOD SAFETY; GLUCOSE INTOLERANCE; HUMAN; IN VIVO STUDY; INTESTINE FLORA; METABOLISM; MICROBIAL DIVERSITY; NONHUMAN; REVIEW; RODENT MODEL; ANIMAL; DRUG EFFECT;

ANIMALS; GASTROINTESTINAL MICROBIOME; HUMANS; SWEETENING AGENTS;

EID: 85058945581     PISSN: 02786915     EISSN: 18736351     Source Type: Journal    
DOI: 10.1016/j.fct.2018.12.005     Document Type: Review

References (79)

1. Abou-Donia, M.B., El-Masry, E.M., Abdel-Rahman, A.A., McLendon, R.E., Schiffman, S.S., Splenda alters gut microflora and increases intestinal P-glycoprotein and cytochrome P-450 in male rats. J. Toxicol. Environ. Health 71 (2008), 1415–1429 https://doi.org/10.1080/15287390802328630.
2. Ambrus, J.L., Ambrus, C.M., Shields, R., Mink, I.B., Cleveland, C., Effect of galactose and sugar substitutes on blood insulin levels in normal and obese individuals. J. Med. 7 (1976), 429–438.
3. Anderson, R.L., Kirkland, J.J., The effect of sodium saccharin in the diet on caecal microflora. Food Chem. Toxicol. 18 (1980), 353–555 https://doi.org/10.1016/0015-6264(80)90188-1.
4. Bian, X., Chi, L., Gao, B., Tu, P., Ru, H., Lu, K., The artificial sweetener acesulfame potassium affects the gut microbiome and body weight gain in CD-1 mice. PLoS One, 12, 2017, 16 e0178426 https://doi.org/10.1371/journal.pone.0178426.
5. Bian, X., Tu, P., Chi, L., Gao, B., Ru, H., Lu, K., Saccharin induced liver inflammation in mice by altering the gut microbiota and its metabolic functions. Food Chem. Toxicol. 107 (2017), 530–539 https://doi.org/10.1016/j.fct.2017.04.045.
6. Bian, X., Chi, L., Gao, B., Tu, P., Ru, H., Lu, K., Gut microbiome response to sucralose and its potential role in inducing liver inflammation in mice. Front. Physiol., 8, 2017, 487 13pp, plus supplementary data https://doi.org/10.3389/fphys.2017.00487.
7. Bianchi, R.G., Muir, E.T., Cook, D.L., Nutting, E.F., The biological properties of aspartame. II. Actions involving the gastrointestinal system. J. Environ. Pathol. Toxicol. 3 (1980), 355–562.
8. Brusick, D., Borzelleca, J.F., Gallo, M., Williams, G., Kille, J., Hayes, A.W., Pi-Sunyer, F.X., Williams, C., Burks, W., Expert panel report on a study of Splenda in male rats. Regul. Toxicol. Pharmacol. 55 (2009), 6–12 https://doi.org/10.1016/j.yrtph.2009.06.013.
9. 14 C-labelled and unlabelled saccharin. Food Chem. Toxicol. 12 (1974), 175–184 https://doi.org/10.1016/0015-6264(73)90006-0.
10. Carvalho-Wells, A.L., Helmolz, K., Nodet, C., Molzer, C., Leonard, C., McKevith, B., Thielecke, F., Jackson, K.G., Tuohy, K.M., Determination of the in vivo prebiotic potential of a maize-based whole grain breakfast cereal: a human feeding study. Br. J. Nutr. 104 (2010), 1353–1356 https://doi.org/10.1017/s0007114510002084.
11. Chi, L., Bian, X., Gao, B., Tu, P., Lai, Y., Ru, H., Lu, K., Effects of the artificial sweetener neotame on the gut microbiome and fecal metabolites in mice. Molecules, 23(2), 2018, 367 11pp https://doi.org/10.3390/molecules23020367.
12. Costabile, A., Fava, F., Röytiö, H., Forssten, S.D., Olli, K., Klievink, J., Rowland, I.R., Ouwehand, A.C., Rastall, R.A., Gibson, G.R., et al. Impact of polydextrose on the faecal microbiota: a double-blind, crossover, placebo-controlled feeding study in healthy human subjects. Br. J. Nutr. 108 (2012), 471–481 https://doi.org/10.1017/s0007114511005782.
