16 ms·

Microbiome-driven effects of non-nutritive sweeteners on human glucose tolerance

136 points by masonhipp 4y ago

api 4y ago
A glance suggests that Saccharine and Sucralose may be problematic. The others may be “complicated” but the effect also looks close to noise. They should have included some non-sweetener molecules of a similar nature as controls. Sucralose was an instant no to me when I saw the molecule. “Here let’s hang a chlorine off this here sugar.” Nope. I recall seeing similar sentiments in a thread over at Reddit where a biochemist remarked that it looked like a pesticide. The weird complicated molecules in Stevia and Monk Fruit seem safe precisely because they look like something the body is going to hack apart right away and look like all the other complicated molecules found in plants that the body is used to dealing with. Things like blueberries and onions are just loaded with random baroque carbon sculptures like this.
- hombre_fatal 4y ago
  Man, and I thought mechanistic arguments were bad. This is a whole new level.
- balderdash 4y ago
  As someone that is relying on a single high school chemistry class as a base of knowledge, why would Cl here give you pause? In other words why is the Cl here bad, but ok in say salt?
  - hinoki 4y ago
    As another person with only high school chemistry, sucralose does look a bit like DDT. https://en.m.wikipedia.org/wiki/DDT https://en.m.wikipedia.org/wiki/DDT https://en.m.wikipedia.org/wiki/Sucralose https://en.m.wikipedia.org/wiki/Sucralose
    - kortex 4y ago
      In the grand scheme of molecules, they look nothing alike. DDT is what we call a "greasy brick", while sucralose is a highly water soluble sugar.
    - FollowingTheDao 4y ago
      I saw someone who looked like my brother. But it was not my brother.
    - simias 4y ago
      Am I supposed to find that this https://upload.wikimedia.org/wikipedia/commons/e/e9/Sucralose2.png https://upload.wikimedia.org/wikipedia/commons/e/e9/Sucralos... looks like this https://upload.wikimedia.org/wikipedia/commons/0/0b/P%2Cp%27-dichlorodiphenyltrichloroethane.svg https://upload.wikimedia.org/wikipedia/commons/0/0b/P%2Cp%27... ? Because I'm not seeing it.
    - photochemsyn 4y ago
      The fundamental difference is between the sugar ring (flexible, which each carbon having tetrahedral geometry, and localized electron density) and the aromatic benzene ring (flat trigonal geometry, with electrons delocalized over the ring). If you attach chlorine to the latter, you end up with something that's very hard to break down (very persistent) and which will often (depending on exact structure) stick tightly to many biological molecules. Thus they can cause developmental disruption, odd forms of cancer, liver damage, etc. For example, TCDD (dioxin, a side product of many herbicide synthesis routes, a notorious component of Agent Orange formulations in Vietnam, etc.): https://en.wikipedia.org/wiki/2,3,7,8-Tetrachlorodibenzodioxin https://en.wikipedia.org/wiki/2,3,7,8-Tetrachlorodibenzodiox... The chlorinated sugar ring is probably easier to break down but if this produces an activated chlorine species during metabolism, say in your liver, it might bind to who-knows-what and cause problems. Or it might just get excreted as a chlorine ion, no different from NaCl (table salt). I'd avoid it myself. Some organo-chlorines (and -bromines) also occur in small amounts in many edible seaweeds, apparently often with the halide attached to fatty acids and lipids. Hence consuming large amounts of seaweed might not be the best idea either.
  - kortex 4y ago
    Chlorine-carbon (or halocarbons in general) bonds are somewhat rare in nature. That is not to say they don't exist, but they are a bit unusual. The problem with halocarbons (aside from fluorine, which has its own issues) is they are generally not very reactive, so they can bioaccumulate. But when they do react with biological systems, it tends to be in unwanted and toxic ways. That said, as a former chemist, I consume sucralose, and I am not worried by it. Unlike most halocarbons, It's very water soluble, so it does not react in the ways the bad halocarbons do.
  - adrian_b 4y ago
    In salts and in sea water, the chlorine is in the form of free chloride ions, which is also the normal form of chlorine in your body. In sucralose, chlorine substitutes a hydroxy group and it is covalently bonded to a carbon atom. Most of the organic substances where hydroxy groups are substituted with chlorine atoms are more or less toxic and some are carcinogenic. For example, substituting the hydroxy groups in carbonic acid with chlorine yields the toxic phosgene, which has been used as a chemical weapon in WWI.
    - naasking 4y ago
      > Most of the organic substances where hydroxy groups are substituted with chlorine atoms are more or less toxic and some are carcinogenic. This kind of argument is so... "weird" to put it politely. H2O also becomes toxic if you add an oxygen atom. The safety of chemical compounds does not follow from a naive classification of bonds.
      - dataangel 4y ago
        It's a heuristic. If you haven't done a randomized placebo controlled double blind exhaustive study of the compound and all you have to go on is the layout of the molecule, is it a bad guess?
        parineum 4y ago
        Guess all you want I suppose but there are fairly exhaustive studies on artificial sweeteners.
        naasking 4y ago
        > If [...] all you have to go on is the layout of the molecule, is it a bad guess? Yes, almost certainly. Like I pointed out, one atom is the difference between a toxin and water.
        dataangel 4y ago
        That doesn't change whether or not it's a good heuristic. Whether it's a good heuristic depends on how often "extra chlorine hanging off the side" is indicative of toxicity. He didn't make a claim about one atom changes in general, and even if you did you would need to show that on average across many instances from the sample population (substances we are likely actually to run into) it's misleading.
  - refurb 4y ago
    Alkyl halides (carbon chains with halogens off of them) can be alkylating agents - basically they can bond to molecules within your body and if it's things like DNA, can cause mutations and other bad stuff. Nitrogen mustards (highly reactive alkyl halides) are used in chemotherapy. They basically damage DNA which is used to kill off fast reproducing cancer cells (but they also kill off normal cells). I was a little surprised when I first saw the structure of sucralose. Chlorides aren't that reactive (bromides and iodides are much more reactive), but a person might consume grams of sucralose so concentrations are high. That said, many experiments have been done and sucralose isn't reactive at all. Due to the shape of the molecule and steric interactions, the chlorines are very difficult to knock off. I wouldn't be concerned with taking it.
