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    Home > Active Ingredient News > Endocrine System > Cell: Sugar substitutes don't make us freer! Scientists have found that sugar substitutes can significantly alter the body's blood sugar response and microbiota, with saccharin and sucralose having the most significant effects

    Cell: Sugar substitutes don't make us freer! Scientists have found that sugar substitutes can significantly alter the body's blood sugar response and microbiota, with saccharin and sucralose having the most significant effects

    • Last Update: 2022-09-21
    • Source: Internet
    • Author: User
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    *For medical professionals only

    Modern people have long fallen into "sweet" anxiety

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

    NNS is generally considered safe and metabolically "inert"

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

    They conducted a randomized controlled trial

    The researchers found that for healthy volunteers who strictly did not use NNS, dietary supplementation with sucralose and saccharin impaired their glycemic response

    This study shows that NNS is not as metabolically "inert" as previously thought, but can profoundly alter the physiological state

    Screenshot of the first page of the article


    Let's take a look at how Eran Elinav's team conducted

    It was an open-label, multi-arm randomized controlled trial (RCT) with primary endpoints of participants' blood glucose levels, and secondary endpoints including participants' stool and oral sample microbiome and plasma metabolome

    A total of 120 participants were included in the study, 65% of whom were women, with a median age of 29.

    Participants were divided into six groups, two for control and four for NNS interventions, with 20 people in each group (Figure 1

    Of the two controls, one group was supplemented with an equal amount of glucose (5 g/day) and the other group did not receive any supplementation

    The four NNS intervention groups were aspartame, saccharin, sucralose, and stevia

    The daily doses taken by the participants were: (1) 0.
    24 g of aspartame + 5.
    76 g of glucose; (2) 0.
    18 g saccharin + 5.
    82 g glucose; (3) 0.
    102 g sucralose + 5.
    898 g glucose; (4) 0.
    18 g of stevia (steviol glycosides) + 5.
    82 g of glucose, all below the acceptable daily intake of
    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, participants in each group were followed up for another 7 days
    after the intervention was stopped.

    To assess the effects of NNS on blood glucose, participants all wore continuous glucose monitors (CGMs) during the trial and underwent a standardized glucose tolerance test (GTT)
    on selected dates.

    In addition, participants took metabolic and microbiome samples on specific days and used the APP to record their food intake and physical activity

    Figure 1: RCT study design


    First, let's look at the effect
    of NNS on glucose tolerance.

    The researchers established two linear mixed-effects models, Model A includes baseline and stem expected 7 GTT data, and Model B includes all GTT data (Figure 2A

    The results of the analysis showed that after dietary supplementation with saccharin and sucralose compared to the two groups of controls, the participants' blood glucose response was significantly increased in model A, but not significantly in model B (Figure 2A

    However, in both models, neither dietary supplementation aspartame nor stevia significantly affected participants' glycemic responses (Figure 2A

    To compare intergroup effects, the investigators standardized the area under the glucose curve (iAUC)
    in the GTT test of participants.

    Overall, participants supplemented with saccharin and sucralose had significantly higher standardized glycemic responses compared to the glucose-only control group (Figures 2B-C

    During the follow-up period, the blood glucose response of the two groups of participants returned to normal (Figure 2D

    In simple terms, even if short-term intakes are lower than acceptable daily intakes, saccharin and sucralose can still impair glucose tolerance in healthy individuals

    Figure 2: Supplementation with saccharin and sucralose adversely affects the body's blood glucose response


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

    Metagenomic data showed that all four NNSs significantly altered the participants' intestinal microbial metabolic function (Figures 3C-F), among which sucralose and saccharin also significantly altered the participants' intestinal microbial structure (Figures 3A-B

    It is worth mentioning that in both control groups, the participants' gut microbiome did not change

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

    As a result, NNS changes the composition and function
    of human microbes in unique ways.

    Figure 3: NNS significantly alters participants' gut microbial structure and function


    So, does NNS affect the body's blood glucose response through gut microbes?

    By analyzing metagenomic data, the researchers first found that the functional and structural changes of the gut microbiome after NNS supplementation were indeed related
    to the blood glucose response.

    For example, after participants supplemented with sucralose, their gut microbiomes' metabolic pathways associated with glycemic control changed


    However, data from human clinical trials only prove correlation, not causation

    To this end, the researchers also used sterile (GF) mouse models to dig

    The researchers selected 7 people in each NNS intervention group, of which 4 people had the most significant increase in blood glucose after NNS supplementation, and the other 3 had the weakest
    blood glucose response.

    The researchers transplanted day 1 and Day 21 fecal samples from these participants into GF mice and observed their blood glucose changes

    The results showed that after receiving fecal transplantation, the mice exhibited a similar glycemic response
    to that of the corresponding participants.

    Specifically, the participants with obvious blood glucose responses had significant changes in blood glucose levels in mice after their fecal bacteria were transplanted to mice (Figures 4A-D); In contrast, after the fecal bacteria were transplanted to mice, only the blood glucose response of the saccharin group was significantly increased, and the blood glucose response of the mice in the remaining group did not change

    It should be noted that if the fecal bacteria of the control group participants were transplanted to GF mice, there was no change in their glycemic response (Figure 4E-F

    Thus, human microbiome alterations associated with NNS interventions are largely causal in relation to mouse hyperglycemia responses

    In the NNS supplementation process, the composition of the gut microbiome in different individuals is highly heterogeneous

    Figure 4: NNS-mediated microbiome alterations are causally related to hyperglycemia in GF mice


    In summary, this study cleverly designed RCTs and combined with animal models, systematically revealed the effects
    of NNS on the human blood glucose response and microbiome.

    The researchers found that saccharin and sucralose adversely affected
    participants' blood glucose responses.

    NNS can also significantly alter the composition and function
    of the human microbiome.

    Animal models also confirm that NNS can influence host responses to blood sugar through gut microbes

    The study shows that many substances that were previously thought to be unable to be metabolized by the body are likely to be perceived and metabolized by the gut microbiome, which in turn affects the host

    Well, food additives that we currently generally consider 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 use of NNS should be assessed more comprehensively, and that the relevant evaluation criteria should also be kept up with the times

    Of course, there are limitations in this study, such as fewer volunteers enrolled in the study, significant differences in the dose of NNS interventions, and shorter NNS interventions and follow-up times, which may affect the reliability
    of relevant conclusions.

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    [1] "Forecast Report on the Supply and Demand Situation and Development Trend of China's Sugar-free Beverage Industry Market from 2020 to 2024"

    [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.
    2016; 8(12):770.
    Published 2016 Nov 30.

    [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.
    2020; 12(6):1594.
    Published 2020 May 29.

    [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].
    2022; S0092-8674(22)00919-9.

    Responsible editor Zhang Eddie

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