13. Daly, K., Darby, A.C., Hall, N., Nau, A., Bravo, D., Shirazi-Beechey, S.P., Dietary supplementation with lactose or artificial sweetener enhances swine gut Lactobacillus population abundance. Br. J. Nutr. 111:Suppl. 1 (2014), S30–S35 https://doi.org/10.1017/s0007114513002274.
14. Daly, K., Darby, A.C., Hall, N., Wilkinson, M.C., Pongchaikul, P., Bravo, D., Shirazi-Beechey, S.P., Bacterial sensing underlies artificial sweetener-induced growth of gut Lactobacillus. Environ. Microbiol. 18 (2016), 2159–2171 https://doi.org/10.1111/1462-2920.12942.
15. Dao, M.C., Everard, A., Clément, K., Cani, P.D., Losing weight for a better health: role for the gut microbiota. Clin. Nutr. Exp. 6 (2016), 39–58 https://doi.org/10.1016/j.yclnex.2015.12.001.
16. David, L.A., Maurice, C.F., Carmody, R.N., Gootenberg, D.B., Button, J.E., Wolfe, B.E., Ling, A.V., Devlin, A.S., Varma, Y., Fischbach, M.A., et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505:7484 (2014), 559–563 https://doi.org/10.1038/nature12820.
17. De Filippo, C., Cavalieri, D., Di Paola, M., Ramazzotti, M., Poullet, J.B., Massart, S., Collini, S., Pieraccini, G., Lionetti, P., Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proc. Natl. Acad. Sci. U.S.A. 107 (2010), 14691–14696 (plus supplementary data) https://doi.org/10.1073/pnas.1005963107.
18. Eckburg, P.B., Bik, E.M., Bernstein, C.N., Purdom, E., Dethlefsen, L., Sargent, M., Gill, S.R., Nelson, K.E., Relman, D.A., Diversity of the human intestinal microbial flora. Science 308:5728 (2005), 1635–1638 https://doi.org/10.1126/science.1110591.
19. EFSA. Scientific opinion on the re-evaluation of aspartame (E 951) as a food additive (EFSA panel on food additives and nutrient sources added to food/ANS) (question no EFSA-Q-2011-00406). EFSA J, 11(12), 2013, 3496 263pp https://doi.org/10.2903/j.efsa.2013.3496.
20. Farzi, A., Reed, F., Zhang, L., Holzer, P., Herzog, H., Peptide YY is a critical regulator of gut microbiota composition specifically under conditions of sucralose or high fat diet exposure. Neuro Gastroenterol. Motil., 29(Suppl. 2), 2017, 86 abstract 171 https://doi.org/10.1111/nmo.13180.
21. Flint, H.J., Duncan, S.H., Scott, K.P., Louis, P., Links between diet, gut microbiota composition and gut metabolism. Proc. Nutr. Soc. 74 (2015), 13–22 https://doi.org/10.1017/s0029665114001463.
22. Frankenfeld, C.L., Sikaroodi, M., Lamb, E., Shoemaker, S., Gillevet, P.M., 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. 25 (2015), 736–742 e4 https://doi.org/10.1016/j.annepidem.2015.06.083.
23. Gardana, C., Simonetti, P., Canzi, E., Zanchi, R., Pietta, P., Metabolism of stevioside and rebaudioside A from Stevia rebaudiana extracts by human microflora. J. Agric. Food Chem. 51 (2003), 6618–6622 https://doi.org/10.1021/jf0303619.
24. Geuns, J.M.C., Buyse, J., Vankeirsbilck, A., Temme, E.H.M., Compernolle, F., Toppet, S., Identification of steviol glucuronide in human urine. J. Agric. Food Chem. 54 (2006), 2794–2798 https://doi.org/10.1021/jf052693e.
25. Geuns, J.M.C., Buyse, J., Vankeirsbilck, A., Temme, E.H.M., Metabolism of stevioside by healthy subjects. Exp. Biol. Med. 232 (2007), 164–173 https://doi.org/10.3181/00379727-207-2320164.
26. Graf, D., Di Cagno, R., Fåk, F., Flint, H.J., Nyman, M., Saarela, M., Watzl, B., Contribution of diet to the composition of the human gut microbiota. Microb. Ecol. Health Dis., 26, 2015, 26164 11pp https://doi.org/10.3402/mehd.v26.26164.
