Microbiome-driven effects of non-nutritive sweeteners on human glucose tolerance
cell.com
cell.com
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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?).
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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?
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.
- 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-...
Are there any things/situations you can't use stevia for?
I found one stevia brand with a 1:8 ratio (1g of stevia = 8g of Sugar i.e. 1:8 ratio). Found that too sweet for me and had a bitter aftertaste. I usually buy stevia with a 1:2 ratio (i.e. 1g of stevia = 2g of Sugar).
I use stevia in tea and coffee. Have also used stevia successfully to make cakes, cookies, and ice cream.
Unrefined ground dried stevia leaf can be quite bitter depending on what it is mixed into. I find it works well in baked goods like cinnamon rolls and corn bread, but makes berry smoothies too bitter to drink.
The refined version is much less bitter-- e.g., it works in berry smoothies (but, there is a very noticeable fake sugar taste/after taste with smoothies).
In either case, mixing with a little regular sugar (naturally occurring sugar content in e.g., berry smoothies is sufficient), generally improves the favor.
And, stevia does not caramelize like sugar when cooked. E.g., replacing most of the sugar in pancake/waffle batter will result in pancakes/waffles that do not brown when cooked.
From what I've read about postprandial glucose levels, the question seems less about whether or not something elicits a glycemic response, but by how much and how that compares to glucose/fructose.
Another useful measure would be comparing satiation after consumption of sugar vs non-caloric sweeteners, to determine if the significant drop in calories leads to more food ingested overall.
Stevia in particular seems to be one of the lesser studied sweeteners, based on a handful of papers postprandial glucose levels doesn't seem to differ a lot compared to sugar. But there seem to be somewhat consistent findings that satiety levels remain largely the same given the same mass of ingested food ( e.g. [0][1]).
To your second question, from my view the understanding of the human microbiome is still rather poor, especially in terms of health implications on various physiological systems (including neurological), optimal composition and applicable ways to maintain it. Although the last time I checked was probably 1-2 years ago, if anyone is aware of useful new data here I would welcome a link.
[0] https://sci-hub.ee/10.3390/nu11123036
[1] https://sci-hub.ee/https://www.sciencedirect.com/science/art...
A healthy subject, say in their mid twenties, should be able to consume 60g glucose almost instantaneously and have little to no affect on blood glucose. That same subject, if they were to repeatedly do that, multiple times a day, for four decades, is highly likely to have Type 2 diabetes and a heart condition, also likely to have a kidney condition, peripheral neuropathy, macular degeneration, etc take your pick.
The interesting question is what are the long term effects. There are no positive outcomes for a long term high sugar content diet, and I argue that taking any one plant derived, or synthetic chemical, concentrating it and consuming it, is either nutritively, or medically, beneficial, or, if not beneficial, will work, at least to some extent, to tax the body by making healthy homeostatic more difficult.
As an aside, and this isn't directed at you in particular, but at the HN community, if such a thing can be said to exist, more broadly: frameworks.
What frameworks exist within which do make sense of nutritional / health information. How are we to live? What are some (any?) of these frameworks, and where should we go to read about them?
In terms of informational frameworks regarding nutrition I have to say the landscape is quite bleak. Understanding broccoli or its effects on the human body make big pharma no money, publications are only slowly picking up speed with new (crowd-) funding options. Even worse, the lack of funding and publishing set a rather low barrier for food industry players to manipulate the field in their favor, which makes for even less solid ground (e.g. https://www.nytimes.com/2016/09/13/well/eat/how-the-sugar-in... ).
But there are exceptions, Rhonda Patrick comes to mind, she's mostly or fully crowdfunded, including her papers iirc. She can go very deep but is usually aimed at non specialists: https://www.youtube.com/c/FoundMyFitness/videos
And Andrew Huberman who finances his podcast through sponsors, quite dense but always trying to explain medical terms and concepts he brings up: https://www.youtube.com/c/AndrewHubermanLab
As for "how are we to live" I think a good starting point nutritionally is to try and watch/feel the body reacting to different foods and maybe reading up after something feels really good or bad to maybe gain some theoretical insights. There are no studies for your body in particular but you have full production test access pretty much all of the time (I would try to prevent restarts though).
It's not like there is any medical need for the body to consume sugar water at all.
