Curr Gastroenterol Rep (2017) 19: 64

https://doi.org/10.1007/s11894-017-0602-9

NUTRITION AND OBESITY (S MCCLAVE AND J OBERT, SECTION EDITORS)

The Association Between Artificial Sweeteners and Obesity

Michelle Pearlman 1 & Jon Obert 2 & Lisa Casey 1

Published online: 21 November 2017

# Springer Science+Business Media, LLC 2017

Abstract Keywords Obesity . Artificial sweeteners . Microbiome .

Purpose of Review The purpose of this paper is to review the Insulin resistance . Metabolic syndrome . Calorie consumption
epidemiology of obesity and the evolution of artificial sweet-
eners; to examine the latest research on the effects of artificial
sweeteners on the host microbiome, the gut-brain axis, glu- Introduction
cose homeostasis, and energy consumption; and to discuss
how all of these changes ultimately contribute to obesity. Epidemiology of Obesity
Recent Findings Although artificial sweeteners were devel-
oped as a sugar substitute to help reduce insulin resistance Obesity is a major public health problem that exhibits no
and obesity, data in both animal models and humans suggest boundaries. It affects children and adults, and spans all ethnic-
that the effects of artificial sweeteners may contribute to met- ities and races. In the USA between 1980 and 2000, the over-
abolic syndrome and the obesity epidemic. Artificial sweet- all prevalence of obesity increased significantly among adult
eners appear to change the host microbiome, lead to decreased men and women. For unclear reasons, though the overall prev-
satiety, and alter glucose homeostasis, and are associated with alence has remained stable since 2000, there seems to be an
increased caloric consumption and weight gain. increasing trend toward obesity in women and the extreme
Summary Artificial sweeteners are marketed as a healthy al- obesity class [1]. Studies suggest that obesity is far more com-
ternative to sugar and as a tool for weight loss. Data however plex than previously thought and is a result of numerous in-
suggests that the intended effects do not correlate with what is ternal host factors and external environmental factors. Several
seen in clinical practice. Future research should focus on the factors that contribute to obesity include but are not limited to
newer plant-based sweeteners, incorporate extended study du- the consumption of energy dense foods, large portion sizes,
rations to determine the long-term effects of artificial sweet- physical inactivity, alterations in the host gut microbiome,
ener consumption, and focus on changes in the microbiome, consumption of a predominantly high fat and/or high sugar
as that seems to be one of the main driving forces behind diet, and the use of artificial sweeteners (AS) [2–5].
nutrient absorption and glucose metabolism.
The Evolution of Artificial Sweeteners
This article is part of the Topical Collection on Nutrition and Obesity
Sugar-laden diets are ubiquitous because humans and animals
* Michelle Pearlman display preferences for sweet taste that starts early in life [6,
[email protected] 7]. The use of AS, also known as non-caloric or non-nutritive
sweeteners (NNS), has grown in popularity as awareness of
1
Department of Medicine, Division of Gastroenterology and
the obesity epidemic increases, and in particular due to the
Hepatology, University of Texas Southwestern Medical Center, 5323 growing concern for obesity-related complications including
Harry Hines, K5.136, Dallas, TX 75390, USA metabolic syndrome and insulin resistance [8, 9]. Based on the
2
Division of Gastroenterology and Hepatology, University of NHANES database, the prevalence of AS from 1999 to 2007
Louisville, Louisville, KY, USA increased from 6.1 to 12.5% among children and 18.7% to
64 Page 2 of 8 Curr Gastroenterol Rep (2017) 19: 64

24.1% among adults, with other studies reporting upwards of potassium (acesulfame K) which is about 300 times sweeter
56% in the Nurses’ Health Study (NHS), 54% in the Health than sucrose, and sucralose which is 600 times sweeter than
Professionals Follow-Up Study (HDFS), and 48% in the San sucrose [24, 26–28]. More recent AS on the market include
Antonio Heart Study over different time periods [9–12]. plant-derived products like stevia, and fermented sugar alco-
Despite the increased use of AS, there does not seem to be a hols like sorbitol and xylitol which have a laxative effect if
corresponding decrease in consumption of foods or beverages consumed in large quantities. Overall, there has been an ex-
sweetened with added sugar over the same time period [13]. ponential increase in the consumption of AS over the last two
The majority of AS are low in calories and are either not decades predominantly from carbonated diet beverages [13].
metabolized by the host or activate sweet taste receptors at
such low concentrations that the calories are negligible in such
Research Limitations
small quantities. AS were originally developed as sugar sub-
stitutes based on the premise that the use of these products
AS are found in non-edible products and are often ingested or
would result in decreased caloric intake, lead to weight loss,
used without consumer awareness, thus making it extremely
and decrease the incidence of diabetes mellitus. Interestingly,
difficult to establish clear causality in human studies that use
AS have also been used since the 1950s to promote feeding
dietary recall questionnaires. Many of the studies evaluating
and weight gain in agricultural animals as a cheaper alterna-
the effects of AS on metabolic parameters avoid this dilemma
tive to sugar [14–16]. Despite the widespread use of AS, the
by using rodent models where all of the variables are strictly
prevalence of obesity has remained stable suggesting that they
controlled [9, 29]. Although rodent models glean some insight
are not an optimal weight loss tool. In addition, there is grow-
into the effects of AS, the outcomes are inconsistent in
ing evidence that the use of AS does not decrease the risk of
humans.
developing certain chronic diseases like hypertension, stroke,
renal disease, coronary artery disease, insulin resistance, or
obesity, but may actually have an equivalent or increased risk
of these diseases compared to sugar containing foods and The Effects of Artificial Sweeteners
beverages [12, 17–20, 21••, 22, 23]. on the Microbiome