27. Hooda, S., Boler, B.M., Serao, M.C., Brulc, J.M., Staeger, M.A., Boileau, T.W., Dowd, S.E., Fahey, G.C. Jr., Swanson, K.S., 454 pyrosequencing reveals a shift in fecal microbiota of healthy adult men consuming polydextrose or soluble corn fiber. J. Nutr. 142 (2012), 1259–1265 (plus supplementary tables) https://doi.org/10.3945/jn.112.158766.
28. JECFA. Saccharin. Toxicological Evaluation of Certain Food Additives. 26th Report of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), Apr. 19-28, 1982, Rome, Italy, 1982, Food & Agriculture Organization of the United Nations (FAO), Rome, Italy World Health Organization (WHO), International Programme on Chemical Safety (IPCS), Geneva, Switz. WHO Food Additives Series, no 17 http://www.inchem.org/documents/jecfa/jecmono/v17je25.htm.
29. JECFA. Saccharin, calcium, potassium and sodium salts. Toxicological Evaluation of Certain Food Additives and Food Contaminants [internet]. Twenty-eighth Report of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), Mar. 19-28, 1984, Rome. Geneva, Switz, 1984, World Health Organization (WHO), Rome, Italy International Programme on Chemical Safety (IPCS), Geneva, Switz. WHO Food Additives Series, no 19 http://www.inchem.org/documents/jecfa/jecmono/v19je11.htm.
30. JECFA. Trichlorogalactosucrose (TGS) [sucralose]. Toxicological Evaluation of Certain Food Additives and Contaminants. Thirty-seventh Meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), June 5-14, 1990, Geneva, Switz, 1991, World Health Organization (WHO), Rome, Italy International Programme on Chemical Safety (IPCS), Geneva, Switz. WHO Food Additives Series, no 26 http://www.inchem.org/documents/jecfa/jecmono/v28je14.htm.
31. JECFA. Evaluation for sucralose by the 33rd meeting of the joint FAO/WHO Expert committee on food additives (JECFA). FFI (Fish Farming Int.) J 182 (1999), 60–75.
32. Kelly, J., Daly, K., Moran, A.W., Ryan, S., Bravo, D., Shirazi-Beechey, S.P., Composition and diversity of mucosa-associated microbiota along the entire length of the pig gastrointestinal tract; dietary influences. Environ. Microbiol. 19 (2017), 1425–1438 https://doi.org/10.1111/1462-2920.13619.
33. Kennedy, N.A., Walker, A.W., Berry, S.H., Duncan, S.H., Farquarson, F.M., Louis, P., Thomson, J.M., Satsangi, J., Flint, H.J., Parkhill, J., et al. The impact of different DNA extraction kits and laboratories upon the assessment of human gut microbiota composition by 16S rRNA gene sequencing. PLoS One, 9, 2014, 9 e88982 https://doi.org/10.1371/journal.pone.0088982.
34. Klinder, A., Shen, Q., Heppel, S., Lovegrove, J.A., Rowland, I., Tuohy, K.M., Impact of increasing fruit and vegetables and flavonoid intake on the human gut microbiota. Food Funct 7 (2016), 1788–1796 https://doi.org/10.1039/c5fo01096a.
35. Koenig, J.E., Spor, A., Scalfone, N., Fricker, A.D., Stombaugh, J., Knight, R., Angenent, L.T., Ley, R.E., Succession of microbial consortia in the developing infant gut microbiome. Proc. Natl. Acad. Sci. U.S.A. 108:Suppl. 1 (2011), 4578–4585 https://doi.org/10.1073/pnas.1000081107.
36. Korpela, K., Flint, H.J., Johnstone, A.M., Lappi, J., Poutanen, K., Dewulf, E., Delzenne, N., De Vos, W., Salonen, A., Gut microbiota signatures predict host and microbiota responses to dietary interventions in obese individuals. PLoS One, 9, 2014, 10 e90702 https://doi.org/10.1371/journal.pone.0090702.
37. Koyama, E., Sakai, N., Ohori, Y., Kitazawa, K., Izawa, O., Kakegawa, K., Fujino, A., Ui, M., Absorption and metabolism of glycosidic sweeteners of stevia mixture and their aglycone, steviol, in rats and humans. Food Chem. Toxicol. 41 (2003), 875–883 https://doi.org/10.1016/S0278-6915(03)00039-5.
38. Lawrie, C.A., Renwick, A.G., Sims, J., The urinary excretion of bacterial amino-acid metabolites by rats fed saccharin in the diet. Food Chem. Toxicol. 23 (1985), 445–450 https://doi.org/10.1016/0278-6915(85)90138-3.
