March 3, 2024

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Why don’t artificial sweeteners make us more heathy?

Why don’t artificial sweeteners make us more heathy?


Why don’t artificial sweeteners make us more heathy?

Scientists have found that artificial sweeteners may significantly alter the body’s blood sugar response and microbiome, with saccharin and sucralose having the most significant effect. 

Modern people have long fallen into “sweet” anxiety. In order to get all of them, many people will: drink milk tea and check “zero-calorie sugar”, all kinds of soft drinks must be sugar-free, and even use “zero-calorie sugar” for cooking.

Data shows that the market penetration rate of sugar-free beverages has been increasing in recent years, and nearly 60% of consumers have purchased sugar-free beverages [1].

In addition, the Zhiyan Consulting report shows that the market size of sugar-free beverages has increased from 1.66 billion yuan in 2014 to 11.78 billion yuan in 2020, with a compound annual growth rate of nearly 40% .


Many sugar-free foods use non-nutritive sweeteners (NNS) such as aspartame, sucralose, and acesulfame potassium as artificial sweeteners.

A survey study covering children from many countries indicated that more than 50% of children had eaten NNS foods [2], and countries that implemented labeling of sugar-containing products also observed an increase in the consumption of NNS-containing products year by year [3].


NNS is generally considered safe and metabolically “inert.” However, with the in-depth study of the human microbiota in recent years, little is known about whether NNS affects the microbiota to alter host physiological metabolism .


Recently, a research team led by Prof. Eran Elinav and Prof. Eran Segal from the Weizmann Institute of Science in Israel published important research results in the journal Cell [4].


They conducted a randomized controlled trial designed to assess the effects of NNS on human metabolic health and microbiome. The researchers tested four NNSs: aspartame, saccharin, stevia, and sucralose.


The researchers found that dietary supplementation with sucralose and saccharin impaired glycemic responses in healthy volunteers who were strictly not using NNS .

In addition, the four NNSs significantly altered the volunteers’ fecal and oral microbiome and plasma metabolome. Animal models further suggest that NNS mediates host responses to blood sugar through gut microbes .


This study demonstrates that NNS is not metabolically “inert” as previously thought, and can profoundly alter human physiology through gut microbes.


Why don't artificial sweeteners make us more heathy?

Screenshot of article homepage


Next, let’s take a look at how Eran Elinav’s team carried out this research.


This is an open-label, multi-arm randomized controlled trial (RCT) with the primary endpoint of participants’ blood glucose levels and secondary endpoints of participants’ fecal and oral sample microbiome and plasma metabolome.


A total of 120 participants were included in the study, 65% were women, and the median age was 29.95.

Participants were divided into six groups, two as the control group, and four as the NNS intervention group, with 20 participants in each group (Figure 1).


Of the two control groups, one was supplemented with the same amount of glucose (5 g/day) and the other group received no supplement. The four NNS intervention groups were aspartame, saccharin, sucralose, and stevia .

The daily doses taken by the participants were:

① 0.24 grams of aspartame + 5.76 grams of glucose;

② 0.18 grams of saccharin + 5.82 grams of glucose;

③ 0.102 grams of sucralose + 5.898 grams of glucose;

④ 0.18 grams of stevia (steviol glycosides) + 5.82 g glucose, both below the acceptable daily intake for the corresponding NNS . (figure 1)


The study consisted of three phases: Baseline data on participants’ metabolism and microbiome were collected on days 0-7.

On days 8-21, participants in each group were exposed to the relevant intervention. On days 22-28, after stopping the intervention, participants in each group were followed up for another 7 days.


To assess the effect of NNS on blood glucose, participants wore a continuous glucose monitor (CGM) throughout the trial and underwent a standardized glucose tolerance test (GTT) on selected days.

In addition, participants had metabolic and microbiome samples collected on specific days, and their food intake and physical activity were recorded using the APP.


Why don't artificial sweeteners make us more heathy?

Figure 1: RCT study design


Let’s first look at the effect of NNS on glucose tolerance.


We constructed two linear mixed-effects models, model A including seven GTT data at baseline and intervention period, and model B including all GTT data (Figure 2A).

The results of the analysis showed that after dietary supplementation with saccharin and sucralose, the glycemic response of participants was significantly increased in model A, but not in model B, compared with the two control groups (Fig. 2A).

However, dietary supplementation with aspartame and stevia did not significantly affect participants’ glycemic responses in either model (Figure 2A).


To compare effects between groups, the investigators normalized to the incremental area under the curve (iAUC) for glucose in participants’ GTT.

Overall, both saccharin- and sucralose-supplemented participants had significantly higher normalized glycemic responses compared with glucose-only controls (Figure 2B-C).

During follow-up, the glycemic responses returned to normal in both groups (Figure 2D).