- FollowingTheDao 4y ago
  Everyone always with this "noise"! Of course there is noise! They are looking at the "noise" and telling you what it is from! Genetics! If you average any trial out in a large population there will be "noise", but these people who live with the "noise" are the ones affected and suffering. Does everyone have microbiome-driven effects of non-nutritive sweeteners? Probably not, but what about the ones that do?
  - simias 4y ago
    If you manage to model the "noise" and make it somewhat deterministic then it's not noise any more. If genetic variations really are the reason for these variations and some people are indeed measurably harmed by these compounds then it would be a very interesting and somewhat alarming result, but that's not what the study says or what we can conclude from it.
    - FollowingTheDao 4y ago
      > If you manage to model the "noise" and make it somewhat deterministic then it's not noise any more. Yes. That is called doing science. > If genetic variations really are the reason for these variations and some people are indeed measurably harmed by these compounds then it would be a very interesting and somewhat alarming result, but that's not what the study says or what we can conclude from it. What would make me not think that? Maybe we should investigate it. That is also called science. Saying anything is noise only disregards the response of that part of the sample as useless. It is not useless. It is why some of us are more sensitive to to certain diets: https://www.chop.edu/conditions-diseases/carbohydrate-malabsorption https://www.chop.edu/conditions-diseases/carbohydrate-malabs...
      - parineum 4y ago
        You know what isn't science? Not doing any of that and just going off on a study that's led to more questions (aka, science) in the comments of Hacker News. Their study had a scope, they did the study and found some results then drew some conclusions. They also found the study wasn't large enough to draw all conclusions because of noise, something they didn't know before the study. > Saying anything is noise only disregards... Saying something is noise indicates that the data isn't clear enough to draw a conclusion and more specific and targeted studies are needed to draw said conclusion. It certainly doesn't mean that they're ignoring the plight of... you.
- naasking 4y ago
  > Sucralose was an instant no to me when I saw the molecule. “Here let’s hang a chlorine off this here sugar.” Nope. I recall seeing similar sentiments in a thread over at Reddit where a biochemist remarked that it looked like a pesticide. If you could infer the properties of a compound by making vague analogies to other similar looking molecules, chemistry would be easy. Changing a single atom can completely change the safety properties of a compound, ie. H2O->H2O2, Hg2Cl2->HgCl2. > The weird complicated molecules in Stevia and Monk Fruit seem safe precisely because they look like something the body is going to hack apart right away and look like all the other complicated molecules found in plants that the body is used to dealing with. Yeah, like the atropa belladonna, the deadly nightshade? I'm sure that's chock full of "baroque carbon sculptures". Maybe biochemistry just isn't so easy.
  - totony 4y ago
    Organic and inorganic molecules are way different. Most small changes to organic molecules are somewhat predictable as to their outcome, afaik.
- ta988 4y ago
  you can't just read a molecule and say "oh it looks like something safe". Digitalin and the cardiac glycosides [1a,1b] may look like completely innocuous compounds (just have to remove a group and they are inactive). Some hormones look like cholesterol. Some steroisomers [2] (think of it as just changing the order atoms are connected in space but not what they are connected to) of molecules kill you while some other forms are safe and that's even harder to grasp on a 2d representation of the structure. [1a] https://en.m.wikipedia.org/wiki/Cardiac_glycoside https://en.m.wikipedia.org/wiki/Cardiac_glycoside [1b] https://en.m.wikipedia.org/wiki/Steroid https://en.m.wikipedia.org/wiki/Steroid [2] https://en.m.wikipedia.org/wiki/Enantiopure_drug https://en.m.wikipedia.org/wiki/Enantiopure_drug
- matheusmoreira 4y ago
  The presence of chlorine does not necessarily imply toxicity. Widely used medications like sertraline and loratadine have chlorine atoms.
- GekkePrutser 4y ago
  Hmm,"let's hang a chlorine of this here sodium" seems to work out pretty well for us in moderation. I guess it's all about the molecule's properties.
- seanhandley 4y ago
  Isn’t bleach just a water molecule with an extra oxygen atom? I’m not a chemist but I didn’t think you could make assumptions about the effect of a substance in the way you describe. Am I missing something?
  - SAI_Peregrinus 4y ago
    Hydrogen peroxide is H2O2 (SMILES `OO`). "Bleach" can refer to any chemical that makes things whiter. Common laundry bleach is usually a chlorine bleach, most often Sodium Hypochlorite (NaClO, SMILES `[Na+].[O-]Cl`). There are a bunch of other bleaches[1]. [1] https://en.wikipedia.org/wiki/Bleach https://en.wikipedia.org/wiki/Bleach
- stjohnswarts 4y ago
  does hanging a chloride off of sodium scare you as well? sodium alone scares me a lot more...
anjel 4y ago
Just wondering why sugar alcohols like sorbitol and erythritol were excluded from this study.
- bloaf 4y ago
  I'm more curious about Allulose[1] which is claimed to have anti-hyperglycemic effects by reducing glucose absorption in the intestines. [1] https://en.wikipedia.org/wiki/Psicose https://en.wikipedia.org/wiki/Psicose https://pubmed.ncbi.nlm.nih.gov/32708827/ https://pubmed.ncbi.nlm.nih.gov/32708827/
- heisenbit 4y ago
  By messing with part of the fructose transport mechanisms sugar alcohols are messing with the microbiome so likely would have stood out. There is a reason at least here there are labels warning of too much consumption.
  - anjel 4y ago
    Erythritol as a NNS is claimed/marketed not to effect the gut biome, indeed to pass through the body unmetabolized.
    - ta988 4y ago
      This is a bit more complicated, it is not really metabolized but it does have a big impact because it is absorbed by the gut and also change bacterial populations... https://academic.oup.com/advances/article/10/suppl_1/S31/5307224 https://academic.oup.com/advances/article/10/suppl_1/S31/530...
      - petra 4y ago