39. Lawrie, C.A., Renwick, A.G., The effect of saccharin ingestion on the excretion of microbial amino acid metabolites in rat and man. Toxicol. Appl. Pharmacol. 91 (1987), 415–428 https://doi.org/10.1016/0041-008X(87)90063-9.
40. Li, S., Chen, T., Dong, S., Xiong, Y., Hua, W., Xu, F., The effects of rebaudioside A on microbial diversity in mouse intestine. Food Sci. Technol. Res. 20 (2014), 459–467 https://doi.org/10.3136/fstr.20.459.
41. Magnuson, B., Council Spokesperson, Berna Magnuson, Reviews Nature Study on Low-calorie Sweeteners. 2015, Calorie Control Council, Atlanta, GA Press release dated March 13, 2015. Available at: http://caloriecontrol.org/council-spokesperson-berna-magnuson-reviews-nature-study-on-low-calorie-sweeteners/.
42. Magnuson, B.A., Burdock, G.l.A., Doull, J., Kroes, R.M., Marsh, G.M., Pariza, M.W., Spencer, P.S., Waddell, W.J., Walker, R., Williams, G.M., Aspartame: a safety evaluation based on current use levels, regulations, and toxicological and epidemiological studies. Crit. Rev. Toxicol. 37 (2007), 629–727 https://doi.org/10.1080/10408440701516184.
43. Martínez, I., Lattimer, J.M., Hubach, K.L., Case, J.A., Yang, J., Weber, C.G., Louk, J.A., Rose, D.J., Kyureghian, G., Peterson, D.A., et al. Gut microbiome composition is linked to whole grain-induced immunological improvements. ISME J. 7 (2013), 269–280 https://doi.org/10.1038/ismej.2012.104.
44. Matsui, M., Hayashi, N., Konuma, H., Tanimura, A., Kurata, H., Studies on metabolism of food additives by microorganisms inhabiting gastrointestinal tract (IV). Fate of faecal flora in monkey administered orally with sodium cyclamate and detection of sodium cyclamate assimilating bacteria in vitro by anaerobic culture. Shokuhin Eiseigaku Zasshi [J. Food Hyg. Soc. Jpn. 17 (1976), 54–58 (Japanese, English abstract) https://doi.org/10.3358/shokueishi.17.54.
45. McChesney, E.W., Golberg, L., The excretion and metabolism of saccharin in man. I. Methods of investigation and preliminary results. Food Chem. Toxicol. 11 (1973), 403–414 https://doi.org/10.1016/0015-6264(73)90006-0.
46. Morgan, X.C., Huttenhower, C., Chapter 12: human microbiome analysis. PLoS Comput. Biol., 8, 2012, 14 e1002808 https://doi.org/10.1371/journal.pcbi.1002808.
47. Muegge, B.D., Kuczynski, J., Knights, D., Clemente, J.C., Gonzalez, A., Fontana, L., Henrissat, B., Knight, R., Gordon, J.I., Diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans. Science 332:6032 (2011), 970–974 https://doi.org/10.1126/science.1198719.
48. Nicholson, J.K., Holmes, E., Kinross, J., Burcelin, R., Gibson, G., Jia, W., Pettersson, S., Host-gut microbiota metabolic interactions. Science 336:6086 (2012), 1262–1267 https://doi.org/10.1126/science.1223813.
49. Olivier-Van Stichelen, S., Rother, K.I., Hanover, J.A., Nascent microbiome and early metabolism are perturbed by pre-and post-natal exposure to artificial sweeteners. Glycobiology 27 (2017), 1185–1186 [abstract 38] https://doi.org/10.1093/glycob/cwx086.
50. Palmnäs, M.S., Cowan, T.E., Bomhof, M.R., Su, J., Reimer, R.A., Vogel, H.J., Hittel, D.S., Shearer, J., Low-dose aspartame consumption differentially affects gut microbiota-host metabolic interactions in the diet-induced obese rat. PLoS One, 9, 2014, 10 e109841 https://doi.org/10.1371/journal.pone.0109841.
51. Qin, J., Li, R., Raes, J., Arumugam, M., Burgdorf, K.S., Manichanh, C., Nielsen, T., Pons, N., Levenez, F., Yamada, T., et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464:7285 (2010), 59–65 https://doi.org/10.1038/nature08821.