In simple terms , saccharin and sucralose impair glucose tolerance in healthy individuals even when short-term intake is below the acceptable daily intake .


Why don't artificial sweeteners make us more heathy?

Figure 2: Supplementation with saccharin and sucralose adversely affects the glycemic response in humans


Next, the researchers looked at the effects of NNS on gut microbes.


Metagenomic data showed that all four NNSs significantly altered the participants’ gut microbial metabolic functions (Fig. 3C-F), and sucralose and saccharin also significantly altered the participants’ gut microbial structure (Fig. 3A-B). ).

Notably, the gut microbes of the participants were not significantly altered in either control group.

In addition, dietary supplementation with NNS also significantly affected participants’ oral microbial composition and function .


Thus, NNS alters human microbial composition and function in characteristic ways.


Why don't artificial sweeteners make us more heathy?

Figure 3: NNS significantly altered participants’ gut microbial structure and function


So, does NNS affect human blood glucose response through gut microbes?


The researchers first analyzed metagenomic data and found that after NNS supplementation, changes in the function and structure of gut microbes were indeed associated with blood glucose responses.

For example, the metabolic pathways associated with glycemic control in the gut microbes of participants were significantly altered after sucralose supplementation .


However, data from human clinical trials can only demonstrate correlation, not causation. To this end, the researchers also used the germ-free (GF) mouse model to further explore .


The researchers selected 7 people in each NNS intervention group.

Among them, 4 people had the most obvious blood sugar increase after NNS supplementation, and the other 3 people had the weakest blood sugar response.

The researchers transplanted fecal bacteria samples from these participants on days 1 and 21 into GF mice and observed changes in blood sugar.


The results showed that after receiving the fecal bacteria transplant, the mice showed a similar blood sugar response to the corresponding participants .

Specifically, participants with obvious blood glucose responses showed significant changes in blood glucose levels after fecal bacteria transplantation into mice (Fig. 4A-D);

in contrast, participants whose blood glucose did not change after NNS supplementation had fecal bacteria After transplantation into mice, only the blood glucose response of the saccharin group was significantly increased, and the blood glucose response of the other groups of mice did not change significantly.


It should be noted that glycemic responses did not change if fecal bacteria from control participants were transplanted into GF mice (Fig. 4E-F).


Thus, the human microbiome alterations associated with NNS intervention are largely causally related to hyperglycemic responses in mice.

The gut microbial composition of different individuals is highly heterogeneous during NNS supplementation .


Figure 4: NNS-mediated microbiome alterations are causally associated with hyperglycemia in GF mice


In conclusion, this study cleverly designed RCTs combined with animal models to systematically reveal the effects of NNS on human blood glucose response and microbiota. The researchers found that saccharin and sucralose adversely affected the participants’ blood sugar responses. NNS also significantly alters human microbiota composition and function. Animal models have also confirmed that NNS can affect the host’s response to blood glucose through gut microbes .


This study shows that many substances that were previously thought not to be metabolized by the body are likely to be sensed and metabolized by gut microbes, thereby affecting the host. Well, food additives that are currently generally considered safe, such as dietary emulsifiers, food preservatives, and colorants, may also pass through the host microbiome and, in some cases, alter the host’s metabolism.


This study reminds us that the metabolic activity and safe dosage of NNS should be evaluated more comprehensively, and the relevant evaluation criteria should also be updated with the times .


Of course, this study also has limitations , such as fewer volunteers enrolled in the study, significant differences in the dose of NNS intervention, and shorter NNS intervention and follow-up time, which may affect the reliability of the relevant conclusions.












[1] “2020~2024 China Sugar-Free Beverage Industry Market Supply and Demand Status and Development Trend Forecast Report”

[2] Katzmarzyk PT, Broyles ST, Champagne CM, et al. Relationship between Soft Drink Consumption and Obesity in 9-11 Years Old Children in a Multi-National Study. Nutrients. 2016;8(12):770. Published 2016 Nov 30. doi: 10.3390/nu8120770

[3] Martínez X, Zapata Y, Pinto V, et al. Intake of Non-Nutritive Sweeteners in Chilean Children after Enforcement of a New Food Labeling Law that Regulates Added Sugar Content in Processed Foods. Nutrients. 2020;12(6): 1594. Published 2020 May 29. doi:10.3390/nu12061594

[4]Suez J, Cohen Y, Valdés-Mas R, et al. Personalized microbiome-driven effects of non-nutritive sweeteners on human glucose tolerance [published online ahead of print, 2022 Aug 17]. Cell. 2022;S0092-8674 (22)00919-9.doi:10.1016/j.cell.2022.07.016

Why don’t artificial sweeteners make us more heathy?

(source:internet, reference only)

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