        According to the article in the link, erythritol doesn't change bacterial populations.
        ta988 4y ago
edwnj 4y ago
no free lunch
vanilla-almond 4y ago
I use stevia as a replacement for sugar. This research is difficult to understand for a layperson like me (I'm too thick). Is anyone able to answer the questions below? --- Extract: "non-nutritive sweeteners (NNS), such as saccharin, sucralose, aspartame, acesulfame-K, and stevia, that do not contain calories and are thereby presumed to be inert and not elicit a postprandial glycemic response." Question: Does this research confirm that stevia elicits a postprandial glycemic response? (Does stevia stimulate insulin?). --- Extract: "Notably, all four tested NNS (saccharin, sucralose, aspartame, and stevia) significantly and distinctly altered the human intestinal and oral microbiome, as would be expected for these chemically diverse compounds." Extract: "Degradation of steviol glycosides by gut bacteria is an established component of their metabolism although some species may be more proficient than others in performing this task and thus, pre-exposure microbiome heterogeneity may conduce to differential responses to stevia." Question: So stevia alters the human intestinal and oral microbiome. Are these changes a negative outcome and thus a concern for anyone using stevia?
- clusterhacks 4y ago
  I just skimmed this study but other RCTs say no to your first question: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103435/#:~:text=In%20fact%2C%20stevia%20does%20not,secretion%20in%20response%20to%20glucose https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103435/#:~:tex.... You can go down a rabbit hole with the references in this paper - I think a generally interested layperson is definitely capable of understanding papers like this. My instinct is that the hardest to understand papers are often actually so special-area related that those papers don't contain useful information except for researchers. So you can skip them. Don't know about the second question and suspect no one else does either. As an aside - how did you manage that transition to stevia? I despise non-sugar sweeteners and can detect them in very small amounts. For "reasons" I don't eat meat and I supplement protein intake with whey. If it wasn't for a small number of high-quality unflavored (and thus lacking artificial sweeteners) whey isolates I would probably re-introduce meat into my diet.
  - kekebo 4y ago
    Not OP but what did the trick for me was a combination of the following sweeteners, listed from largest to least amount: - erythritol (~0 calories, ~2/3s as sweet as sugar), - xylitol (~60% of sugar calories, improves oral biome, inhibits enamel demineralization), - stevia or sucralose for added sweetness. After experimenting with different ratios I now rarely crave sugar at all anymore. Another thing to consider is that the initial dopamine response to sweeteners seems to generally be lower than with sugar, but there are indications that this gap may lessen with continued use over a matter of weeks (at least in mice in a small number of studies). Andrew Huberman from Stanford brought it up in a recent episode about nutrition: https://hubermanlab.com/how-foods-and-nutrients-control-our-moods/ https://hubermanlab.com/how-foods-and-nutrients-control-our-...
clearwind 4y ago
Anecdotally, as a type 1 diabetic it’s very interesting to observe different effects of sugars and sweeteners on my continuous blood glucose sensor over time. For example DASH is a zero-calorie but sweet drink I have tried a couple of times and it makes my body chart a course for the moon. Another drink called Gusto seems to have replaced sugars with Agave syrup, which works well at first but after several days builds up intolerance or something. Modern regular orange juice is like a load of TNT with a 4 minute fuse. Recently white wine and sparkling white wine instantly start making my sugar readings hop around erratically, moment by moment. (Not something I saw before about 4 months ago - before that it would be more like a steady incline. The disruptors have made their way over to food and drink, it seems.
- inetsee 4y ago
  Somewhat unrelated to the article: I am a LADA diabetic (Latent Autoimmune Diabetes in Adults, sometimes referred to as Type 1.5). I am insulin dependent, but I didn't become symptomatic until my early 40s. Lately, I have been experimenting with the "grazing diet". Instead of eating three meals a day one would eat a dozen or more really small meals; basically snacks. The motivation was that the glucose response profile of my insulin was poorly matched with the glucose response profile of the foods I eat. My insulin (Humalog), has a profile lasting three to four hours, while most of my foods have a much shorter profile, some with a profile of an hour or less. By spreading my carbohydrate intake over more time I get a better match to my insulin response. For example, I spend two or more hours eating lunch. So far, it seems to be helping noticeably.
- stjohnswarts 4y ago
  have you ever tested diet soda with the various artificial sweeteners? I've tried it personally and never seen the slightest notch above what would random noise whereas sugar is "straight to the moon, lois" a half hour to hour later.
  - clearwind 4y ago
    I have a similar effect to you usually with diet soda, maybe a slight rise. Only some of the newer ones caused my readings to funk up.
tejohnso 4y ago
They indicate: > Notably, all four tested NNS (saccharin, sucralose, aspartame, and stevia) significantly and distinctly altered the human intestinal and oral microbiome, as would be expected for these chemically diverse compounds. But also: > Non-nutritive sweeteners (NNS) are commonly integrated into human diet and presumed to be inert So they are presumed to be inert, but also significantly alter microbiome, as would be expected since they are chemically diverse compounds. They indicate it should be obvious that they are not inert at the same time as they are presumed to be inert? And if it's obvious that they are not inert then why are there so many unanswered questions while they're still allowed into our food system? Is it unreasonable to expect that some newly popular food additive is properly studied before it stats to gain massive adoption in prepared foods?
- Tagbert 4y ago
  The assertion of them being "inert" is probably in terms of interaction with the human metabolism. That is likely what is studied when deciding if a compound is safe for ingestion. What you are calling out is the wider impact to our internal ecology and that is s much more complex thing to measure and something that we are only beginning to understand. There are no regulatory frameworks that take that into account.
