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Impact of Dietary Sugars on Gut Microbiota and Metabolic Health

Institute of Pharmacology & Experimental Therapeutics & Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal
Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, 3004-504 Coimbra, Portugal
Clinical Academic Center of Coimbra (CACC), 3004-504 Coimbra, Portugal
Pharmacy, Coimbra Health School, Polytechnic Institute of Coimbra, Rua 5 de Outubro-SM Bispo, Apartado 7006, 3046-854 Coimbra, Portugal
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Diabetology 2022, 3(4), 549-560;
Submission received: 17 September 2022 / Revised: 9 October 2022 / Accepted: 20 October 2022 / Published: 28 October 2022


Excessive sugar consumption is a risk factor for the development of several disorders, including metabolic, cardiovascular, neurological conditions and even some cancers, and has been linked to increased morbidity and mortality. The popularization of the typical Western diet, featured by an excessive intake of saturated fats and added sugars and a low consumption of unprocessed fruits, vegetables and fiber, may directly affect the composition and functionality of the gut microbiota, staggering the balance of the intestinal microbiome that ultimately culminates into gut dysbiosis. Although added sugars in the form of nutritive and non-nutritive sweeteners are generally considered as safe, a growing body of evidence correlate their consumption with adverse effects on gut microbial ecosystem; namely an abnormal synthesis of short-chain fatty acids, altered intestinal barrier integrity and chronic inflammation that often fuel a panoply of metabolic conditions. Accordingly, this work revisited the available preclinical evidence concerning the impact of different types of dietary sugars—nutritive and non-nutritive sweeteners—on gut microbiota and metabolic health. Future research should consider gender and species vulnerability when the impact of such substances on GM community and metabolic health is scrutinized in order to guide their adequate use at doses relevant to human use.

1. Introduction

Sugar consumption is increasing in a global scale with a negative impact on human health [1]. Sugars can be categorized as: (i) natural dietary sugars (e.g., glucose, fructose, sucrose), typically added as extrinsic sugars to foods and beverages during processing to sweeten and increase the flavor, being classified as nutritive sweeteners [2,3]; (ii) sugar alcohols (e.g., xylitol, sorbitol), also nutritive sweetener often used as alternatives to natural dietary sugars due to their low-caloric content [4]; and (iii) non-nutritive sweeteners (e.g., sucralose, saccharin) that, due to their noncaloric value, have gained popularity and are widely used in the scope of sugar reduction strategies [5,6].
The high consumption of dietary sugars is closely related with westernized diets, comprising highly processed foods and sugar-sweetened beverages that are strongly associated with an increased risk of poor health conditions [7,8,9]. For instance, sweetened foods display a key role for the development of dental caries, hyperactivity, obesity, diabetes, cardiovascular disease, hypertension, fatty liver disease, dyslipidemias and even some cancers [10,11,12,13]. Notably, a large number of abovementioned diseases display a gut dysbiotic scenario as well [14,15,16,17]. The overload of dietary sugar intake drives major changes in microbiota composition and function, namely a decreased bacterial diversity and altered metabolism that closely modulate epithelial integrity and gut inflammation [18,19,20,21]. Interestingly, gut dysbiotic scenarios driven by excessive sugar intake are strongly implicated in the development of dysmetabolic conditions, for instance metabolic syndrome, insulin resistance, dyslipidemia and type 2 diabetes and associated microvascular complications (e.g., nephropathy, retinopathy) [22,23,24,25,26]. Accordingly, this work aims to shed light to the impact of dietary sugars in GM composition and function and the ensuing effects in the metabolic health of the host.

2. Dietary Sugars—An Overview

Dietary sugars include distinct sources of sugars, which can be naturally occurring or added. The distinction between different types of sugars (i.e., total, free and naturally occurring) is crucial to best appreciate the association between sugar intake and health [27]. The World Health Organization (WHO) defines “free sugars” as all monosaccharides and disaccharides added to foods/beverages by the manufacturer, cook or consumption and sugars naturally present in honey, syrups, and fruit juices, including those concentrated [28,29]. The term “total sugars” refers to the combination of naturally occurring sugars and free sugars [29,30].
A healthy, well-balanced diet contains naturally occurring sugars present in fruits, vegetables, dairy products and many grains [31]. They can be in the form of simple molecules, monosaccharides (e.g., glucose, fructose, galactose) or disaccharides (e.g., sucrose, maltose, lactose), or more complex ones (e.g., polymers or polysaccharides) [32]. However, when these types of sugars are added as ingredients in processed foods to impart a sweet taste, they often correlate with excessive sugar intakes being associated with chronic disease conditions [33]. For example, fructose in the form of added sugar is particularly implicated in metabolic syndrome, hypertension, insulin resistance, lipogenesis, diabetes and associated retinopathy, kidney disease and inflammation [22,23,24]. Sucrose, glucose and fructose, when used in high amounts, have also a negative influence on oral hygiene and increase the risk of dental caries in children [34]. Therefore, WHO recommends in both adults and children a reduction in free sugars intake to less than 5–10% of total energy intake [29]. Furthermore, added sugars also comprise sweeteners-chemical compounds with an intrinsic sweet taste that determines their usage as sweetening agents [35,36]. Briefly, they can be classified due to their origin (natural or synthetic agents) or nutritional value (nutritive and non-nutritive) [37,38,39]. The structural formula of some nutritive and non-nutritive sweeteners is presented in Figure 1.
Nutritive sweeteners (NSs) enclose abovementioned carbohydrates (e.g., glucose sucrose, fructose) that provide approximately 4 kcal/g of energy and polyols (sugar alcohols), mostly hydrogenated carbohydrates that provide an average of 2 kcal/g of energy being often used as low-caloric sugar replacers [40]. Until now, several polyols have been approved to commercialization, such as xylitol (E967), maltitol (E953), sorbitol (E420), erythritol (E968), lactitol (E953) and mannitol (E421), to name just a few [41]. Such compounds elicit low glycemic and insulinemic responses due to the incomplete absorption from the small intestine into the blood stream. Moreover, they are also associated with lipogenesis inhibition [42]. However, since they are poorly absorbed in the colon, some laxative effects have been described and are not recommended for toddlers under 1 year of age [36,43].
Non-nutritive sweeteners (NNSs) or artificial sweeteners comprise substances with a great chemical diversity and a very intense sweet taste and offer little or no energy when ingested [32,44]. They are also known as high-intensity sweeteners since they are many times sweeter than sucrose. The most used NNSs are acesulfame potassium, aspartame, advantame, cyclamates, saccharin, sucralose, neohesperidin dihydrochalcone and neotame. Yet, some NNSs used in foods may also be isolated from natural sources, steviol glycosides, glycyrrhizin and thaumatin being some examples [40]. Notably, saccharin can have 300 times the potency of sucrose in terms of sweetening and has the acceptable daily intake (ADI) of 5 mg/kg of body weight. Aspartame and neotame display ADI values of 40 mg/kg and 18 mg/kg of body weight, respectively. However, due to their phenylalanine content, they are not advised for people with phenylketonuria [35,45]. Steviol glycosides are molecules extracted from the leaves of Stevia rebaudiana plant with an ADI limit of 4 mg/kg of body weight [46].
Even though NSs and NNSs are approved food additives that attempt to lower the overall daily caloric intake towards weight loss, concerns have emerged given their ability to modify the GM in such a way that there is the potential for an enhanced risk of glucose intolerance, insulin resistance, diabetes and increased weight [6,47,48].