52. Queipo-Ortuño, M.I., Boto-Ordóñez, M., Murri, M., Gomez-Zumaquero, J.M., Clemente-Postigo, M., Estruch, R., Cardona Diaz, F., Andrés-Lacueva, C., Tinahones, F.J., Influence of red wine polyphenols and ethanol on the gut microbiota ecology and biochemical biomarkers. Am. J. Clin. Nutr. 95 (2012), 1323–1324 https://doi.org/10.3945/ajcn.111.027847.
53. Rajilic-Stojanovic, M., De Vos, W.M., The first 1000 cultured species of the human gastrointestinal microbiota. FEMS Microbiol. Rev. 38 (2014), 996–1047 https://doi.org/10.1111/1574-6976.12075.
54. Rastall, R.A., Gibson, G.R., Recent developments in prebiotics to selectively impact beneficial microbes and promote intestinal health. Curr. Opin. Biotechnol. 32 (2015), 42–46 https://doi.org/10.1016/j.copbio.2014.11.002.
55. Renwick, A.G., The metabolism of intense sweeteners. Xenobiotica 16 (1986), 1057–1072 https://doi.org/10.3109/00498258609038983.
56. Renwick, A.G., The use of a sweetener substitution method to predict dietary exposures for the intense sweetener rebaudioside A. Food Chem. Toxicol. 46:7, Suppl. l (2008), S61–S69 https://doi.org/10.1016/j.fct.2008.05.009.
57. Renwick, A.G., Tarka, S.M., Microbial hydrolysis of steviol glycosides. Food Chem. Toxicol. 46:7, Suppl. l (2008), S70–S74 https://doi.org/10.1016/j.fct.2008.05.008.
58. Roberts, A., Renwick, A.G., The effect of saccharin on the microbial metabolism of tryptophan in man. Food Chem. Toxicol. 23 (1985), 451–455 https://doi.org/10.1016/0278-6915(85)90139-5.
59. Roberts, A., Renwick, A.G., Sims, J., Snodin, D.J., Sucralose metabolism and pharmacokinetics in man. Food Chem. Toxicol. 38:Suppl. 2 (2000), S31–S41 https://doi.org/10.1016/S0278-6915(00)00026-0.
60. Rodriguez-Palacios, A., Harding, A., Menghini, P., Himmelman, C., Retuerto, M., Nickerson, K.P., Lam, M., Croniger, C.M., McLean, M.H., Durum, S.K., Pizarro, T.T., Ghannoum, M.A., Ilic, S., McDonald, C., Cominelli, F., The artificial sweetener Splenda promotes gut proteobacteria, dysbiosis, and myeloperoxidase reactivity in Crohn's disease-like Ileitis. Inflamm. Bowel Dis. 24 (2018), 1005–1020 (plus supplementary data) https://doi.org/10.1093/ibd/izy060.
61. Salonen, A., Lahti, L., Salojärvi, J., Holtrop, G., Korpela, K., Duncan, S.H., Date, P., Farquharson, F., Johnstone, A.M., Lobley, G.E., et al. Impact of diet and individual variation on intestinal microbiota composition and fermentation products in obese men. ISME J. 8 (2014), 2218–2230 https://doi.org/10.1038/ismej.2014.63.
62. Sankar, S.A., Lagier, J.-C., Pontarotti, P., Raoult, D., Fournier, P.-E., The human gut microbiome, a taxonomic conundrum. Syst. Appl. Microbiol. 38 (2015), 276–286 https://doi.org/10.1016/j.syapm.2015.03.004.
63. Sims, J., Renwick, A.G., The effects of saccharin on the metabolism of dietary tryptophan to indole, a known cocarcinogen for the urinary bladder of the rat. Toxicol. Appl. Pharmacol. 67 (1983), 132–151 https://doi.org/10.1016/0041-008x(83)90252-1.
64. Sims, J., Roberts, A., Daniel, J.W., Renwick, A.G., The metabolic fate of sucralose in rats. Food Chem. Toxicol. 38:Suppl. 2 (2000), S115–S121 https://doi.org/10.1016/S0278-6915(00)00034-X.
65. Suez, J., Korem, T., Zeevi, D., Zilberman-Schapira, G., Thaiss, C.A., Maza, O., Israeli, D., Zmora, N., Gilad, S., Weinberger, A., et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature 514:7521 (2014), 181–186 https://doi.org/10.1038/nature13793.