wdwvt1 4y ago
Microbiome researcher here - I feel like this is the time I get to shine in HN threads. The Segal and Elinav labs are powerhouses in computational and gnotobiotic microbiome study. They've published several highly cited papers around interactions between diet, the microbiome, and various host parameters. A couple highlights include this [1] 2015 Cell paper predicting host glycemic response from microbial and dietary information, and this [2] 2014 Nature paper identifying artificial sweeteners as a source of glucose intolerance (mediated through the microbiome). In the current work, they show that two non-nutritive sweeteners (NNS, saccharin and sucralose) impair glucose tolerance, and that the microbiome of individuals most susceptible to NNS-induced glucose-intolerance can transmit some of the phenotype to mice. These data are generated with human cohorts of good size (n=20 per sweetener) over a reasonable time frame (2 weeks of daily NNS administration). Importantly, the levels of NNS that are administered are well below the acceptable daily intake (ADI). For example, sucralose is given at 102 mg/day, about 34% of the ADI of 5 mg/kg, and reasonably close to an estimate of 1.6 mg/kg as average daily consumption in humans (reference in [3]). The strongest data for the paper is with sucralose (and saccharin). The researchers show that consumption of sucralose causes a shift in glycemic response: participants consuming sucralose had higher glucose excursion in a glucose tolerance test (GTT) than those consuming either control diet (Fig 2A, E, F). In addition to GTT changes, sucralose-consuming participants had altered level of 9 identified metabolites (Fig 4B-D). After establishing these baseline results, the researchers search for mechanism by stratifying the sucralose cohort in the top and bottom responders. These are, respectively, the individuals who show most change from baseline in GTT at the end of intervention (2 weeks) and those that show the least. There are differences in metabolites, as well as the biochemical pathways those metabolites come from (TCA cycle) in these two groups (Fig 4E, F). There are correlations between changes in the microbiome (both specific taxa and functional gene categories) and the changes in measured metabolite levels as well (Fig 5). In figure 6, the researchers present their strongest data. The researchers inoculate groups of germ-free mice with fecal samples from the sucralose participants from either the baseline or end of intervention. 4 groups of mice receive the feces of the top 1-4 responders (most perturbed GTT), 3 groups receive feces from the bottom 1-3 responders, and each of these is compared to a group receiving baseline feces. The purpose of this test is to see if the microbiome, altered by sucralose administration, can cause impaired glucose tolerance in mice that have never been exposed to sucralose. The researchers show that indeed there is significant glucose-tolerance impairment in mice that receive post-sucralose feeding feces, though interetingly they show that both bottom- and top-responder feces causes this (Fig 6A, G). They show that baseline samples from bottom- and top-responders do not cause differences in glucose tolerance (Fig 8C), showing that something about the sucralose treatment changes microbial composition to promote glucose intolerance. The researchers attempt to find a mechanistic explanation for the differences by comparing groups of mice colonized with top- and bottom-responder (grouped by baseline or end of intervention) feces. Ultimately, this is an extremely impressive paper representing a lot of work (and many storied I haven't recapped). Like many microbiome papers, I think it oversells the mechanistic and physiologically relevant aspects of the research. 1. The data is presented in ways that maximize statistical significance with very little reference to the scale of the actual change. a. Fig 4 B-D and Fig 5 B, D, F show significant metabolite differences but give no reference to actual changes in blood concentration (also Fig 5 metabolites not significant after FDR correction). Without isotope-dilution mass spectrometry (which this is not), it's hard to tell how large the changes are in the blood metabolites. The relationship between concentration of a metabolite and measured area on a mass spec is a power function (for different metabolites exponents can be less or greater than 1), and so this data may represent a lot of change in concentration or very little. In addition, the authors rely on GTT differences to tell the story, but what is the scale of these changes? It is not clear that there is physiological relevance to this scale of change. b. Many of the metrics used are hard to relate to physiologically relevant quantities and allow researcher degrees of freedom. As an example Fig 3 ordinates the participant samples using a principal components projection of the microbial gene annotations. The loadings determining the ordination - and selected for highlight are shown in Fig 3 G-J. The researchers group several of these loadings into super pathways (e.g. purine metabolism) but it's very hard to tell if this kind of difference reflects a functional capacity change in the microbiome (and certainly gives no data about the actual transcription of these genes). Any of these groupings could be highlighted, allowing a lot of flexibility in the storytelling with no penalization for multiple hypotheses. c. Fig 8J "Spearman correlation of sucrose degradation pathway fold change abundance (day 21/baseline) with fold difference in GTT-AUC of each of the conventionalized mouse groups." This is so far away from physiology it's hard to say what it means. 2. Both Eran Segal and Eran Elinav are co-founders of the company DayTwo - a personalized microbiome company that helps diabetics manage their symptoms with microbiome based analytics and treatments. The paper feels like it explores the 'personalization angle' and the expense of other mechanistic studies. For example, the importance of osmolarity on the microbiome and how phenotypes around osmostress might be contributing to the resulting host phenotypes. [1] https://www.sciencedirect.com/science/article/pii/S0092867415014816 https://www.sciencedirect.com/science/article/pii/S009286741... [2] https://www.nature.com/articles/nature13793?tdc_uid=921043 https://www.nature.com/articles/nature13793?tdc_uid=921043 [3] https://foodinsight.org/everything-you-need-to-know-about-sucralose/ https://foodinsight.org/everything-you-need-to-know-about-su...
ohiovr 4y ago
Would this show on an A1C assay?