3. Insights of Gut Microbiota Composition and Function

The term “microbiome”, firstly utilized by Joshua Lederberg, has been gaining increasing importance, especially since 2001 [49]. Microbiome refers to a group of microorganisms living in a symbiotic way in our body. In a normal condition, the majority of GM is constituted by four main families: Firmicutes (64%), Bacteroidetes (23%), Proteobacteria (8%) and Actinobacteria (3%). Several studies recognize the key role of these bacteria in the extraction process of nutrients and energy from food as well as in human metabolism [50,51]. Accordingly, many researchers have depicted the deleterious impact of GM dysbiosis in the development of several host diseases [52]. For instance, the change in the GM composition in patients who have type 2 diabetes (T2D) is characterized by high levels of Streptococcus mutans, Escherichia coli and Lactobacillus gasseri, as well as by decreased levels of butyrate-producing bacteria such as Clostridium Butyricum, Anaerostipes, Eubacterium halii, Roseburia and Faecalibacterium prauznitzii [53]. Low Firmicutes abundance was also found in similar studies [54,55].
In addition, some metagenome-wide association studies support the idea that unbalanced intestinal environment can lead to the development of several diseases, affecting the integrity of the intestinal barrier, the production of short-chain fatty acids (SCFAs) and the metabolism of bile acids, among others [53]. SCFAs are metabolites produced by the microbial decomposition of nondigestible food and display chief roles for intestinal health [56]. Acetate (C2), propionate (C3) and butyrate (C4) are the most abundant SCFAs (60:20:20 ratio in the human gastrointestinal tract) [57]. Several studies have shown that an abnormal synthesis of SCFAs impact the integrity of intestinal barrier [58,59]. These microbial metabolites signal by distinct G protein-coupled receptors (GPRs), namely the GPR109a, GPR43 (FFAR2), GPR41 (FFAR3) and Olfactory receptor 78 [60]. Such receptors are expressed in several types of cells such as adipose, immune, hepatic or skeletal muscle cells [61,62]. Among all SCFAs, it has been reported that GPR41 receptor is activated by propionate, GPR43 receptor by propionate, acetate and butyrate and GPR109A receptor by butyrate [63,64,65]. In addition, several studies have shown that the activation of these receptors by SCFAs leads to the secretion of PYY (peptide tyrosine-tyrosine) into the colon with subsequent effects on central nervous system, namely appetite reduction [66]. Furthermore, the activation of GPR41 receptor stimulates the expression of leptin by adipocytes, resulting in the inhibition of neuropeptide Y (NPY) while the activation of GPR43 receptor leads to several positive effects, such as the suppression of glucagon from pancreatic α-cell or the release of GLP-1 (glucagon-like peptide-1) by endocrine L-cells who act in β-cell via stimulation of insulin biosynthesis and enhancement of glucose-stimulated insulin secretion [50,67].
Acetate is the most abundant SCFA in the gastrointestinal tract and several positive effects have been reported [68]. Den Besten and colleagues have shown that increased levels of acetate could improve insulin sensitivity, glucose homeostasis and reduce body weight [57,69]. However, other studies have shown contradictory evidence. For instance, a study from Perry and colleagues disclosed that high levels of acetate lead to the activation of parasympathetic nervous system, promoting an increased glucose stimulated insulin secretion and a higher production and secretion of ghrelin, resulting in weight gain [70,71].
Butyrate also displays important metabolic roles such as the activation of intestinal gluconeogenesis or macrophage M2 polarization towards anti-inflammatory effects through peroxisome proliferator-activated receptor gamma (PPARγ) up-regulation [72,73]. Furthermore, several studies have shown that the activation of this receptor also improves insulin sensitivity [74]. In addition, butyrate is also able to suppress NF-kB (nuclear factor kappa B) activation, an important transcription factor involved in the regulation of some genes encoding pro-inflammatory cytokines, growth factors, adhesion molecules, and immune receptors among others [75]. Several studies suggest that butyrate confers oxidative stress protection, regulates cell proliferation and cell differentiation, intestinal gluconeogenesis activation and maintains gut barrier permeability [76].
Remarkably, propionate supplementation was found to stimulate the release of the hormones PYY and GLP-1 in healthy adults resulting in a reduced appetite, hepatic fat, adipose tissue and a higher sensitivity to insulin [77]. Other studies also found the effects of propionate in Treg cells differentiation and production of interleukin (IL)-10 [78,79].

4. Impact of Dietary Sugars on Gut Microbiota and Metabolic Health

Several studies highlight the role of carbohydrates and sweeteners on satiety control, lipid metabolism, protein glycosylation, SCFAs production and the modulation of GM itself [80]. The ability of carbohydrates to modify the GM mostly relies on the non-digestible or digestible nature of these substrates [81]. Digestible carbohydrates such as sucrose or lactose are absorbed in the small intestine following degradation into monosaccharides (e.g., glucose, fructose) through a panoply of gastrointestinal enzymes [82]. Fructose, sugar alcohols and some non-nutritive sweeteners (e.g., sucralose) are passively, slowly or very poorly absorbed in the small intestine and overflow to the large intestine [2]. Such dynamics induce significant alterations in GM, including a reduced microbial diversity and altered relative abundance of certain bacterial phylum that correlates with metabolic health status, as highlighted in the following sections.

4.1. Nutritive Sweeteners

4.1.1. Glucose, Fructose, Sucrose

Consistent evidence from studies with animal models demonstrate that dietary patterns enclosing a high intake of glucose, fructose or sucrose lead to gut dysbiosis and metabolic imbalances, as summarized in Table 1. For example, in male C57BL/6J mice, the administration of a high-glucose diet (HGD) for 12 weeks elicited hyperglycemia, glucose intolerance, dyslipidemia and increased fat mass deposition [83]. In addition, the loss of gut microbial diversity, characterized by a lower proportion of Bacteroidetes and an increased proportion of Proteobacteria, has been observed [83]. Moreover, the HGD-fed animals displayed an increased gut permeability due to alterations in tight junction proteins as well as intestinal inflammation [83]. In the same study, similar results were noticed with the administration of a high-fructose diet (HfrD). Other authors also found that the administration of fructose at a low dose (2.6 g/kg/day), moderate dose (5.3 g/kg/day) and a high dose (10.5 g/kg/day) for 20 weeks leads to an increase in the serum pro-inflammatory cytokines (IL-6 and TNF-α: tumor necrosis factor-alpha) and a decrease in anti-inflammatory cytokine IL-10 in male Sprague Dawley rats. Notably, the higher fructose intake was associated to an increase abundancy of Parasutterella and Blantia and decreased Intestinimonas [84]. Furthermore, Sun and colleagues showed that male Wistar rats fed with a high-sucrose diet for 4 weeks significantly increased the serum triglycerides and cholesterol levels. Such changes were coincident with a scenario of gut dysbiosis, featured by an altered Bacteroidetes/Firmicutes ratio with an increase in Bacteroidetes and Verrucomicriobia and decreased Firmicutes [85].