66. Suez, J., Korem, T., Zilberman-Schapira, G., Segal, E., Elinav, E., Non-caloric artificial sweeteners and the microbiome: findings and challenges. Gut Microb. 6 (2015), 149–155 https://doi.org/10.1080/19490976.2015.1017700.
67. Tilg, H., Kaser, A., Gut microbiome, obesity, and metabolic dysfunction. J. Clin. Invest. 121 (2011), 2126–2132 https://doi.org/10.1172/JCI58109.
68. Tuohy, K.M., Kolida, S., Lustenberger, A.M., Gibson, G.R., The prebiotic effects of biscuits containing partially hydrolysed guar gum and fructo-oligosaccharides - a human volunteer study. Br. J. Nutr. 86 (2001), 341–348 https://doi.org/10.1079/BJN2001394.
69. Turnbaugh, P.J., Ridaura, V.K., Faith, J.J., Rey, F.E., Knight, R., Gordon, J.I., The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci. Transl. Med., 1, 2009 6ra14 (10pp, plus supplementary data) https://doi.org/10.1126/scitranslmed.3000322.
70. Tzounis, X., Rodriguez-Mateos, A., Vulevic, J., Gibson, G.R., Kwik-Uribe, C., Spencer, J.P., Prebiotic evaluation of cocoa-derived flavanols in healthy humans by using a randomized, controlled, double-blind, crossover intervention study. Am. J. Clin. Nutr. 93 (2011), 62–72 https://doi.org/10.3945/ajcn.110.000075.
71. Uebanso, T., Ohnishi, A., Kitayama, R., Yoshimoto, A., Nakahashi, M., Shimohata, T., Mawatari, K., Takahashi, A., Effects of low-dose non-caloric sweetener consumption on gut microbiota in mice. Nutrients, 9, 2017, 560 11pp https://doi.org/10.3390/nu9060560.
72. Ursell, L.K., Metcalf, J.L., Parfrey, L.W., Knight, R., Defining the human microbiome. Nutr. Rev. 70:Suppl. 1 (2012), S38–S44 https://doi.org/10.1111/j.1753-4887.2012.00493.x.
73. Vendrame, S., Guglielmetti, S., Riso, P., Arioli, S., Klimis-Zacas, D., Porrini, M., Six-week consumption of a wild blueberry powder drink increases bifidobacteria in the human gut. J. Agric. Food Chem. 59 (2011), 12815–12820 https://doi.org/10.1021/jf2028686.
74. Volz, M., Christ, O., Eckert, H.G., Herok, J., Kellner, H.M., Rupp, W., Kinetics and biotransformation of Acelsulfame-K. Mayer, D.G., Kemper, F.H., (eds.), 47, 1991, Acesulfame-K. Marcel Dekker, Inc., New York, NY, 7–26 Food Science and Technology.
75. Walker, A.W., Duncan, S.H., Louis, P., Flint, H.J., Phylogeny, culturing, and metagenomics of the human gut microbiota. Trends Microbiol. 22 (2014), 267–274 https://doi.org/10.1016/j.tim.2014.03.001.
76. Walker, A.W., Martin, J.C., Scott, P., Parkhill, J., Flint, H.J., Scott, K.P., 16S rRNA gene-based profiling of the human infant gut microbiota is strongly influenced by sample processing and PCR primer choice. Microbiome, 3, 2015, 26 11pp https://doi.org/10.1186/s40168-015-0087-4.
77. Wheeler, A., Boileau, A.C., Winkler, P.C., Compton, J.C., Prakash, I., Jiang, X., Mandarino, D.A., Pharmacokinetics of rebaudioside A and stevioside after single oral doses in healthy men. Food Chem. Toxicol. 46:7, Suppl. l (2008), S54–S60 https://doi.org/10.1016/j.fct.2008.04.041.
78. Wu, G.D., Chen, J., Hoffmann, C., Bittinger, K., Chen, Y.Y., Keilbaugh, S.A., Bewtra, M., Knights, D., Walters, W.A., Knight, R., et al. Linking long-term dietary patterns with gut microbial enterotypes. Science 334:6052 (2011), 105–108 https://doi.org/10.1126/science.1208344.
79. Xu, Z., Knight, R., Dietary effects on human gut microbiome diversity. Br. J. Nutr. 113:Suppl. l (2015), S1–S5 https://doi.org/10.1017/s0007114514004127.