Structure and Function of the Microbiome

Types of Artificial Sweeteners
The microbiome is a heterogeneous population of bacteria
Over the past several decades, there has been a surge in the use which has an immense spatial distribution throughout the gas-
of AS with over 6000 products on the market in the USA trointestinal tract covering a surface area of approximately 300
alone (Table 1) [24]. Saccharin is the oldest artificial sweeten- to 400 m2. The internal milieu of the host and the external
er and was developed at Johns Hopkins University in 1879. It environment significantly influence the diversity and viru-
is 200 to 700 times sweeter than sucrose and is commonly lence genes of the host intestinal flora. Studies of the
used in soft drinks, candy, salad dressings, chewing gum, microbiome are now possible because of advances in gene-
and non-edible products like toothpaste, mouthwash, and based sequencing techniques. Using a 16S ribosomal RNA
medications [25]. Second-generation sweeteners include as- sequence, a significant number of bacteria have been identi-
partame which was approved by the FDA in 1981, and is fied that were previously not found using culture techniques
approximately 200 times sweeter than sucrose, acesulfame alone. Further application of gene sequencing methods allows

Table 1 Common FDA-approved artificial sweeteners and their uses

Artificial sweetener Trade names FDA-approved date # X sweetness of sucrose Common uses

Saccharin Sweet ‘N Low, Sugar 1879 200–700 Soft drinks, candy, medicine, toothpaste,
Twin Necta Sweet lip gloss, baked goods, dressing
Aspartame NutraSweet, Equal 1981 200 Gum, diet soda, instant tea/coffee, yogurt,
pudding
Acesulfame K Sweet One, Sweet and 1967 200 Soft drinks, baked goods, gum, gelatin
Safe, Sunette, Swiss Sweet
Sucralose Splenda 1998 600 Baked goods
Stevia/erythritol Truvia, PureVia 1955 300 Baked goods, soft drinks
Sugar alcohols Sorbitol, Mannitol, Xylitol Naturally occurring 0.5–1 Candy, gum, naturally in fruits/vegetables
Curr Gastroenterol Rep (2017) 19: 64 Page 3 of 8 64

investigators to study the impact of AS on the microbiome and that the heterogeneity in the human microbiome makes some
examine downstream effects on the host metabolism and nu- more vulnerable to glucose intolerance than others after AS
trient absorption [30, 31]. exposure [39••].
The microorganisms in the gut employ specific enzymes that
are not encoded in the human genome that enable the host to
extract calories from otherwise indigestible foods [32]. The Effects of Artificial Sweeteners on the Gut-Brain
Alterations in the microbiome lead to changes in energy extrac- Axis
tion and influence the body fat composition of the host [33].
The gut microbiome is predominantly inhabited by strict Neuro-Hormonal Changes After Sugar and Artificial
anaerobic bacteria with lower levels of facultative anaerobes Sweetener Consumption: the Reward Phenomenon
and aerobes. In humans and rodents, most of these bacteria
reside in the colon and are dominated by bacteroidetes and Sugar has a high addictive potential because of its downstream
firmicutes [34–36]. Prior studies suggest that obese rodents effects on behavioral and neurochemical pathways including
have a lower abundance of bacteroidetes and a greater abun- changes in dopamine, opioid receptor binding, and acetylcho-
dance of firmicutes compared to their lean counterparts [37]. line release in the nucleus accumbens. These neuronal adap-
tations contribute to the “reward phenomenon” and ultimately
The Effects of Artificial Sweeteners on the Microbiome: lead to excessive sugar intake [42]. Food reward involves both
Rodent Model sensory and post-ingestion pathways.
The sensory pathway involves two G-protein receptors
Palmnas et al. studied the effects of low-dose aspartame con- (T1R2 and T1R3) that form the sweet taste receptor in the
sumption on the microbiome and body fat composition. After oropharynx [43]. The ingestion of sugar or AS activates the
8 weeks, fecal analysis in the aspartame group showed a great- sweet taste receptor and sends signals to the hypothalamus
er abundance of enterobacteriaceae and clostridium leptim. and the amygdala which is associated with reward and satis-
The rats fed a high fat diet had an increased ratio of firmicutes faction [24, 44•]. The post-ingestion pathway is influenced by
to bacteroidetes, and this ratio was attenuated in those who the energy content of the food or beverage being consumed.
were also exposed to aspartame. Rats in the aspartame group When AS are ingested instead of sugar, the sweet taste recep-
consumed fewer calories and gained less weight; however, tors are activated; however, the rise in blood glucose and in-
they exhibited more fasting hyperglycemia and more signifi- sulin secretion do not occur at the same degree [45]. Because
cant impairment in insulin tolerance testing independent of AS either have no energy content or are not metabolized, the
their body fat composition [38••]. Suez et al. demonstrated post-ingestion pathway is significantly altered.
that in both lean and obese mice, ingestion of AS (saccharin, AS activate the oral taste receptors, only partially acti-
sucralose, and aspartame) compared to water, glucose, or su- vate the food reward pathway, and fail to activate the
crose containing water leads to increased glucose intolerance. post-ingestion pathway because of the lack of caloric en-
By transplanting fecal material from mice on a saccharin- or ergy. Changes in these pathways ultimately lead to in-
glucose-containing chow into normal chow-consuming germ- creased appetite, increased food craving, and greater ca-
free mice, mice that received the fecal transplant from the loric consumption [46].
saccharin group exhibited greater impaired glucose tolerance
compared to the control group. These findings illustrate that Anticipatory or Cephalic Phase Insulin Release
the effect of AS on metabolic parameters including insulin
resistance is at least in part due to alterations in the Humans exhibit the ability to use flavor and taste cues that
microbiome [39••]. activate certain physiologic responses also known as anticipa-
tory or cephalic phase insulin release. This process refers to
The Effects of Artificial Sweeteners on the Microbiome: the release of insulin in response to sensory stimulation or
Human Studies activation of the sweet taste receptors in the oral cavity prior
to nutrient absorption in anticipation of sugar intake. The nor-
The increased prevalence of bacteroides and decreased abun- mal physiologic response after sugar stimulation of the sweet
dance of clostridiales that occurs in mice consuming AS is taste receptors involves increased heat production (energy ex-
similar to what is seen in humans with type 2 diabetes [40, 41]. penditure) and the release of various hormones that contribute
Suez et al. examined the effects of AS on blood glucose con- to effective metabolism of energy and satiety signals [47]. In
trol in seven healthy volunteers who did not previously con- the era of widespread artificial sweetener use, the body de-
sume significant amounts of AS. Four of seven subjects ex- velops a dampened hormonal response because the intake of
hibited worse glucose tolerance at 5 to 7 days of exposure food that stimulates the sweet taste receptors in the orophar-
when compared to the first 4 days. This study further suggests ynx is no longer predictably followed by a sugar load [48].
64 Page 4 of 8 Curr Gastroenterol Rep (2017) 19: 64