4.1.2. Polyols

The relationship between polyols (also known as sugar alcohols) and GM composition and function has been also highlighted in distinct animal models. Xiang and colleagues reported no significant effects on pancreas, liver, brain and colon organ weights although it was observed increased levels of the GM metabolites butyrate and propionate in the intestinal mucosa and lumen of male C57BL/6 mice exposed to 2% (2.17 g/kg/day) and 5% (5.42 g/kg/day) of xylitol for 3 months. At the higher dose, xylitol elicited an increased abundance of Bifidobacterium, Lactobacillus, and Erysipelotrichaceae and decreased contents of Blautia and Staphylococcus [86]. Nevertheless, rodent species exhibit different susceptibilities as demonstrated by Zuo and colleagues who reported a decreased abundance of Ruminococacaeae/Provotella and increased Bacteroides levels in male Sprague Dawley rats but only when xylitol was administered at a higher-dose (xylitol 9.90 g/kg/day) [87].
Similarly, several studies demonstrated a disturbed GM upon sorbitol consumption. Accordingly, male Wistar rats exposed to 10% sorbitol (2.07 g/day) for 16 days showed an increase in Lactobacillus abundance and butyrate levels in the cecum and colon. Such changes paralleled lower levels of seric triglycerides, total cholesterol, HDL-cholesterol and LDL-cholesterol concentrations [88]. The consumption of 2% of lactitol also elicited a decrease in fecal pH and an increase in IgA hypersecretion in male Wistar rats without major differences in body weight curves [89]. Table 1 summarizes the alterations of GM composition and function upon polyols consumption.
Table 1. Effects of nutritive sweeteners on gut microbiota and metabolic health.
Table 1. Effects of nutritive sweeteners on gut microbiota and metabolic health.
Intervention Animal ModelOutcomesRef.
Administration of high-glucose and high-fructose diet (65.0% of calories in carbohydrate: 85% from glucose or fructose and 15% from sucrose)
(12 weeks)
Male C57BL/6J mice↑ Glucose intolerance and fasting blood glucose concentration
↑ Total and LDL cholesterol
↑ Serum endotoxin levels
↑ Proteobacteria, in particular Desulfovibrio vulgaris
↓ Bacteroidetes (Muribaculum intestinale)
↑ Akkermansia muciniphila
↓ ZO-1 and occludin expression in the colon
↑ Inflammatory cytokines, TNF-α and IL-1β, in the colon
Administration of fructose at low dose (Fru-L), (2.6 g/kg/day), moderate dose (Fru-M), (5.3 g/kg/day), high dose (Fru-H), (10.5 g/kg/day)
(20 weeks)
Male Sprague Dawley ratsNo significant differences in body weight and fasting blood glucose
↑ Hepatic lipid accumulation and inflammatory cell infiltration in pancreas and colon
↑ Expression of lipid accumulation proteins (perilipin-1, ADRP, and Tip-47) in the colon
↑ Uric acid levels
↓ TJ proteins including ZO-1 and occludin
↑ Parasutterella and Blantia
↓ Intestinimonas
Fru-L, Fru-M, Fru-H
↑ IL-6, TNF-α, and MIP-2
↓ IL-10
↓ isobutyric acid
High-sucrose diet (5.3 g sucrose/kg/day)
(4 weeks)
Male Wistar rats↑ Liver organ weight
↑ Serum triglycerides and cholesterol levels
↑ Hepatic lipids levels
↑ Bacteroidetes and Verrucomicriobia, Erysipelotrichaceae, Turicibacteraceae, Bacteroidaceae
↓ Firmicutes, Ruminococcaceae, Clostridiales, and Lactobacillacae
2% (2.17 g/kg/day), or 5% (5.42 g/kg/day) (w/w) xylitol
(3 months)
Male C57BL/6 wild-type miceNo significant changes in brain, pancreas, colon and liver organ weights
↑ SCFA’s, especially butyrate in the mucosa and propionate in the lumen
5% xylitol
↑ Bifidobacterium, Lactobacillus, and Erysipelotrichaceae
↓ Blautia and Staphylococcus
ApproachAnimal ModelOutcomesRef.
Xylitol solution of
40 mg/kg and 200 mg/kg body weight/day
(16 weeks)
Male C57B1/6J miceBody composition, hepatic and serum lipid parameters, oral glucose tolerance were unaffected
↓ Bacteroidetes phylum and genus Barnesiella
1.0 g/100 kcal or 2.0 g/100 kcal of xylitol in the diet
(8 weeks)
obese male
Sprague Dawley rats
↓ Visceral fat mass, plasmatic insulin and lipid profile
↑ Fatty acid oxidation-related genes
GM assessment was not evaluated
10% sorbitol (2.07 g/day) in water
(16 days)
Male Wistar rats Colonic and cecal wall weights
↓ Serum lipid levels, triglycerides, total cholesterol, HDL-cholesterol and LDL-cholesterol
↑ Butyrate level in the cecum and colon
Lactobacillus in feces, colon, cecum
2% (w/w) lactilol or 2% (w/w) polydextrose and lactilol
(3 weeks)
Male Wistar ratsNo differences in body weight
No changes in the crypt:villus ratio
↑ IgA (lack of mucosal inflammation)
↑ Production of butyrate
↓ pH

4.2. Non-Nutritive Sweeteners

Likewise, a dysbiotic scenario has been reported upon the oral consumption of distinct non-nutritive sweeteners. Diet-induced obese male C57B1/6 mice presented impaired glucose tolerance and a reduction in Lactobacillus reuteri and an increase in fecal Bacteroides genus and Clostridiales order when 0.1 mg/mL of saccharin was administered for 10 weeks [92]. Similarly, the administration of 0.3 mg/mL saccharin for 6 months in male C57BL/6J mice triggered the hepatic overexpression of TNF-α and iNOS (Inducible nitric oxide synthase) along with an increase abundance of Turicibacter Corynebacterium and Roseburia and decreased contents of Ruminococcus and Anaerostipes [93]. In another study, an increase in Lactobacillus genus along with intraluminal lactic acid concentrations were observed in landrace X large white piglets fed with a diet supplemented with SUCRAM® 0.015% (w/w) saccaharin and neohesperidin dihydrochalcone for 2 weeks [94]. According to Abou-Donia and colleagues, the administration of 1.1, 3.3, 5.5 or 11 mg/kg/day of sucralose to Sprague Dawley rats for 12 weeks resulted in an increased body weight and a fewer number of Bacteroides, Bifidobacterium, Clostridium and Lactobacilli [95]. Yet, there are conflicting reports. For instance, the chronic administration of Acesulfame K solution (15 mg/kg/day) in male C57BL/6J mice did not elicit any significant change in GM composition. [96]. Nonetheless, Bian and colleagues have shown an increase in Bacteroides in male CD-1 mice fed with 37.5 mg/kg/day of Acesulfame-K along with an expressive body weight gain. Interestingly, these results were less pronounced in the female mice group, suggesting that gender differences must be taken into account [97]. In addition, aspartame and steviol glucosides are non-nutritive sweeteners that significantly disturb GM composition and function in obese and lactating rodents as well [98,99]. Table 2 outlines recent evidence focused on the impact of non-nutritive sweeteners on GM and metabolic health.