136 points by masonhipp 4y ago

api 4y ago

A glance suggests that Saccharine and Sucralose may be problematic. The others may be “complicated” but the effect also looks close to noise. They should have included some non-sweetener molecules of a similar nature as controls. Sucralose was an instant no to me when I saw the molecule. “Here let’s hang a chlorine off this here sugar.” Nope. I recall seeing similar sentiments in a thread over at Reddit where a biochemist remarked that it looked like a pesticide. The weird complicated molecules in Stevia and Monk Fruit seem safe precisely because they look like something the body is going to hack apart right away and look like all the other complicated molecules found in plants that the body is used to dealing with. Things like blueberries and onions are just loaded with random baroque carbon sculptures like this.

hombre_fatal 4y ago
Man, and I thought mechanistic arguments were bad. This is a whole new level.
balderdash 4y ago
As someone that is relying on a single high school chemistry class as a base of knowledge, why would Cl here give you pause? In other words why is the Cl here bad, but ok in say salt?
- hinoki 4y ago
  As another person with only high school chemistry, sucralose does look a bit like DDT. https://en.m.wikipedia.org/wiki/DDT https://en.m.wikipedia.org/wiki/DDT https://en.m.wikipedia.org/wiki/Sucralose https://en.m.wikipedia.org/wiki/Sucralose
  - kortex 4y ago
    In the grand scheme of molecules, they look nothing alike. DDT is what we call a "greasy brick", while sucralose is a highly water soluble sugar.
  - FollowingTheDao 4y ago
    I saw someone who looked like my brother. But it was not my brother.
  - simias 4y ago
    Am I supposed to find that this https://upload.wikimedia.org/wikipedia/commons/e/e9/Sucralose2.png https://upload.wikimedia.org/wikipedia/commons/e/e9/Sucralos... looks like this https://upload.wikimedia.org/wikipedia/commons/0/0b/P%2Cp%27-dichlorodiphenyltrichloroethane.svg https://upload.wikimedia.org/wikipedia/commons/0/0b/P%2Cp%27... ? Because I'm not seeing it.
  - photochemsyn 4y ago
    The fundamental difference is between the sugar ring (flexible, which each carbon having tetrahedral geometry, and localized electron density) and the aromatic benzene ring (flat trigonal geometry, with electrons delocalized over the ring). If you attach chlorine to the latter, you end up with something that's very hard to break down (very persistent) and which will often (depending on exact structure) stick tightly to many biological molecules. Thus they can cause developmental disruption, odd forms of cancer, liver damage, etc. For example, TCDD (dioxin, a side product of many herbicide synthesis routes, a notorious component of Agent Orange formulations in Vietnam, etc.): https://en.wikipedia.org/wiki/2,3,7,8-Tetrachlorodibenzodioxin https://en.wikipedia.org/wiki/2,3,7,8-Tetrachlorodibenzodiox... The chlorinated sugar ring is probably easier to break down but if this produces an activated chlorine species during metabolism, say in your liver, it might bind to who-knows-what and cause problems. Or it might just get excreted as a chlorine ion, no different from NaCl (table salt). I'd avoid it myself. Some organo-chlorines (and -bromines) also occur in small amounts in many edible seaweeds, apparently often with the halide attached to fatty acids and lipids. Hence consuming large amounts of seaweed might not be the best idea either.
- kortex 4y ago
  Chlorine-carbon (or halocarbons in general) bonds are somewhat rare in nature. That is not to say they don't exist, but they are a bit unusual. The problem with halocarbons (aside from fluorine, which has its own issues) is they are generally not very reactive, so they can bioaccumulate. But when they do react with biological systems, it tends to be in unwanted and toxic ways. That said, as a former chemist, I consume sucralose, and I am not worried by it. Unlike most halocarbons, It's very water soluble, so it does not react in the ways the bad halocarbons do.
- adrian_b 4y ago
  In salts and in sea water, the chlorine is in the form of free chloride ions, which is also the normal form of chlorine in your body. In sucralose, chlorine substitutes a hydroxy group and it is covalently bonded to a carbon atom. Most of the organic substances where hydroxy groups are substituted with chlorine atoms are more or less toxic and some are carcinogenic. For example, substituting the hydroxy groups in carbonic acid with chlorine yields the toxic phosgene, which has been used as a chemical weapon in WWI.
  - naasking 4y ago
    > Most of the organic substances where hydroxy groups are substituted with chlorine atoms are more or less toxic and some are carcinogenic. This kind of argument is so... "weird" to put it politely. H2O also becomes toxic if you add an oxygen atom. The safety of chemical compounds does not follow from a naive classification of bonds.
    - dataangel 4y ago
      It's a heuristic. If you haven't done a randomized placebo controlled double blind exhaustive study of the compound and all you have to go on is the layout of the molecule, is it a bad guess?
      - parineum 4y ago
        Guess all you want I suppose but there are fairly exhaustive studies on artificial sweeteners.
      - naasking 4y ago
        > If [...] all you have to go on is the layout of the molecule, is it a bad guess? Yes, almost certainly. Like I pointed out, one atom is the difference between a toxin and water.
        dataangel 4y ago
        That doesn't change whether or not it's a good heuristic. Whether it's a good heuristic depends on how often "extra chlorine hanging off the side" is indicative of toxicity. He didn't make a claim about one atom changes in general, and even if you did you would need to show that on average across many instances from the sample population (substances we are likely actually to run into) it's misleading.
- refurb 4y ago