Energy Balance consumption inhibit anticipatory responses that normally

serve to maintain physiological homeostasis after a sugar load.
Energy balance is a complex system with negative and pos-
itive feedback mechanisms that help maintain homeostasis.
Ghrelin is the main peripheral hormone involved in appetite The Effects of Artificial Sweeteners on Glucose
stimulation, while cholecystokinin (CCK), polypeptide Y Homeostasis
(PYY), and glucagon-like-peptide 1 (GLP-1) are the main
peripheral hormones involved in appetite suppression and Changes in Glucose Homeostasis: Rodent Studies
satiety signaling [49]. GLP-1 secretion is dependent on the
presence of nutrients in the small intestine and stimulates One of the most important metabolic processes that are mod-
the pancreatic beta cells to secrete insulin in response to a ified by AS is glucose regulation. There are several proposed
rising blood glucose and inhibits glucagon secretion [50]. mechanisms that may explain the negative effect of aspartame
Sugar ingestion leads to increase in blood glucose and up- on glucose homeostasis and hormonal dysregulation besides
regulation of GLP-1, GIP, and PYY; stimulates the pancre- its effect on GLP-1 and other gut hormones previously
atic beta cells to secrete insulin; and promotes cellular up- discussed.
take of glucose for energy [50]. One theory is that aspartame is associated with increased
Animal models suggest that AS interfere with the gut-brain levels of the short-chain fatty acid (SCFA) propionate which is
axis, but these changes are more difficult to illustrate in located in the colon. Increased levels of propionate may be
humans [44•]. associated with increased gluconeogenesis in the liver and
ultimately leads to increased hepatic glucose production and
hyperglycemia [38••, 55•].
Hormonal Changes After Artificial Sweetener
Another proposed theory that links aspartame consump-
Consumption: Rodent Studies
tion to glucose intolerance involves intestinal alkaline phos-
phatase (IAP). IAP has been associated with a reduced risk
Studies in rats suggest that prior exposure to saccharin-
of metabolic syndrome in mice. Phenylalanine is one of the
sweetened supplements and other AS affect the release of
breakdown products of aspartame and is a known inhibitor
GLP-1. Rats previously exposed to saccharin have higher
of IAP [56]. Gul et al. demonstrated that mice fed a high fat
rates of hyperglycemia after a sugar load, decreased thermo-
diet plus aspartame for 18 weeks compared to a high fat diet
genic effect of food, decreased satiety, and overall increased
plus water had lower levels of IAP (p < 0.05), gained more
caloric intake compared to those who were previously ex-
weight (p = 0.0001), had higher fasting glucose levels
posed to glucose-containing supplements [47, 51]. Although
(p = 0.006), had higher serum tumor necrosis-alpha levels
these effects have been studied in rodents, it is difficult to
(p = 0.01), and demonstrated greater glucose intolerance
assess the same end points in humans because of inaccurate
(p = 0.02) [57•].
dietary recall questionnaires and reliance on subjective scor-
ing systems to assess satiety and hunger [24].
Changes in Glucose Homeostasis: Conflicting Data
in Human Studies
Hormonal Changes After Artificial Sweetener
Consumption: Human Studies Pepino et al. evaluated the effects of sucralose ingestion in 17
obese insulin-sensitive humans who were previously artificial
Previous studies have shown that consumption of AS leads to sweetener naïve. Sucralose ingestion prior to a glucose load
increased subjective ratings of motivation to eat and increased leads to a greater increase in peak plasma glucose concentra-
subjective appetite relative to controls [52, 53]. More recent tions and insulin secretion compared to the control group who
data suggests that AS do not induce satiety the same way that ingested water 10 min prior to a glucose load [58]. Contrary to
sugar does and have numerous downstream effects on diges- the prior study, Anton et al. evaluated the effects of stevia,
tion, absorption of nutrients, and metabolism [47]. A study by aspartame, and sucrose in 19 healthy lean and 12 obese sub-
Wu et al. demonstrated that the ingestion of glucose stimulat- jects prior to lunch and dinner. The stevia and aspartame
ed GLP-1 and GIP at greater levels compared to those that groups did not over-compensate by eating more at lunch and
were given sucralose. Stimulation of these gut hormones cor- dinner, and all groups had similar self-reported hunger and
related with more delayed gastric emptying and increased sa- satiety levels. Interestingly, the stevia group had significantly
tiety [54]. lower postprandial glucose levels compared to the aspartame
In summary, studies suggest that AS interfere with basic and sucrose groups [59]. O’Connor et al. evaluated the asso-
learned behaviors. Changes in the activation of sweet taste ciation between various sugar-containing beverages and arti-
receptors and the post-ingestion pathway after AS ficially sweetened beverages on incident type 2 diabetes.
Curr Gastroenterol Rep (2017) 19: 64 Page 5 of 8 64