5. Conclusions

Reduction in the dietary intake of sugars has been strongly advised for some years now to cope with the prevention of non-communicable diseases such as diabetes, cardiovascular disease and/or obesity, among others. Accordingly, the use of alternative sweeteners, particularly those with a low-caloric content, has gained popularity. However, available preclinical evidence raises awareness on the dietary use of such substances in human health since they can also display putatively unfavorable effects on GM and metabolic health, as reviewed in this work. For instance, the decrease in SCFAs biosynthesis and intestinal barrier damage due to sweeteners-induced GM dysbiosis are well-described features of cardiovascular diseases, T2D and pancreatic damage, to name just a few [102,103,104].
Given the multifaceted roles of GM community in human health, future studies are warranted to provide adequate evidence regarding the impact of nutritive and non-nutritive sweeteners on metabolic status, with a major focus on gender and species vulnerability. Moreover, it would be of interest to further disclose key disease-altering properties of sweeteners and their candidate roles in nutrition therapy programs [105,106]. Such information will be paramount to guide their adequate use at doses relevant to human use.

Author Contributions

Conceptualization, S.V.; writing—original draft preparation, G.F. and K.G.; writing—review and editing, S.V., F.R. and K.G.; visualization, S.V. and F.R.; supervision, S.V. and F.R.; project administration, S.V. and F.R.; funding acquisition, S.V. and F.R. All authors have read and agreed to the published version of the manuscript.


This research was funded by National and European Funds, via Portuguese Science and Technology Foundation (FCT), European Regional Development Fund (FEDER), and Programa Operacional Factores de Competitividade (COMPETE): UIDP/04539/2020 (CIBB), PTDC/SAU-NUT/31712/2017, and POCI-01-0145-FEDER-031712.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available on request from the corresponding author.

Conflicts of Interest

The authors declare no conflict of interest.