  Alkyl halides (carbon chains with halogens off of them) can be alkylating agents - basically they can bond to molecules within your body and if it's things like DNA, can cause mutations and other bad stuff. Nitrogen mustards (highly reactive alkyl halides) are used in chemotherapy. They basically damage DNA which is used to kill off fast reproducing cancer cells (but they also kill off normal cells). I was a little surprised when I first saw the structure of sucralose. Chlorides aren't that reactive (bromides and iodides are much more reactive), but a person might consume grams of sucralose so concentrations are high. That said, many experiments have been done and sucralose isn't reactive at all. Due to the shape of the molecule and steric interactions, the chlorines are very difficult to knock off. I wouldn't be concerned with taking it.
FollowingTheDao 4y ago
Everyone always with this "noise"! Of course there is noise! They are looking at the "noise" and telling you what it is from! Genetics! If you average any trial out in a large population there will be "noise", but these people who live with the "noise" are the ones affected and suffering. Does everyone have microbiome-driven effects of non-nutritive sweeteners? Probably not, but what about the ones that do?
- simias 4y ago
  If you manage to model the "noise" and make it somewhat deterministic then it's not noise any more. If genetic variations really are the reason for these variations and some people are indeed measurably harmed by these compounds then it would be a very interesting and somewhat alarming result, but that's not what the study says or what we can conclude from it.
  - FollowingTheDao 4y ago
    > If you manage to model the "noise" and make it somewhat deterministic then it's not noise any more. Yes. That is called doing science. > If genetic variations really are the reason for these variations and some people are indeed measurably harmed by these compounds then it would be a very interesting and somewhat alarming result, but that's not what the study says or what we can conclude from it. What would make me not think that? Maybe we should investigate it. That is also called science. Saying anything is noise only disregards the response of that part of the sample as useless. It is not useless. It is why some of us are more sensitive to to certain diets: https://www.chop.edu/conditions-diseases/carbohydrate-malabsorption https://www.chop.edu/conditions-diseases/carbohydrate-malabs...
    - parineum 4y ago
      You know what isn't science? Not doing any of that and just going off on a study that's led to more questions (aka, science) in the comments of Hacker News. Their study had a scope, they did the study and found some results then drew some conclusions. They also found the study wasn't large enough to draw all conclusions because of noise, something they didn't know before the study. > Saying anything is noise only disregards... Saying something is noise indicates that the data isn't clear enough to draw a conclusion and more specific and targeted studies are needed to draw said conclusion. It certainly doesn't mean that they're ignoring the plight of... you.
naasking 4y ago
> Sucralose was an instant no to me when I saw the molecule. “Here let’s hang a chlorine off this here sugar.” Nope. I recall seeing similar sentiments in a thread over at Reddit where a biochemist remarked that it looked like a pesticide. If you could infer the properties of a compound by making vague analogies to other similar looking molecules, chemistry would be easy. Changing a single atom can completely change the safety properties of a compound, ie. H2O->H2O2, Hg2Cl2->HgCl2. > The weird complicated molecules in Stevia and Monk Fruit seem safe precisely because they look like something the body is going to hack apart right away and look like all the other complicated molecules found in plants that the body is used to dealing with. Yeah, like the atropa belladonna, the deadly nightshade? I'm sure that's chock full of "baroque carbon sculptures". Maybe biochemistry just isn't so easy.
- totony 4y ago
  Organic and inorganic molecules are way different. Most small changes to organic molecules are somewhat predictable as to their outcome, afaik.
ta988 4y ago
you can't just read a molecule and say "oh it looks like something safe". Digitalin and the cardiac glycosides [1a,1b] may look like completely innocuous compounds (just have to remove a group and they are inactive). Some hormones look like cholesterol. Some steroisomers [2] (think of it as just changing the order atoms are connected in space but not what they are connected to) of molecules kill you while some other forms are safe and that's even harder to grasp on a 2d representation of the structure. [1a] https://en.m.wikipedia.org/wiki/Cardiac_glycoside https://en.m.wikipedia.org/wiki/Cardiac_glycoside [1b] https://en.m.wikipedia.org/wiki/Steroid https://en.m.wikipedia.org/wiki/Steroid [2] https://en.m.wikipedia.org/wiki/Enantiopure_drug https://en.m.wikipedia.org/wiki/Enantiopure_drug
matheusmoreira 4y ago
The presence of chlorine does not necessarily imply toxicity. Widely used medications like sertraline and loratadine have chlorine atoms.
GekkePrutser 4y ago
Hmm,"let's hang a chlorine of this here sodium" seems to work out pretty well for us in moderation. I guess it's all about the molecule's properties.
seanhandley 4y ago
Isn’t bleach just a water molecule with an extra oxygen atom? I’m not a chemist but I didn’t think you could make assumptions about the effect of a substance in the way you describe. Am I missing something?
- SAI_Peregrinus 4y ago
  Hydrogen peroxide is H2O2 (SMILES `OO`). "Bleach" can refer to any chemical that makes things whiter. Common laundry bleach is usually a chlorine bleach, most often Sodium Hypochlorite (NaClO, SMILES `[Na+].[O-]Cl`). There are a bunch of other bleaches[1]. [1] https://en.wikipedia.org/wiki/Bleach https://en.wikipedia.org/wiki/Bleach
stjohnswarts 4y ago
does hanging a chloride off of sodium scare you as well? sodium alone scares me a lot more...