Using an adjusted Cox regression analysis, substituting artifi- compared to the caloric intake from a conventional diet with-
cially sweetened beverages for sugar-containing beverages out AS. Interestingly, when the diet was covertly changed to
did not reduce the incidence of developing diabetes although aspartame-containing products, patients had a 25% spontane-
substituting with unsweetened tea, coffee, or water did have a ous reduction in caloric intake compared to the conventional
significant reduction [20•]. In a prospective study, 30 healthy diet. This suggests that at least part of the increased caloric
males were randomized into one of four groups: aspartame, consumption attributed to AS is based on a conscious decision
monk fruit, stevia, or sucrose-sweetened beverages. Blood to overcompensate [64].
glucose and insulin levels were measured after consumption
of the designated beverage as well as daily total calorie con-
sumption using food diaries [60••]. Although the sucrose-
containing beverages cause greater spikes in serum glucose The Association Between Artificial Sweeteners
and insulin within the first hour of consumption, there were no and Obesity
differences in the total area under the curve for either glucose
of insulin during the subsequent 3 h when compared to the There is an overwhelming amount of data suggesting that AS
artificial sweetener groups. alter normal physiologic processes that are involved in metab-
olism and nutrient absorption and thus influence changes in
body adiposity.
The Effects of Artificial Sweeteners on Energy
Consumption
Effects on Obesity: Rodent Studies
Despite the overall goal of decreased caloric intake, AS may
paradoxically increase caloric consumption. With the addition Feijo et al. showed that consumption of saccharin or aspar-
of AS to otherwise unsweetened foods or liquids, the im- tame was both associated with increased weight gain and ad-
proved palatability promotes increased feeding in both animal iposity and unrelated to caloric intake [65]. Mitsutomi et al.
models and humans [15, 26]. found that after 4 weeks, sucrose supplementation led to in-
creased hyperglycemia, greater weight gain, and increased
Changes in Energy Consumption: Rodent Studies adiposity; however, the mice in the artificial sweetener group
also showed increases in adiposity [66••].
Studies in rodents show that when fed artificial sweetener
supplements, they consume more calories and gain more
weight compared to their counterparts who were provided Effects on Obesity: Human Studies
supplements with real sugar [61]. Another study with sim-
ilar findings demonstrated that rodents fed foods or bev- Numerous large-scale prospective cohort studies have shown
erages containing either saccharin or acesulfame K had a positive association between artificial sweetener use and
increased food intake, greater weight gain, and increased increased BMI in a dose-dependent fashion [10, 12, 67].
adiposity compared to rodents who were fed glucose- Azad et al. demonstrated that maternal consumption of artifi-
containing diets [62]. cially sweetened beverages during pregnancy was associated
with a greater infant body mass index (BMI). The study re-
Changes in Energy Consumption: Human Studies cruited 3033 healthy mothers between 2009 and 2012 and
assessed artificial sweetener and sugar-sweetened beverage
Human studies demonstrate a less clear association, however. consumption based on dietary assessments during pregnancy.
One study found that humans given diet beverages compared The study showed that daily consumption of artificially sweet-
to water had similar caloric intake but reduced consumption of ened beverages was associated with a twofold higher risk of
desserts [63]. In 30 healthy males. Tey et al. found that despite being overweight at 1 year of age [68••]. A recent meta-
saving calories with a diet beverage compared to a sucrose- analysis including 11 studies showed a pooled relative risk
containing beverage, those that consumed an artificial sweet- (RR) of obesity of 1.18 (95% CI, 1.10–1.27) in patients that
ener beverage (aspartame, monk fruit, or stevia) prior to an ad consumed sugar-containing soda compared to a RR of 1.59
libitum lunch had similar daily caloric intake because of over- (95% CI, 1.22–2.08) of obesity in those that consumed artifi-
compensation during subsequent meals [60••]. This phenom- cially sweetened soda [69•]. In a cohort study of 1454 partic-
enon of overcompensation was again demonstrated in eight ipants from 1984 to 2012 with a median follow-up of 10 years,
obese patients in a metabolic ward setting. When patients were participants who consumed AS based on dietary recall had a
aware they were consuming aspartame-containing products, significantly increased BMI and increased waist circumfer-
their caloric intake was maintained or slightly increased ence compared to non-users [70••].
64 Page 6 of 8 Curr Gastroenterol Rep (2017) 19: 64