  1. Stanhope, K.L. Sugar consumption, metabolic disease and obesity: The state of the controversy. Crit. Rev. Clin. Lab. Sci. 2016, 53, 52–67. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Di Rienzi, S.C.; Britton, R.A. Adaptation of the Gut Microbiota to Modern Dietary Sugars and Sweeteners. Adv. Nutr. 2020, 11, 616–629. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Heidari-Beni, M.; Kelishadi, R. The Role of Dietary Sugars and Sweeteners in Metabolic Disorders and Diabetes. In Sweeteners: Pharmacology, Biotechnology, and Applications; Mérillon, J.-M., Ramawat, K.G., Eds.; Springer International Publishing: Cham, Switzerland, 2018; pp. 225–243. [Google Scholar]
  4. Hattori, K.; Akiyama, M.; Seki, N.; Yakabe, K.; Hase, K.; Kim, Y.G. Gut Microbiota Prevents Sugar Alcohol-Induced Diarrhea. Nutrients 2021, 13, 2029. [Google Scholar] [CrossRef]
  5. Shankar, P.; Ahuja, S.; Sriram, K. Non-nutritive sweeteners: Review and update. Nutrition 2013, 29, 1293–1299. [Google Scholar] [CrossRef] [PubMed]
  6. Liauchonak, I.; Qorri, B.; Dawoud, F.; Riat, Y.; Szewczuk, M.R. Non-Nutritive Sweeteners and Their Implications on the Development of Metabolic Syndrome. Nutrients 2019, 11, 644. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Rodriguez-Ramirez, S.; Martinez-Tapia, B.; Gonzalez-Castell, D.; Cuevas-Nasu, L.; Shamah-Levy, T. Westernized and Diverse Dietary Patterns Are Associated with Overweight-Obesity and Abdominal Obesity in Mexican Adult Men. Front. Nutr. 2022, 9, 891609. [Google Scholar] [CrossRef] [PubMed]
  8. Shi, Z. Gut Microbiota: An Important Link between Western Diet and Chronic Diseases. Nutrients 2019, 11, 2287. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  9. Garcia-Gutierrez, E.; Sayavedra, L. 3.07—Diet, Microbiota and the Gut-Brain Axis. In Comprehensive Gut Microbiota; Glibetic, M., Ed.; Elsevier: Oxford, UK, 2022; pp. 69–83. [Google Scholar]
  10. Monteiro-Alfredo, T.; Caramelo, B.; Arbelaez, D.; Amaro, A.; Barra, C.; Silva, D.; Oliveira, S.; Seica, R.; Matafome, P. Distinct Impact of Natural Sugars from Fruit Juices and Added Sugars on Caloric Intake, Body Weight, Glycaemia, Oxidative Stress and Glycation in Diabetic Rats. Nutrients 2021, 13, 2956. [Google Scholar] [CrossRef] [PubMed]
  11. Paglia, L. The sweet danger of added sugars. Eur. J. Paediatr. Dent. 2019, 20, 89. [Google Scholar] [CrossRef]
  12. Schiano, C.; Grimaldi, V.; Scognamiglio, M.; Costa, D.; Soricelli, A.; Nicoletti, G.F.; Napoli, C. Soft drinks and sweeteners intake: Possible contribution to the development of metabolic syndrome and cardiovascular diseases. Beneficial or detrimental action of alternative sweeteners? Food Res. Int. 2021, 142, 110220. [Google Scholar] [CrossRef]
  13. Te Morenga, L.; Mallard, S.; Mann, J. Dietary sugars and body weight: Systematic review and meta-analyses of randomised controlled trials and cohort studies. BMJ 2012, 346, e7492. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Fan, X.; Jin, Y.; Chen, G.; Ma, X.; Zhang, L. Gut Microbiota Dysbiosis Drives the Development of Colorectal Cancer. Digestion 2021, 102, 508–515. [Google Scholar] [CrossRef] [PubMed]
  15. Nikolova, V.L.; Hall, M.R.B.; Hall, L.J.; Cleare, A.J.; Stone, J.M.; Young, A.H. Perturbations in Gut Microbiota Composition in Psychiatric Disorders: A Review and Meta-analysis. JAMA Psychiatry 2021, 78, 1343–1354. [Google Scholar] [CrossRef] [PubMed]
  16. Zhong, W.; Zhou, Z. Alterations of the gut microbiome and metabolome in alcoholic liver disease. World J. Gastrointest. Pathophysiol. 2014, 5, 514–522. [Google Scholar] [CrossRef] [PubMed]
  17. Yang, T.; Santisteban, M.M.; Rodriguez, V.; Li, E.; Ahmari, N.; Carvajal, J.M.; Zadeh, M.; Gong, M.; Qi, Y.; Zubcevic, J.; et al. Gut dysbiosis is linked to hypertension. Hypertension 2015, 65, 1331–1340. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Del Pozo, S.; Gomez-Martinez, S.; Diaz, L.E.; Nova, E.; Urrialde, R.; Marcos, A. Potential Effects of Sucralose and Saccharin on Gut Microbiota: A Review. Nutrients 2022, 14, 1682. [Google Scholar] [CrossRef]
  19. Rinninella, E.; Cintoni, M.; Raoul, P.; Lopetuso, L.R.; Scaldaferri, F.; Pulcini, G.; Miggiano, G.A.D.; Gasbarrini, A.; Mele, M.C. Food Components and Dietary Habits: Keys for a Healthy Gut Microbiota Composition. Nutrients 2019, 11, 2393. [Google Scholar] [CrossRef] [Green Version]
  20. Satokari, R. High Intake of Sugar and the Balance between Pro- and Anti-Inflammatory Gut Bacteria. Nutrients 2020, 12, 1348. [Google Scholar] [CrossRef]
  21. Adithya, K.K.; Rajeev, R.; Selvin, J.; Seghal Kiran, G. Dietary Influence on the Dynamics of the Human Gut Microbiome: Prospective Implications in Interventional Therapies. ACS Food Sci. Technol. 2021, 1, 717–736. [Google Scholar] [CrossRef]
  22. Freeman, C.R.; Zehra, A.; Ramirez, V.; Wiers, C.E.; Volkow, N.D.; Wang, G.J. Impact of sugar on the body, brain, and behavior. Front. Biosci. 2018, 23, 2255–2266. [Google Scholar] [CrossRef]
  23. Shi, Y.N.; Liu, Y.J.; Xie, Z.; Zhang, W.J. Fructose and metabolic diseases: Too much to be good. Chin. Med. J. 2021, 134, 1276–1285. [Google Scholar] [CrossRef] [PubMed]
  24. Softic, S.; Stanhope, K.L.; Boucher, J.; Divanovic, S.; Lanaspa, M.A.; Johnson, R.J.; Kahn, C.R. Fructose and hepatic insulin resistance. Crit. Rev. Clin. Lab. Sci. 2020, 57, 308–322. [Google Scholar] [CrossRef] [PubMed]
  25. Fernandes, R.; Viana, S.D.; Nunes, S.; Reis, F. Diabetic gut microbiota dysbiosis as an inflammaging and immunosenescence condition that fosters progression of retinopathy and nephropathy. Biochim. Biophys. Acta (BBA)—Mol. Basis Dis. 2019, 1865, 1876–1897. [Google Scholar] [CrossRef] [PubMed]
  26. Viana, S.D.; Nunes, S.; Reis, F. ACE2 imbalance as a key player for the poor outcomes in COVID-19 patients with age-related comorbidities—Role of gut microbiota dysbiosis. Ageing Res. Rev. 2020, 62, 101123. [Google Scholar] [CrossRef] [PubMed]
  27. Bergeron, A.; Labonte, M.E.; Brassard, D.; Bedard, A.; Laramee, C.; Robitaille, J.; Desroches, S.; Provencher, V.; Couillard, C.; Vohl, M.C.; et al. Intakes of Total, Free, and Naturally Occurring Sugars in the French-Speaking Adult Population of the Province of Quebec, Canada: The PREDISE Study. Nutrients 2019, 11, 2317. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  28. van Loveren, C. Sugar Restriction for Caries Prevention: Amount and Frequency. Which Is More Important? Caries Res. 2019, 53, 168–175. [Google Scholar] [CrossRef]
  29. World Health Organization. WHO Guideline: Sugars Intake for Adults and Children; World Health Organization: Geneva, Switzerland, 2015. [Google Scholar]
  30. Fidler Mis, N.; Braegger, C.; Bronsky, J.; Campoy, C.; Domellof, M.; Embleton, N.D.; Hojsak, I.; Hulst, J.; Indrio, F.; Lapillonne, A.; et al. Sugar in Infants, Children and Adolescents: A Position Paper of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J. Pediatr. Gastroenterol. Nutr. 2017, 65, 681–696. [Google Scholar] [CrossRef] [Green Version]