anjel 4y ago

Just wondering why sugar alcohols like sorbitol and erythritol were excluded from this study.

bloaf 4y ago
I'm more curious about Allulose[1] which is claimed to have anti-hyperglycemic effects by reducing glucose absorption in the intestines. [1] https://en.wikipedia.org/wiki/Psicose https://en.wikipedia.org/wiki/Psicose https://pubmed.ncbi.nlm.nih.gov/32708827/ https://pubmed.ncbi.nlm.nih.gov/32708827/
heisenbit 4y ago
By messing with part of the fructose transport mechanisms sugar alcohols are messing with the microbiome so likely would have stood out. There is a reason at least here there are labels warning of too much consumption.
- anjel 4y ago
  Erythritol as a NNS is claimed/marketed not to effect the gut biome, indeed to pass through the body unmetabolized.
  - ta988 4y ago
    This is a bit more complicated, it is not really metabolized but it does have a big impact because it is absorbed by the gut and also change bacterial populations... https://academic.oup.com/advances/article/10/suppl_1/S31/5307224 https://academic.oup.com/advances/article/10/suppl_1/S31/530...
    - petra 4y ago
      According to the article in the link, erythritol doesn't change bacterial populations.
      - ta988 4y ago

edwnj 4y ago

no free lunch

vanilla-almond 4y ago

I use stevia as a replacement for sugar. This research is difficult to understand for a layperson like me (I'm too thick). Is anyone able to answer the questions below? --- Extract: "non-nutritive sweeteners (NNS), such as saccharin, sucralose, aspartame, acesulfame-K, and stevia, that do not contain calories and are thereby presumed to be inert and not elicit a postprandial glycemic response." Question: Does this research confirm that stevia elicits a postprandial glycemic response? (Does stevia stimulate insulin?). --- Extract: "Notably, all four tested NNS (saccharin, sucralose, aspartame, and stevia) significantly and distinctly altered the human intestinal and oral microbiome, as would be expected for these chemically diverse compounds." Extract: "Degradation of steviol glycosides by gut bacteria is an established component of their metabolism although some species may be more proficient than others in performing this task and thus, pre-exposure microbiome heterogeneity may conduce to differential responses to stevia." Question: So stevia alters the human intestinal and oral microbiome. Are these changes a negative outcome and thus a concern for anyone using stevia?

clusterhacks 4y ago
I just skimmed this study but other RCTs say no to your first question: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103435/#:~:text=In%20fact%2C%20stevia%20does%20not,secretion%20in%20response%20to%20glucose https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103435/#:~:tex.... You can go down a rabbit hole with the references in this paper - I think a generally interested layperson is definitely capable of understanding papers like this. My instinct is that the hardest to understand papers are often actually so special-area related that those papers don't contain useful information except for researchers. So you can skip them. Don't know about the second question and suspect no one else does either. As an aside - how did you manage that transition to stevia? I despise non-sugar sweeteners and can detect them in very small amounts. For "reasons" I don't eat meat and I supplement protein intake with whey. If it wasn't for a small number of high-quality unflavored (and thus lacking artificial sweeteners) whey isolates I would probably re-introduce meat into my diet.
- kekebo 4y ago
  Not OP but what did the trick for me was a combination of the following sweeteners, listed from largest to least amount: - erythritol (~0 calories, ~2/3s as sweet as sugar), - xylitol (~60% of sugar calories, improves oral biome, inhibits enamel demineralization), - stevia or sucralose for added sweetness. After experimenting with different ratios I now rarely crave sugar at all anymore. Another thing to consider is that the initial dopamine response to sweeteners seems to generally be lower than with sugar, but there are indications that this gap may lessen with continued use over a matter of weeks (at least in mice in a small number of studies). Andrew Huberman from Stanford brought it up in a recent episode about nutrition: https://hubermanlab.com/how-foods-and-nutrients-control-our-moods/ https://hubermanlab.com/how-foods-and-nutrients-control-our-...

clearwind 4y ago

Anecdotally, as a type 1 diabetic it’s very interesting to observe different effects of sugars and sweeteners on my continuous blood glucose sensor over time. For example DASH is a zero-calorie but sweet drink I have tried a couple of times and it makes my body chart a course for the moon. Another drink called Gusto seems to have replaced sugars with Agave syrup, which works well at first but after several days builds up intolerance or something. Modern regular orange juice is like a load of TNT with a 4 minute fuse. Recently white wine and sparkling white wine instantly start making my sugar readings hop around erratically, moment by moment. (Not something I saw before about 4 months ago - before that it would be more like a steady incline. The disruptors have made their way over to food and drink, it seems.

inetsee 4y ago
Somewhat unrelated to the article: I am a LADA diabetic (Latent Autoimmune Diabetes in Adults, sometimes referred to as Type 1.5). I am insulin dependent, but I didn't become symptomatic until my early 40s. Lately, I have been experimenting with the "grazing diet". Instead of eating three meals a day one would eat a dozen or more really small meals; basically snacks. The motivation was that the glucose response profile of my insulin was poorly matched with the glucose response profile of the foods I eat. My insulin (Humalog), has a profile lasting three to four hours, while most of my foods have a much shorter profile, some with a profile of an hour or less. By spreading my carbohydrate intake over more time I get a better match to my insulin response. For example, I spend two or more hours eating lunch. So far, it seems to be helping noticeably.
stjohnswarts 4y ago
have you ever tested diet soda with the various artificial sweeteners? I've tried it personally and never seen the slightest notch above what would random noise whereas sugar is "straight to the moon, lois" a half hour to hour later.
- clearwind 4y ago
  I have a similar effect to you usually with diet soda, maybe a slight rise. Only some of the newer ones caused my readings to funk up.

tejohnso 4y ago

They indicate: > Notably, all four tested NNS (saccharin, sucralose, aspartame, and stevia) significantly and distinctly altered the human intestinal and oral microbiome, as would be expected for these chemically diverse compounds. But also: > Non-nutritive sweeteners (NNS) are commonly integrated into human diet and presumed to be inert So they are presumed to be inert, but also significantly alter microbiome, as would be expected since they are chemically diverse compounds. They indicate it should be obvious that they are not inert at the same time as they are presumed to be inert? And if it's obvious that they are not inert then why are there so many unanswered questions while they're still allowed into our food system? Is it unreasonable to expect that some newly popular food additive is properly studied before it stats to gain massive adoption in prepared foods?