Conclusions 7. Ganchrow JR, Steiner JE, Canetto S. Behavioral displays to gusta-

tory stimuli in newborn rat pups. Dev Psychobiol. 1986;19(3):163–
74. https://doi.org/10.1002/dev.420190303.
Although AS were created as a sugar substitute to help with 8. Sharma A, Amarnath S, Thulasimani M, Ramaswamy S. Artificial
weight loss and insulin resistance, there is a significant sweeteners as a sugar substitute: are they really safe? Indian J
amount of data suggesting that AS have a profound impact Pharmacol. 2016;48(3):237–40. https://doi.org/10.4103/0253-
7613.182888.
of the host microbiome, gut-brain axis, glucose homeostasis,
9. Sylvetsky AC, Welsh JA, Brown RJ, Vos MB. Low-calorie sweet-
energy consumption, and overall weight gain and body adi- ener consumption is increasing in the United States. Am J Clin
posity. Although AS are marketed as a healthier option to Nutr. 2012;96(3):640–6. https://doi.org/10.3945/ajcn.112.034751.
sugar, the vast majority of data does not support this claim. 10. Colditz GA, Willett WC, Stampfer MJ, London SJ, Segal MR,
Speizer FE. Patterns of weight change and their relation to diet in
One of the main limitations making the outcomes difficult to
a cohort of healthy women. Am J Clin Nutr. 1990;51(6):1100–5.
interpret in human studies is that consumption of AS is com- 11. de Koning L, Malik VS, Rimm EB, Willett WC, Hu FB. Sugar-
monly based on dietary recall. Because many products like sweetened and artificially sweetened beverage consumption and
mouthwash, toothpaste, sauces, and frozen dinners contain risk of type 2 diabetes in men. Am J Clin Nutr. 2011;93(6):1321–
7. https://doi.org/10.3945/ajcn.110.007922.
AS, consumers may not be aware of their consumption.
12. Fowler SP, Williams K, Resendez RG, Hunt KJ, Hazuda HP, Stern
Future research should include the newer plant-based MP. Fueling the obesity epidemic? Artificially sweetened beverage
sweeteners with a focus on changes in the microbiome, as that use and long-term weight gain. Obesity (Silver Spring). 2008;16(8):
seems to be one of the main driving forces behind nutrient 1894–900. https://doi.org/10.1038/oby.2008.284.
absorption and glucose metabolism. 13. Mattes RD, Popkin BM. Nonnutritive sweetener consumption in
humans: effects on appetite and food intake and their putative
mechanisms. Am J Clin Nutr. 2009;89(1):1–14. https://doi.org/10.
Compliance with Ethical Standards 3945/ajcn.2008.26792.
14. Shearer J, Swithers SE. Artificial sweeteners and metabolic dysreg-
Conflict of Interest The authors declare that they have no conflict of ulation: lessons learned from agriculture and the laboratory. Rev
interest. Endocr Metab Disord. 2016;17(2):179–86. https://doi.org/10.
1007/s11154-016-9372-1.
Human and Animal Rights and Informed Consent This article does 15. Sterk A, Schlegel P, Mul AJ, Ubbink-Blanksma M, Bruininx EM.
not contain any studies with human or animal subjects performed by any Effects of sweeteners on individual feed intake characteristics and
of the authors. performance in group-housed weanling pigs. J Anim Sci.
2008;86(11):2990–7. https://doi.org/10.2527/jas.2007-0591.
16. Ponce CH, Brown MS, Silva JS, Schlegel P, Rounds W, Hallford
DM. Effects of a dietary sweetener on growth performance and
References health of stressed beef calves and on diet digestibility and plasma
and urinary metabolite concentrations of healthy calves. J Anim
Sci. 2014;92(4):1630–8. https://doi.org/10.2527/jas.2013-6795.
Papers of particular interest, published recently, have been 17. Bernstein AM, de Koning L, Flint AJ, Rexrode KM, Willett WC.
highlighted as: Soda consumption and the risk of stroke in men and women. Am J
• Of importance Clin Nutr. 2012;95(5):1190–9. https://doi.org/10.3945/ajcn.111.
030205.
•• Of major importance
18. Duffey KJ, Steffen LM, Van Horn L, Jacobs DR Jr, Popkin BM.
Dietary patterns matter: diet beverages and cardiometabolic risks in
1. Sturm R, Hattori A. Morbid obesity rates continue to rise rapidly in the longitudinal Coronary Artery Risk Development in Young
the United States. Int J Obes. 2013;37(6):889–91. https://doi.org/ Adults (CARDIA) Study. Am J Clin Nutr. 2012;95(4):909–15.
10.1038/ijo.2012.159. https://doi.org/10.3945/ajcn.111.026682.
2. Segata N. Gut microbiome: westernization and the disappearance of 19. Gardener H, Rundek T, Markert M, Wright CB, Elkind MS, Sacco
intestinal diversity. Curr Biol. 2015;25(14):R611–3. https://doi.org/ RL. Diet soft drink consumption is associated with an increased risk
10.1016/j.cub.2015.05.040. of vascular events in the Northern Manhattan Study. J Gen Intern
3. Mbakwa CA, Scheres L, Penders J, Mommers M, Thijs C, Med. 2012;27(9):1120–6. https://doi.org/10.1007/s11606-011-
Arts IC. Early life antibiotic exposure and weight develop- 1968-2.
ment in children. J Pediatr. 2016;176:105–13.e2. https://doi. 20.• O'Connor L, Imamura F, Lentjes MA, Khaw KT, Wareham NJ,
org/10.1016/j.jpeds.2016.06.015. Forouhi NG. Prospective associations and population impact of
4. De Filippo C, Cavalieri D, Di Paola M, Ramazzotti M, Poullet JB, sweet beverage intake and type 2 diabetes, and effects of substitu-
Massart S, et al. Impact of diet in shaping gut microbiota revealed tions with alternative beverages. Diabetologia. 2015;58(7):1474–
by a comparative study in children from Europe and rural Africa. 83. https://doi.org/10.1007/s00125-015-3572-1. This study
Proc Natl Acad Sci U S A. 2010;107(33):14691–6. https://doi.org/ compared sugar-sweetened beverages versus artificial sweet-
10.1073/pnas.1005963107. eners on incident type 2 diabetes in 25639 adults over a 10.8-
5. Panduro A, Rivera-Iniguez I, Sepulveda-Villegas M, Roman S. year follow-up period. Using artificial sweeteners as a sugar
Genes, emotions and gut microbiota: the next frontier for the gas- substitute did not reduce the incidence of diabetes.
troenterologist. World J Gastroenterol. 2017;23(17):3030–42. 21.•• Sakurai M, Nakamura K, Miura K, Takamura T, Yoshita K,
https://doi.org/10.3748/wjg.v23.i17.3030. Nagasawa SY, et al. Sugar-sweetened beverage and diet soda con-
6. Nowlis GH, Kessen W. Human newborns differentiate differing sumption and the 7-year risk for type 2 diabetes mellitus in middle-
concentrations of sucrose and glucose. Science. 1976;191(4229): aged Japanese men. Eur J Nutr. 2014;53(1):251–8. https://doi.org/
865–6. 10.1007/s00394-013-0523-9. This study evaluated the
Curr Gastroenterol Rep (2017) 19: 64 Page 7 of 8 64