  31. Johnson, R.K.; Appel, L.J.; Brands, M.; Howard, B.V.; Lefevre, M.; Lustig, R.H.; Sacks, F.; Steffen, L.M.; Wylie-Rosett, J.; American Heart Association Nutrition Committee of the Council on Nutrition, Physical Activity, and Metabolism and the Council on Epidemiology and Prevention. Dietary sugars intake and cardiovascular health: A scientific statement from the American Heart Association. Circulation 2009, 120, 1011–1020. [Google Scholar] [CrossRef] [Green Version]
  32. Plaza-Diaz, J.; Gil, A. Sucrose: Dietary Importance. In Encyclopedia of Food and Health; Caballero, B., Finglas, P.M., Toldrá, F., Eds.; Academic Press: Oxford, UK, 2016; pp. 199–204. [Google Scholar] [CrossRef]
  33. Amarra, M.S.; Khor, G.L.; Chan, P. Intake of added sugar in Malaysia: A review. Asia Pac. J. Clin. Nutr. 2016, 25, 227–240. [Google Scholar] [CrossRef]
  34. Piekara, A.; Krzywonos, M.; Szymańska, A. Sweetening Agents and Sweeteners in Dietary Supplements for Children-Analysis of the Polish Market. Nutrients 2020, 12, 2387. [Google Scholar] [CrossRef]
  35. Fitch, C.; Keim, K.S. Position of the Academy of Nutrition and Dietetics: Use of nutritive and nonnutritive sweeteners. Acad. Nutr. Diet. 2012, 112, 739–758. [Google Scholar] [CrossRef] [PubMed]
  36. Grembecka, M. Natural sweeteners in a human diet. Rocz. Panstw. Zakl. Hig. 2015, 66, 195–202. [Google Scholar] [PubMed]
  37. MC, Y.-B. Sweeteners. In Encyclopedia of Analytical Science, 2nd ed.; Worsfold, P., Townshend, A., Poole, C., Eds.; Elsevier: Oxford, UK, 2005; pp. 562–572. [Google Scholar]
  38. Blekas, G.A. Food Additives: Classification, Uses and Regulation. In Encyclopedia of Food and Health; Caballero, B., Finglas, P.M., Toldrá, F., Eds.; Academic Press: Oxford, UK, 2016; pp. 731–736. [Google Scholar] [CrossRef]
  39. Hess, J.; Latulippe, M.E.; Ayoob, K.; Slavin, J. The confusing world of dietary sugars: Definitions, intakes, food sources and international dietary recommendations. Food Funct. 2012, 3, 477–486. [Google Scholar] [CrossRef] [PubMed]
  40. Das, A.K.; Chakraborty, R. Sweeteners: Classification, Sensory and Health Effects. In Encyclopedia of Food and Health; Academic Press: Cambridge, MA, USA, 2016. [Google Scholar] [CrossRef]
  41. Lenhart, A.; Chey, W.D. A Systematic Review of the Effects of Polyols on Gastrointestinal Health and Irritable Bowel Syndrome. Adv. Nutr. 2017, 8, 587–596. [Google Scholar] [CrossRef]
  42. Msomi, N.Z.; Erukainure, O.L.; Islam, M.S. Suitability of sugar alcohols as antidiabetic supplements: A review. J. Food Drug Anal. 2021, 29, 1–14. [Google Scholar] [CrossRef]
  43. Plaza-Diaz, J.; Pastor-Villaescusa, B.; Rueda-Robles, A.; Abadia-Molina, F.; Ruiz-Ojeda, F.J. Plausible Biological Interactions of Low- and Non-Calorie Sweeteners with the Intestinal Microbiota: An Update of Recent Studies. Nutrients 2020, 12, 1153. [Google Scholar] [CrossRef]
  44. Carocho, M.; Morales, P.; Ferreira, I. Sweeteners as food additives in the XXI century: A review of what is known, and what is to come. Food Chem. Toxicol. 2017, 107, 302–317. [Google Scholar] [CrossRef]
  45. Ruiz-Ojeda, F.J.; Plaza-Diaz, J.; Saez-Lara, M.J.; Gil, A. Effects of Sweeteners on the Gut Microbiota: A Review of Experimental Studies and Clinical Trials. Adv. Nutr. 2019, 10, S31–S48. [Google Scholar] [CrossRef] [Green Version]
  46. Chaturvedula, V.S.; Upreti, M.; Prakash, I. Diterpene glycosides from Stevia rebaudiana. Molecules 2011, 16, 3552–3562. [Google Scholar] [CrossRef] [Green Version]
  47. Baker-Smith, C.M.; de Ferranti, S.D.; Cochran, W.J.; Abrams, S.A.; Fuchs, G.J.; Kim, J.H.; Lindsey, C.W.; Magge, S.N.; Rome, E.S.; Schwarzenberg, S.J.; et al. The Use of Nonnutritive Sweeteners in Children. Pediatrics 2019, 144, e20192765. [Google Scholar] [CrossRef] [Green Version]
  48. Walbolt, J.; Koh, Y. Non-nutritive Sweeteners and Their Associations with Obesity and Type 2 Diabetes. J. Obes. Metab. Syndr. 2020, 29, 114–123. [Google Scholar] [CrossRef] [PubMed]
  49. Liu, X. Microbiome. Yale J. Biol. Med. 2016, 89, 275–276. [Google Scholar]
  50. Cunningham, A.L.; Stephens, J.W.; Harris, D.A. Intestinal microbiota and their metabolic contribution to type 2 diabetes and obesity. J. Diabetes Metab. Disord. 2021, 20, 1855–1870. [Google Scholar] [CrossRef] [PubMed]
  51. Turnbaugh, P.J.; Ley, R.E.; Hamady, M.; Fraser-Liggett, C.M.; Knight, R.; Gordon, J.I. The human microbiome project. Nature 2007, 449, 804–810. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Bull, M.J.; Plummer, N.T. Part 1: The Human Gut Microbiome in Health and Disease. Integr. Med. 2014, 13, 17–22. [Google Scholar]
  53. Borse, S.P.; Chhipa, A.S.; Sharma, V.; Singh, D.P.; Nivsarkar, M. Management of Type 2 Diabetes: Current Strategies, Unfocussed Aspects, Challenges, and Alternatives. Med. Princ. Pract. 2021, 30, 109–121. [Google Scholar] [CrossRef] [PubMed]
  54. Doumatey, A.P.; Adeyemo, A.; Zhou, J.; Lei, L.; Adebamowo, S.N.; Adebamowo, C.; Rotimi, C.N. Gut Microbiome Profiles Are Associated With Type 2 Diabetes in Urban Africans. Front. Cell Infect. Microbiol. 2020, 10, 63. [Google Scholar] [CrossRef] [Green Version]
  55. Larsen, N.; Vogensen, F.K.; van den Berg, F.W.; Nielsen, D.S.; Andreasen, A.S.; Pedersen, B.K.; Al-Soud, W.A.; Sorensen, S.J.; Hansen, L.H.; Jakobsen, M. Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults. PLoS ONE 2010, 5, e9085. [Google Scholar] [CrossRef] [PubMed]
  56. Silva, Y.P.; Bernardi, A.; Frozza, R.L. The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication. Front. Endocrinol 2020, 11, 25. [Google Scholar] [CrossRef]
  57. den Besten, G.; van Eunen, K.; Groen, A.K.; Venema, K.; Reijngoud, D.J.; Bakker, B.M. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J. Lipid Res. 2013, 54, 2325–2340. [Google Scholar] [CrossRef] [Green Version]
  58. He, J.; Zhang, P.; Shen, L.; Niu, L.; Tan, Y.; Chen, L.; Zhao, Y.; Bai, L.; Hao, X.; Li, X.; et al. Short-Chain Fatty Acids and Their Association with Signalling Pathways in Inflammation, Glucose and Lipid Metabolism. Int. J. Mol. Sci. 2020, 21, 6356. [Google Scholar] [CrossRef] [PubMed]
  59. Peng, L.; Li, Z.R.; Green, R.S.; Holzman, I.R.; Lin, J. Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers. J. Nutr. 2009, 139, 1619–1625. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  60. Priyadarshini, M.; Kotlo, K.U.; Dudeja, P.K.; Layden, B.T. Role of Short Chain Fatty Acid Receptors in Intestinal Physiology and Pathophysiology. Compr. Physiol. 2018, 8, 1091–1115. [Google Scholar] [CrossRef] [PubMed]
  61. Correa-Oliveira, R.; Fachi, J.L.; Vieira, A.; Sato, F.T.; Vinolo, M.A. Regulation of immune cell function by short-chain fatty acids. Clin. Transl. Immunol. 2016, 5, e73. [Google Scholar] [CrossRef] [PubMed]