Tagbert 4y ago
The assertion of them being "inert" is probably in terms of interaction with the human metabolism. That is likely what is studied when deciding if a compound is safe for ingestion. What you are calling out is the wider impact to our internal ecology and that is s much more complex thing to measure and something that we are only beginning to understand. There are no regulatory frameworks that take that into account.

wdwvt1 4y ago

Microbiome researcher here - I feel like this is the time I get to shine in HN threads. The Segal and Elinav labs are powerhouses in computational and gnotobiotic microbiome study. They've published several highly cited papers around interactions between diet, the microbiome, and various host parameters. A couple highlights include this [1] 2015 Cell paper predicting host glycemic response from microbial and dietary information, and this [2] 2014 Nature paper identifying artificial sweeteners as a source of glucose intolerance (mediated through the microbiome). In the current work, they show that two non-nutritive sweeteners (NNS, saccharin and sucralose) impair glucose tolerance, and that the microbiome of individuals most susceptible to NNS-induced glucose-intolerance can transmit some of the phenotype to mice. These data are generated with human cohorts of good size (n=20 per sweetener) over a reasonable time frame (2 weeks of daily NNS administration). Importantly, the levels of NNS that are administered are well below the acceptable daily intake (ADI). For example, sucralose is given at 102 mg/day, about 34% of the ADI of 5 mg/kg, and reasonably close to an estimate of 1.6 mg/kg as average daily consumption in humans (reference in [3]). The strongest data for the paper is with sucralose (and saccharin). The researchers show that consumption of sucralose causes a shift in glycemic response: participants consuming sucralose had higher glucose excursion in a glucose tolerance test (GTT) than those consuming either control diet (Fig 2A, E, F). In addition to GTT changes, sucralose-consuming participants had altered level of 9 identified metabolites (Fig 4B-D). After establishing these baseline results, the researchers search for mechanism by stratifying the sucralose cohort in the top and bottom responders. These are, respectively, the individuals who show most change from baseline in GTT at the end of intervention (2 weeks) and those that show the least. There are differences in metabolites, as well as the biochemical pathways those metabolites come from (TCA cycle) in these two groups (Fig 4E, F). There are correlations between changes in the microbiome (both specific taxa and functional gene categories) and the changes in measured metabolite levels as well (Fig 5). In figure 6, the researchers present their strongest data. The researchers inoculate groups of germ-free mice with fecal samples from the sucralose participants from either the baseline or end of intervention. 4 groups of mice receive the feces of the top 1-4 responders (most perturbed GTT), 3 groups receive feces from the bottom 1-3 responders, and each of these is compared to a group receiving baseline feces. The purpose of this test is to see if the microbiome, altered by sucralose administration, can cause impaired glucose tolerance in mice that have never been exposed to sucralose. The researchers show that indeed there is significant glucose-tolerance impairment in mice that receive post-sucralose feeding feces, though interetingly they show that both bottom- and top-responder feces causes this (Fig 6A, G). They show that baseline samples from bottom- and top-responders do not cause differences in glucose tolerance (Fig 8C), showing that something about the sucralose treatment changes microbial composition to promote glucose intolerance. The researchers attempt to find a mechanistic explanation for the differences by comparing groups of mice colonized with top- and bottom-responder (grouped by baseline or end of intervention) feces. Ultimately, this is an extremely impressive paper representing a lot of work (and many storied I haven't recapped). Like many microbiome papers, I think it oversells the mechanistic and physiologically relevant aspects of the research. 1. The data is presented in ways that maximize statistical significance with very little reference to the scale of the actual change. a. Fig 4 B-D and Fig 5 B, D, F show significant metabolite differences but give no reference to actual changes in blood concentration (also Fig 5 metabolites not significant after FDR correction). Without isotope-dilution mass spectrometry (which this is not), it's hard to tell how large the changes are in the blood metabolites. The relationship between concentration of a metabolite and measured area on a mass spec is a power function (for different metabolites exponents can be less or greater than 1), and so this data may represent a lot of change in concentration or very little. In addition, the authors rely on GTT differences to tell the story, but what is the scale of these changes? It is not clear that there is physiological relevance to this scale of change. b. Many of the metrics used are hard to relate to physiologically relevant quantities and allow researcher degrees of freedom. As an example Fig 3 ordinates the participant samples using a principal components projection of the microbial gene annotations. The loadings determining the ordination - and selected for highlight are shown in Fig 3 G-J. The researchers group several of these loadings into super pathways (e.g. purine metabolism) but it's very hard to tell if this kind of difference reflects a functional capacity change in the microbiome (and certainly gives no data about the actual transcription of these genes). Any of these groupings could be highlighted, allowing a lot of flexibility in the storytelling with no penalization for multiple hypotheses. c. Fig 8J "Spearman correlation of sucrose degradation pathway fold change abundance (day 21/baseline) with fold difference in GTT-AUC of each of the conventionalized mouse groups." This is so far away from physiology it's hard to say what it means. 2. Both Eran Segal and Eran Elinav are co-founders of the company DayTwo - a personalized microbiome company that helps diabetics manage their symptoms with microbiome based analytics and treatments. The paper feels like it explores the 'personalization angle' and the expense of other mechanistic studies. For example, the importance of osmolarity on the microbiome and how phenotypes around osmostress might be contributing to the resulting host phenotypes. [1] https://www.sciencedirect.com/science/article/pii/S0092867415014816 https://www.sciencedirect.com/science/article/pii/S009286741... [2] https://www.nature.com/articles/nature13793?tdc_uid=921043 https://www.nature.com/articles/nature13793?tdc_uid=921043 [3] https://foodinsight.org/everything-you-need-to-know-about-sucralose/ https://foodinsight.org/everything-you-need-to-know-about-su...

ohiovr 4y ago

Would this show on an A1C assay?