association between sugar-sweetened beverages and diet soda rat. PloS One. 2014;9(10):e109841. https://doi.org/10.1371/
on incident type 2 diabetes in a cohort of 2037 Japanese men journal.pone.0109841. This study demonstrated that rats fed
over a 7-year period and showed that diet soda consumption aspartame consumed less calories and gained less weight
was associated with increased risk for diabetes. compared to rats fed a high fat diet, but had higher fasting
22. Fung TT, Malik V, Rexrode KM, Manson JE, Willett WC, Hu FB. glucose levels, increased insulin intolerance, and an increased
Sweetened beverage consumption and risk of coronary heart dis- firmicutes/bacteroidetes ratio on fecal analysis.
ease in women. Am J Clin Nutr. 2009;89(4):1037–42. https://doi. 39.•• Suez J, Korem T, Zeevi D, Zilberman-Schapira G, Thaiss CA,
org/10.3945/ajcn.2008.27140. Maza O, et al. Artificial sweeteners induce glucose intolerance by
23. Lin J, Curhan GC. Associations of sugar and artificially sweetened altering the gut microbiota. Nature. 2014;514(7521):181–6. https://
soda with albuminuria and kidney function decline in women. Clin doi.org/10.1038/nature13793. This study examined the effects of
J Am Soc Nephrol. 2011;6(1):160–6. https://doi.org/10.2215/CJN. artificial sweeteners on blood glucose control in seven healthy
03260410. volunteers who did not previously consume significant amounts
24. Yang Q. Gain weight by “going diet?” Artificial sweeteners and the of artificial sweeteners. Four of seven subjects exhibited worse
neurobiology of sugar cravings: neuroscience 2010. Yale J Biol glucose tolerance at 5 to 7 days of exposure when compared to
Med. 2010;83(2):101–8. the first 4 days.
25. Shankar P, Ahuja S, Sriram K. Non-nutritive sweeteners: review 40. Karlsson FH, Tremaroli V, Nookaew I, Bergstrom G, Behre CJ,
and update. Nutrition. 2013;29(11–12):1293–9. https://doi.org/10. Fagerberg B, et al. Gut metagenome in European women with
1016/j.nut.2013.03.024. normal, impaired and diabetic glucose control. Nature.
26. Benton D. Can artificial sweeteners help control body weight and 2013;498(7452):99–103. https://doi.org/10.1038/nature12198.
prevent obesity? Nutr Res Rev. 2005;18(1):63–76. https://doi.org/ 41. Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, et al. A metagenome-wide
10.1079/NRR200494. association study of gut microbiota in type 2 diabetes. Nature.
27. Mazur RH, Goldkamp AH, James PA, Schlatter JM. Structure-taste 2012;490(7418):55–60. https://doi.org/10.1038/nature11450.
relationships of aspartic acid amides. J Med Chem. 1970;13(6): 42. Avena NM, Rada P, Hoebel BG. Evidence for sugar addiction:
1217–21. behavioral and neurochemical effects of intermittent, excessive sug-
28. Clauss K, Luck E, von Rymon Lipinski GW. Acetosulfam, a new ar intake. Neurosci Biobehav Rev. 2008;32(1):20–39. https://doi.
sweetener. 1. Synthesis and properties (author's transl). Z Lebensm org/10.1016/j.neubiorev.2007.04.019.
Unters Forsch. 1976;162(1):37–40. 43. Sclafani A. Sweet taste signaling in the gut. Proc Natl Acad Sci U S
29. Suez J, Korem T, Zilberman-Schapira G, Segal E, Elinav E. Non- A. 2007;104(38):14887–8. https://doi.org/10.1073/pnas.
caloric artificial sweeteners and the microbiome: findings and chal- 0707410104.
lenges. Gut Microbes. 2015;6(2):149–55. https://doi.org/10.1080/ 44.• Bryant C, McLaughlin J. Low calorie sweeteners: evidence remains
19490976.2015.1017700. lacking for effects on human gut function. Physiol Behav.
30. Schloss PD, Gevers D, Westcott SL. Reducing the effects of PCR 2016;164(Pt B):482–5. https://doi.org/10.1016/j.physbeh.2016.04.
amplification and sequencing artifacts on 16S rRNA-based studies. 026. This study discusses the effects of artificial sweeteners and