As recreation, sure, but doing something daily is routine, not recreation. That last part is the strange bit. Consume it every tenth meal and you can pick any type of sugar, an otherwise healthy individual would suffer no long term effects. Consume it every meal and you will.
As a though experiment, it would be interesting to think about how much research would be made into finding out which alcohol we could ingest 50 g of to every meal while minimizing long term damage.
Given that huge populations are consuming sugar water daily, and given the health consequences of this, information on which type of sugar water has the least-bad long-term effects is extremely valuable for harm-reduction efforts.
If "everyone should just stop drinking soda" was actually a strategy that worked, then the problem would have already been solved. It didn't work, or hasn't worked yet, so it's worth trying to check whether the variations advertised as less-harmful are actually less-harmful or not.
The same is true of sugar water too. Nobody has to stop drinking it. Just do it sensibly and it's not a problem.
Since you asked about insulin response; (some?) artificial sweeteners seem to be safe for diabetics. There is no other group of people I can think of that should consider using these products.
On a somewhat related note, the soft drink industry has replaced some "diet" drinks with "light" versions that contain sugar and NNS.
I've found that this causes (intentional?) confusion, especially at restaurants, and multiple servers have inadvertently tried to serve our kids that stuff when we ordered things like "lemonade".
In addition to all the above, consuming NNS causes migraines for some people, and they interact badly with some medications. I disagree with the abstract's use of the term "presumed inert", but I suppose they are trying to be diplomatic.
> 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?
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.
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.
https://en.m.wikipedia.org/wiki/DDT https://en.m.wikipedia.org/wiki/Sucralose
DDT is what we call a "greasy brick", while sucralose is a highly water soluble sugar.
Because I'm not seeing it.
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-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.
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.
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.
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.
Yes, almost certainly. Like I pointed out, one atom is the difference between a toxin and water.
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.
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?
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-malabs...
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.
Listen, the term noise is probably the worst term for this data. Because we don’t know if it’s noise until we examine to see if it is noise. So until we know it’s noise we can’t call it noise. It’s like you’re walking into a crowded room and you’re trying to hear one thing but there is too much “noise”. This assumes we know what we’re looking for in the first place.
Yes, that is my point. As the OP remarked; "The others may be “complicated” but the effect also looks close to noise. " is disregarding that data.
When one thinks of the word "noise" one hears something that bothers them, like "there is too much noise in here". This is the problem with research. By getting rid of the "noise" they will only zero in to the thing they wish to hear clearly.
If you do a trial in a large population of a drug, device, or clinical practice that does nothing- a perfect placebo- you'll see a variety of effects: statistical noise.
If you do a trial in a large population of a drug, device, or clinical practice that has an effect-- you'll measure that effect, plus the statistical noise.
You can't generally tell for any individual whether the drug helped or hurt. But you can tell that more people did well (or badly) in group A than group B.
You can't even really know exactly how big the effect is precisely: just a range of likely effect sizes.
The more things you try to measure to more precisely zero in on an effect, the greater the chance that statistical noise spuriously makes one of these look important (and the larger the effect must be to be reliably measured). https://xkcd.com/882/
That is what they found in this study, but the OP said it was likely "noise" and had no scientific basis for saying that. My point; saying something is "noise" is a way to look cool on HN and dismiss any finding that does not fit your world view.
It's a small finding in both effect size and statistical significance, and prior probabilities count.
Barely statistically significant findings don't change my beliefs much, because the base rate and prior knowledge matter.
E.g. if you show me a p<0.05 finding that ESP exists, I'm going to dismiss it as statistical noise-- even if the study methodology is perfect it's only 10-20x more likely that ESP works than before, and 20x my prior belief of very near 0 is still very near 0.
If you show me a p<0.05 finding that green jelly beans cause acne, after studying all colors-- I don't care at all.
Here, the commenter you replied to-- api-- suggested that the study clearly indicates that there's reason to be concerned about saccharine and sucralose. It raises a general level of concern about other NNS's, but the data is ambiguous and weak. This is a reasonable reading of the study.
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.
[1a] https://en.m.wikipedia.org/wiki/Cardiac_glycoside
"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].
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/S009286741... [2] https://www.nature.com/articles/nature13793?tdc_uid=921043 [3] https://foodinsight.org/everything-you-need-to-know-about-su...
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.
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.