  62. Carretta, M.D.; Quiroga, J.; Lopez, R.; Hidalgo, M.A.; Burgos, R.A. Participation of Short-Chain Fatty Acids and Their Receptors in Gut Inflammation and Colon Cancer. Front. Physiol. 2021, 12, 662739. [Google Scholar] [CrossRef] [PubMed]
  63. Brown, A.J.; Goldsworthy, S.M.; Barnes, A.A.; Eilert, M.M.; Tcheang, L.; Daniels, D.; Muir, A.I.; Wigglesworth, M.J.; Kinghorn, I.; Fraser, N.J.; et al. The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J. Biol. Chem. 2003, 278, 11312–11319. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Park, J.; Wang, Q.; Wu, Q.; Mao-Draayer, Y.; Kim, C.H. Author Correction: Bidirectional regulatory potentials of short-chain fatty acids and their G-protein-coupled receptors in autoimmune neuroinflammation. Sci. Rep. 2019, 9, 17511. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Layden, B.T.; Angueira, A.R.; Brodsky, M.; Durai, V.; Lowe, W.L. Short chain fatty acids and their receptors: New metabolic targets. Transl. Res. 2013, 161, 131–140. [Google Scholar] [CrossRef] [PubMed]
  66. Larraufie, P.; Martin-Gallausiaux, C.; Lapaque, N.; Dore, J.; Gribble, F.M.; Reimann, F.; Blottiere, H.M. SCFAs strongly stimulate PYY production in human enteroendocrine cells. Sci. Rep. 2018, 8, 74. [Google Scholar] [CrossRef] [PubMed]
  67. Tazoe, H.; Otomo, Y.; Kaji, I.; Tanaka, R.; Karaki, S.I.; Kuwahara, A. Roles of short-chain fatty acids receptors, GPR41 and GPR43 on colonic functions. J. Physiol. Pharmacol. 2008, 59 (Suppl. S2), 251–262. [Google Scholar] [PubMed]
  68. Hernandez, M.A.G.; Canfora, E.E.; Jocken, J.W.E.; Blaak, E.E. The Short-Chain Fatty Acid Acetate in Body Weight Control and Insulin Sensitivity. Nutrients 2019, 11, 1943. [Google Scholar] [CrossRef] [Green Version]
  69. Martin-Gallausiaux, C.; Marinelli, L.; Blottiere, H.M.; Larraufie, P.; Lapaque, N. SCFA: Mechanisms and functional importance in the gut. Proc. Nutr. Soc. 2021, 80, 37–49. [Google Scholar] [CrossRef] [PubMed]
  70. Perry, R.J.; Peng, L.; Barry, N.A.; Cline, G.W.; Zhang, D.; Cardone, R.L.; Petersen, K.F.; Kibbey, R.G.; Goodman, A.L.; Shulman, G.I. Acetate mediates a microbiome-brain-beta-cell axis to promote metabolic syndrome. Nature 2016, 534, 213–217. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  71. Trent, C.M.; Blaser, M.J. Microbially Produced Acetate: A “Missing Link” in Understanding Obesity? Cell Metab. 2016, 24, 9–10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Hamer, H.M.; Jonkers, D.; Venema, K.; Vanhoutvin, S.; Troost, F.J.; Brummer, R.J. Review article: The role of butyrate on colonic function. Aliment. Pharmacol. Ther. 2008, 27, 104–119. [Google Scholar] [CrossRef]
  73. Ji, J.; Shu, D.; Zheng, M.; Wang, J.; Luo, C.; Wang, Y.; Guo, F.; Zou, X.; Lv, X.; Li, Y.; et al. Microbial metabolite butyrate facilitates M2 macrophage polarization and function. Sci. Rep. 2016, 6, 24838. [Google Scholar] [CrossRef]
  74. Leonardini, A.; Laviola, L.; Perrini, S.; Natalicchio, A.; Giorgino, F. Cross-Talk between PPARgamma and Insulin Signaling and Modulation of Insulin Sensitivity. PPAR Res. 2009, 2009, 818945. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Wang, D.; Shi, L.; Xin, W.; Xu, J.; Xu, J.; Li, Q.; Xu, Z.; Wang, J.; Wang, G.; Yao, W.; et al. Activation of PPARgamma inhibits pro-inflammatory cytokines production by upregulation of miR-124 in vitro and in vivo. Biochem. Biophys. Res. Commun. 2017, 486, 726–731. [Google Scholar] [CrossRef] [PubMed]
  76. Peng, L.; He, Z.; Chen, W.; Holzman, I.R.; Lin, J. Effects of butyrate on intestinal barrier function in a Caco-2 cell monolayer model of intestinal barrier. Pediatr. Res. 2007, 61, 37–41. [Google Scholar] [CrossRef] [PubMed]
  77. De Vadder, F.; Kovatcheva-Datchary, P.; Goncalves, D.; Vinera, J.; Zitoun, C.; Duchampt, A.; Backhed, F.; Mithieux, G. Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell 2014, 156, 84–96. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  78. Feuerer, M.; Herrero, L.; Cipolletta, D.; Naaz, A.; Wong, J.; Nayer, A.; Lee, J.; Goldfine, A.B.; Benoist, C.; Shoelson, S.; et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 2009, 15, 930–939. [Google Scholar] [CrossRef] [PubMed]
  79. Shimizu, J.; Kubota, T.; Takada, E.; Takai, K.; Fujiwara, N.; Arimitsu, N.; Murayama, M.A.; Ueda, Y.; Wakisaka, S.; Suzuki, T.; et al. Propionate-producing bacteria in the intestine may associate with skewed responses of IL10-producing regulatory T cells in patients with relapsing polychondritis. PLoS ONE 2018, 13, e0203657. [Google Scholar] [CrossRef] [PubMed]
  80. Ludwig, D.S.; Hu, F.B.; Tappy, L.; Brand-Miller, J. Dietary carbohydrates: Role of quality and quantity in chronic disease. BMJ 2018, 361, k2340. [Google Scholar] [CrossRef] [Green Version]
  81. Seo, Y.S.; Lee, H.B.; Kim, Y.; Park, H.Y. Dietary Carbohydrate Constituents Related to Gut Dysbiosis and Health. Microorganisms 2020, 8, 427. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Goodman, B.E. Insights into digestion and absorption of major nutrients in humans. Adv. Physiol. Educ. 2010, 34, 44–53. [Google Scholar] [CrossRef] [PubMed]
  83. Do, M.H.; Lee, E.; Oh, M.-J.; Kim, Y.; Park, H.-Y. High-Glucose or -Fructose Diet Cause Changes of the Gut Microbiota and Metabolic Disorders in Mice without Body Weight Change. Nutrients 2018, 10, 761. [Google Scholar] [CrossRef] [Green Version]
  84. Wang, Y.; Qi, W.; Song, G.; Pang, S.; Peng, Z.; Li, Y.; Wang, P. High-Fructose Diet Increases Inflammatory Cytokines and Alters Gut Microbiota Composition in Rats. Mediat. Inflamm. 2020, 2020, 6672636. [Google Scholar] [CrossRef] [PubMed]
  85. Sun, S.; Araki, Y.; Hanzawa, F.; Umeki, M.; Kojima, T.; Nishimura, N.; Ikeda, S.; Mochizuki, S.; Oda, H. High sucrose diet-induced dysbiosis of gut microbiota promotes fatty liver and hyperlipidemia in rats. J. Nutr. Biochem. 2021, 93, 108621. [Google Scholar] [CrossRef] [PubMed]
  86. Xiang, S.; Ye, K.; Li, M.; Ying, J.; Wang, H.; Han, J.; Shi, L.; Xiao, J.; Shen, Y.; Feng, X.; et al. Xylitol enhances synthesis of propionate in the colon via cross-feeding of gut microbiota. Microbiome 2021, 9, 62. [Google Scholar] [CrossRef] [PubMed]
  87. Zuo, Q.-L.; Cai, X.; Zheng, X.-Y.; Chen, D.-S.; Li, M.; Liu, Z.-Q.; Chen, K.-Q.; Han, F.-F.; Zhu, X. Influences of Xylitol Consumption at Different Dosages on Intestinal Tissues and Gut Microbiota in Rats. J. Agric. Food Chem. 2021, 69, 12002–12011. [Google Scholar] [CrossRef]
  88. Sarmiento-Rubiano, L.A.; Zuniga, M.; Perez-Martinez, G.; Yebra, M.J. Dietary supplementation with sorbitol results in selective enrichment of lactobacilli in rat intestine. Res. Microbiol. 2007, 158, 694–701. [Google Scholar] [CrossRef] [PubMed]