PLoS One. 2011;6(12):e27310. https://doi.org/10.1371/journal. natural sugars on the gut-brain axis in both animal and human
pone.0027310. models.
31. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, 45. Smeets PA, de Graaf C, Stafleu A, van Osch MJ, van der Grond J.
Gordon JI. An obesity-associated gut microbiome with increased Functional magnetic resonance imaging of human hypothalamic
capacity for energy harvest. Nature. 2006;444(7122):1027–31. responses to sweet taste and calories. Am J Clin Nutr. 2005;82(5):
https://doi.org/10.1038/nature05414. 1011–6.
32. Xu J, Bjursell MK, Himrod J, Deng S, Carmichael LK, Chiang HC, 46. Stice E, Spoor S, Bohon C, Veldhuizen MG, Small DM. Relation of
et al. A genomic view of the human-Bacteroides thetaiotaomicron reward from food intake and anticipated food intake to obesity: a
symbiosis. Science. 2003;299(5615):2074–6. https://doi.org/10. functional magnetic resonance imaging study. J Abnorm Psychol.
1126/science.1080029. 2008;117(4):924–35. https://doi.org/10.1037/a0013600.
33. Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, et al. 47. Swithers SE. Not so sweet revenge: unanticipated consequences of
The gut microbiota as an environmental factor that regulates fat high-intensity sweeteners. Behav Anal. 2015;38(1):1–17. https://
storage. Proc Natl Acad Sci U S A. 2004;101(44):15718–23. doi.org/10.1007/s40614-015-0028-3.
https://doi.org/10.1073/pnas.0407076101. 48. Teff KL. How neural mediation of anticipatory and compensatory
34. Backhed F, Ley RE, Sonnenburg JL, Peterson DA, Gordon JI. insulin release helps us tolerate food. Physiol Behav. 2011;103(1):
Host-bacterial mutualism in the human intestine. Science. 44–50. https://doi.org/10.1016/j.physbeh.2011.01.012.
2005;307(5717):1915–20. https://doi.org/10.1126/science. 49. Blundell JE, Gibbons C, Caudwell P, Finlayson G, Hopkins M.
1104816. Appetite control and energy balance: impact of exercise. Obes
35. Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Rev. 2015;16(Suppl 1):67–76. https://doi.org/10.1111/obr.12257.
et al. A human gut microbial gene catalogue established by 50. Suzuki K, Jayasena CN, Bloom SR. Obesity and appetite control.
metagenomic sequencing. Nature. 2010;464(7285):59–65. https:// Exp Diabetes Res. 2012;2012:824305. https://doi.org/10.1155/
doi.org/10.1038/nature08821. 2012/824305.
36. Kleerebezem M, Vaughan EE. Probiotic and gut lactobacilli and 51. Swithers SE, Laboy AF, Clark K, Cooper S, Davidson TL.
bifidobacteria: molecular approaches to study diversity and activity. Experience with the high-intensity sweetener saccharin impairs
Annu Rev Microbiol. 2009;63:269–90. https://doi.org/10.1146/ glucose homeostasis and GLP-1 release in rats. Behav Brain Res.
annurev.micro.091208.073341. 2012;233(1):1–14. https://doi.org/10.1016/j.bbr.2012.04.024.
37. Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD, 52. Black RM, Leiter LA, Anderson GH. Consuming aspartame with
Gordon JI. Obesity alters gut microbial ecology. Proc Natl Acad and without taste: differential effects on appetite and food intake of
Sci U S A. 2005;102(31):11070–5. https://doi.org/10.1073/pnas. young adult males. Physiol Behav. 1993;53(3):459–66.
0504978102. 53. Rogers PJ, Carlyle JA, Hill AJ, Blundell JE. Uncoupling sweet taste
38.•• Palmnas MS, Cowan TE, Bomhof MR, Su J, Reimer RA, Vogel HJ, and calories: comparison of the effects of glucose and three intense
et al. Low-dose aspartame consumption differentially affects gut sweeteners on hunger and food intake. Physiol Behav. 1988;43(5):
microbiota-host metabolic interactions in the diet-induced obese 547–52.
64 Page 8 of 8 Curr Gastroenterol Rep (2017) 19: 64

54. Wu T, Zhao BR, Bound MJ, Checklin HL, Bellon M, Little TJ, et al. 63. Piernas C, Tate DF, Wang X, Popkin BM. Does diet-beverage in-
Effects of different sweet preloads on incretin hormone secretion, take affect dietary consumption patterns? Results from the Choose
gastric emptying, and postprandial glycemia in healthy humans. Healthy Options Consciously Everyday (CHOICE) randomized
Am J Clin Nutr. 2012;95(1):78–83. https://doi.org/10.3945/ajcn. clinical trial. Am J Clin Nutr. 2013;97(3):604–11. https://doi.org/
111.021543. 10.3945/ajcn.112.048405.
55.• De Vadder F, Kovatcheva-Datchary P, Goncalves D, Vinera J, 64. Porikos KP, Booth G, Van Itallie TB. Effect of covert nutritive
Zitoun C, Duchampt A, et al. Microbiota-generated metabolites dilution on the spontaneous food intake of obese individuals: a pilot
promote metabolic benefits via gut-brain neural circuits. Cell. study. Am J Clin Nutr. 1977;30(10):1638–44.
2014;156(1–2):84–96. https://doi.org/10.1016/j.cell.2013.12.016. 65. Feijo Fde M, Ballard CR, Foletto KC, Batista BA, Neves AM,
This paper describes the proposed mechanisms behind the Ribeiro MF, et al. Saccharin and aspartame, compared with sucrose,
role of short-chain fatty acids on glucose and energy induce greater weight gain in adult Wistar rats, at similar total ca-
homeostasis. loric intake levels. Appetite. 2013;60(1):203–7. https://doi.org/10.
56. Kaliannan K, Hamarneh SR, Economopoulos KP, Nasrin Alam S, 1016/j.appet.2012.10.009.
Moaven O, Patel P, et al. Intestinal alkaline phosphatase prevents 66.•• Mitsutomi K, Masaki T, Shimasaki T, Gotoh K, Chiba S, Kakuma
metabolic syndrome in mice. Proc Natl Acad Sci U S A. T, et al. Effects of a nonnutritive sweetener on body adiposity and
2013;110(17):7003–8. https://doi.org/10.1073/pnas.1220180110. energy metabolism in mice with diet-induced obesity. Metab Clin
57.• Gul SS, Hamilton AR, Munoz AR, Phupitakphol T, Liu W, Hyoju Exp. 2014;63(1):69–78. https://doi.org/10.1016/j.metabol.2013.09.
SK, et al. Inhibition of the gut enzyme intestinal alkaline phospha- 002. This study found that after 4 weeks, sucrose
tase may explain how aspartame promotes glucose intolerance and supplementation led to increased hyperglycemia, greater
obesity in mice. Appl Physiol Nutr Metab. 2017;42(1):77–83. weight gain, and increased adiposity; however, the mice in the
https://doi.org/10.1139/apnm-2016-0346. This study artificial sweetener group also showed increases in adiposity.
demonstrated that mice fed a high fat diet plus aspartame for 67. Stellman SD, Garfinkel L. Artificial sweetener use and one-year
18 weeks compared to a high fat diet plus water had lower levels weight change among women. Prev Med. 1986;15(2):195–202.
of intestinal alkaline phosphatase, gained more weight, had
68.•• Azad MB, Sharma AK, de Souza RJ, Dolinsky VW, Becker AB,
higher fasting glucose levels, and demonstrated greater
Mandhane PJ, et al. Association between artificially sweetened
glucose intolerance.
beverage consumption during pregnancy and infant body mass in-
58. Pepino MY, Tiemann CD, Patterson BW, Wice BM, Klein S.
dex. JAMA Pediatr. 2016;170(7):662–70. https://doi.org/10.1001/
Sucralose affects glycemic and hormonal responses to an oral glu-
jamapediatrics.2016.0301. This study showed that maternal
cose load. Diabetes Care. 2013;36(9):2530–5. https://doi.org/10.
consumption of artificially sweetened beverages during
2337/dc12-2221.
pregnancy was associated with a greater infant body mass
59. Anton SD, Martin CK, Han H, Coulon S, Cefalu WT, Geiselman P,
index and a twofold higher risk of being overweight at 1 year
et al. Effects of stevia, aspartame, and sucrose on food intake, sati-
of age.
ety, and postprandial glucose and insulin levels. Appetite.
2010;55(1):37–43. https://doi.org/10.1016/j.appet.2010.03.009. 69.• Ruanpeng D, Thongprayoon C, Cheungpasitporn W,
60.•• Tey SL, Salleh NB, Henry J, Forde CG. Effects of aspartame-, Harindhanavudhi T. Sugar and artificially-sweetened beverages
monk fruit-, stevia-, and sucrose-sweetened beverages on postpran- linked to obesity: a systematic review and meta-analysis. QJM.
dial glucose, insulin and energy intake. Int J Obes. 2016; https://doi. 2017; https://doi.org/10.1093/qjmed/hcx068. This meta-analysis
org/10.1038/ijo.2016.225. This study showed that despite saving showed a pooled relative risk of obesity of 1.18 in patients that
calories with a diet beverage compared to a sucrose-containing consumed sugar-containing soda compared to a RR of 1.59 of
beverage, those that consumed an artificial sweetener beverage obesity in those that consumed artificially sweetened soda.
had similar daily caloric intake because of overcompensation 70.•• Chia CW, Shardell M, Tanaka T, Liu DD, Gravenstein KS,
during subsequent meals. Simonsick EM, et al. Chronic low-calorie sweetener use and risk
61. Davidson TL, Martin AA, Clark K, Swithers SE. Intake of high- of abdominal obesity among older adults: a cohort study. PLoS
intensity sweeteners alters the ability of sweet taste to signal caloric One. 2016;11(11):e0167241. https://doi.org/10.1371/journal.pone.
consequences: implications for the learned control of energy and 0167241. In a cohort study of 1454 participants, those that
body weight regulation. Q J Exp Psychol (Hove). 2011;64(7): consumed artificial sweeteners had a significantly increased
1430–41. https://doi.org/10.1080/17470218.2011.552729. BMI and increased waist circumference compared to non-
62. Swithers SE, Martin AA, Davidson TL. High-intensity sweeteners users.
and energy balance. Physiol Behav. 2010;100(1):55–62. https://doi.
org/10.1016/j.physbeh.2009.12.021.