  89. Peuranen, S.; Tiihonen, K.; Apajalahti, J.; Kettunen, A.; Saarinen, M.; Rautonen, N. Combination of polydextrose and lactitol affects microbial ecosystem and immune responses in rat gastrointestinal tract. Br. J. Nutr. 2004, 91, 905–914. [Google Scholar] [CrossRef]
  90. Uebanso, T.; Kano, S.; Yoshimoto, A.; Naito, C.; Shimohata, T.; Mawatari, K.; Takahashi, A. Effects of Consuming Xylitol on Gut Microbiota and Lipid Metabolism in Mice. Nutrients 2017, 9, 756. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  91. Amo, K.; Arai, H.; Uebanso, T.; Fukaya, M.; Koganei, M.; Sasaki, H.; Yamamoto, H.; Taketani, Y.; Takeda, E. Effects of xylitol on metabolic parameters and visceral fat accumulation. J. Clin. Biochem. Nutr. 2011, 49, 1–7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  92. 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 2014, 514, 181–186. [Google Scholar] [CrossRef] [PubMed]
  93. 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. 2017, 107 Pt B, 530–539. [Google Scholar] [CrossRef] [Green Version]
  94. 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. 2014, 111 (Suppl. S1), S30–S35. [Google Scholar] [CrossRef] [Green Version]
  95. 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 A 2008, 71, 1415–1429. [Google Scholar] [CrossRef] [PubMed]
  96. 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 2017, 9, 560. [Google Scholar] [CrossRef] [PubMed]
  97. 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 2017, 12, e0178426. [Google Scholar] [CrossRef] [Green Version]
  98. De la Garza, A.L.; Romero-Delgado, B.; Martinez-Tamez, A.M.; Cardenas-Tueme, M.; Camacho-Zamora, B.D.; Matta-Yee-Chig, D.; Sanchez-Tapia, M.; Torres, N.; Camacho-Morales, A. Maternal Sweeteners Intake Modulates Gut Microbiota and Exacerbates Learning and Memory Processes in Adult Male Offspring. Front. Pediatr. 2021, 9, 746437. [Google Scholar] [CrossRef]
  99. Palmnas, 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 2014, 9, e109841. [Google Scholar] [CrossRef]
  100. Lu, J.F.; Zhu, M.Q.; Zhang, H.; Liu, H.; Xia, B.; Wang, Y.L.; Shi, X.; Peng, L.; Wu, J.W. Neohesperidin attenuates obesity by altering the composition of the gut microbiota in high-fat diet-fed mice. FASEB J. 2020, 34, 12053–12071. [Google Scholar] [CrossRef]
  101. 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 2018, 23, 367. [Google Scholar] [CrossRef] [Green Version]
  102. Li, X.Y.; He, C.; Zhu, Y.; Lu, N.H. Role of gut microbiota on intestinal barrier function in acute pancreatitis. World J. Gastroenterol. 2020, 26, 2187–2193. [Google Scholar] [CrossRef]
  103. Verhaar, B.J.H.; Prodan, A.; Nieuwdorp, M.; Muller, M. Gut Microbiota in Hypertension and Atherosclerosis: A Review. Nutrients 2020, 12, 2982. [Google Scholar] [CrossRef]
  104. Zaky, A.; Glastras, S.J.; Wong, M.Y.W.; Pollock, C.A.; Saad, S. The Role of the Gut Microbiome in Diabetes and Obesity-Related Kidney Disease. Int. J. Mol. Sci. 2021, 22, 9641. [Google Scholar] [CrossRef]
  105. Gardner, C.; Wylie-Rosett, J.; Gidding, S.S.; Steffen, L.M.; Johnson, R.K.; Reader, D.; Lichtenstein, A.H.; American Heart Association Nutrition Committee of the Council on Nutrition, Physical Activity and Metabolism, Council on Arteriosclerosis, Thrombosis and Vascular Biology, Council on Cardiovascular Disease in the Young, and the American Diabetes Association. Nonnutritive sweeteners: Current use and health perspectives: A scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care 2012, 35, 1798–1808. [Google Scholar] [CrossRef] [Green Version]
  106. Narayanan, S.; Bhutiani, N.; Adamson, D.T.; Jones, C.M. Pancreatectomy, Islet Cell Transplantation, and Nutrition Considerations. Nutr. Clin. Pract. 2021, 36, 385–397. [Google Scholar] [CrossRef]
Figure 1. Nutritive and non-nutritive sweeteners chemical structures (Taken from:, accessed on 23 August 2022).
Figure 1. Nutritive and non-nutritive sweeteners chemical structures (Taken from:, accessed on 23 August 2022).
Diabetology 03 00042 g001
Table 2. Effects of non-nutritive sweeteners on gut microbiota and metabolic health.
Table 2. Effects of non-nutritive sweeteners on gut microbiota and metabolic health.
Approach Animal ModelOutcomesRef.
0.1 mg/mL saccharin in drinking water
(10 weeks)
obese male C57Bl/6
Impaired glucose tolerance
Bacteroides genus and Clostridiales order
Lactobacillus reuteri
Oral dosing of Splenda (gavage) at 1.1, 3.3, 5.5 or 11 mg/kg/day sucralose
(12 weeks)
Male Sprague Dawley rats Body weight
Bacteroides, bifidobacterium, lactobacilli and Clostridium
↑ pH
Group 1: Administration of a high dose of sucralose (HS, 15 mg/kg body weight per day
Group 2: Administration of Acesulfame K solution of 15 mg/kg body weight per day
(8 weeks)
Male C57B1/6J miceGroup 1
↑ Hepatic cholesterol concentration
Clostridium cluster XIVa
↓ Butyrate concentration in cecal contents
Group 2
GM was found unchanged
Oral dosing of Acesulfame K (gavage) at 37.5 mg/kg body weigh/day
(4 weeks)
Male and female CD-1 mice↑ Body weight (male mice only)
Bacteroides (male mice group)
Lactobacillus and Clostridium (female mice group)
High stevia diet (2.5% steviol glycosides)
(Gestation and lactation period)
Female Wistar
Male offspring (with standard diet)
↑ Fasting glucose levels of male offspring
↓ Bacteroides, Cyanobacteria
↑ Firmicutes, Elusimicrobia, Lactobacillus
aspartame (5–7 mg/kg/day) in drinking water
(8 weeks)
Diet-induced obese male Sprague Dawley rats↓ Body fat percentage, insulin levels
Fasting hyperglycemia and impaired insulin tolerance
↑ Enterobacteriaceae, Clostridium leptum
Serum propionate
50 mg/kg/day of neohesperidin by gavage (4 groups: normal diet; normal diet + neo; High fat diet (HFD); HFD + neo) (12 weeks)Male C57BL/6J mice↓ Weight gain, dysfunctional glucose homeostasis, fatty liver, and systemic inflammation in HFD-fed mice
↑ Firmicutes Bacteroidetes (neo group)
0.75 mg/kg/day of neotame in
drinking water
(4 weeks)
Male CD-1 miceNo differences in body weight
↑ concentration of lipids and fatty acids in feces (linoleic acid, stearic acid, 1-monopalmitin and 1,3-dipalmitate)
Bacteroidetes phylum
↓ Firmicutes, Blautia, Dorea, Oscillospira and Ruminococcus
Microbial dysbiosis index
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Garcia, K.; Ferreira, G.; Reis, F.; Viana, S. Impact of Dietary Sugars on Gut Microbiota and Metabolic Health. Diabetology 2022, 3, 549-560.

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Garcia K, Ferreira G, Reis F, Viana S. Impact of Dietary Sugars on Gut Microbiota and Metabolic Health. Diabetology. 2022; 3(4):549-560.

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Garcia, Karina, Gonçalo Ferreira, Flávio Reis, and Sofia Viana. 2022. "Impact of Dietary Sugars on Gut Microbiota and Metabolic Health" Diabetology 3, no. 4: 549-560.

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