Well now, this is very interesting on a number of levels. I don’t know if you recall, but it was some years ago the Paleo Diet community (perhaps Low-Carb as well) was a buzz with how the use of artificial sweeteners led to physiologically high insulin levels in test subjects. Connecting the dots: elevated insulin —> insulin resistance —> glucose intolerance ~~~> diabetes(?)
Now let’s bring in a few additional dots to connect.
- I’ve made quite a bit of noise about the poor glucose tolerance in subjects put into a state of ketosis. 
- Heretofore, I’ve never seen #1 discussed (and it’s uniformly ignored in Paleo / LC circles currently—very telling), but only physiological insulin resistance; so-called, because it’s supposedly ‘no big’ and reverses in a few days with normal carbohydrate intake.
- Never asked—that I notice—in regard to #2, is why fasting blood gluclose of 120-130 mg/dL is pre-diabetes and very very bad for someone who eats normal levels of carbohydrates, say 150-300g per day, but very very good in people who eat low carbohydrate or ketogenic.
- Recall what happened to so many people who introduced various forms of Resistant Starch and later, even Dirt-Based Probiotics back when we began our little revolution around here? Two things were observed by hundreds of low-carb dieters basking in ‘the wonders of physiological insulin resistance and glucose intolerance’ (when they did a carb ‘cheat’): their fasting BG numbers decreased (for many, down below 100) and they began experiencing 2nd-meal effects when they did that ‘cheat.’
Now, low and behold, we have some pretty good science to hang our hats on in terms of unifying all of the above experimentation and anecdotal observation. In Nature.
Jotham Suez, Tal Korem, David Zeevi, Gili Zilberman-Schapira, Christoph A. Thaiss, Ori Maza, David Israeli, Niv Zmora, Shlomit Gilad, Adina Weinberger, Yael Kuperman, Alon Harmelin, Ilana Kolodkin-Gal, Hagit Shapiro, Zamir Halpern, Eran Segal & Eran Elinav
Non-caloric artificial sweeteners (NAS) are among the most widely used food additives worldwide, regularly consumed by lean and obese individuals alike. NAS consumption is considered safe and beneficial owing to their low caloric content, yet supporting scientific data remain sparse and controversial. Here we demonstrate that consumption of commonly used NAS formulations drives the development of glucose intolerance through induction of compositional and functional alterations to the intestinal microbiota. These NAS-mediated deleterious metabolic effects are abrogated by antibiotic treatment, and are fully transferrable to germ-free mice upon faecal transplantation of microbiota configurations from NAS-consuming mice, or of microbiota anaerobically incubated in the presence of NAS. We identify NAS-altered microbial metabolic pathways that are linked to host susceptibility to metabolic disease, and demonstrate similar NAS-induced dysbiosis and glucose intolerance in healthy human subjects. Collectively, our results link NAS consumption, dysbiosis and metabolic abnormalities, thereby calling for a reassessment of massive NAS usage. [emphasis added]
Well, of course, Paleo dieters (LC or otherwise) never advocated for NAS usage anyway. But equally of course, they’re in rampant use pretty much across the board in weight loss or diabetes controlling diets (LC or otherwise). My interest is in the connection to the gut microbiome and how this independently jives with what at least hundreds out there have observed in terms of correcting the ‘healthful wonders of high fasting blood glucose and glucose intolerance’ in a low-carb or ketogenic diet context.
Ira Flatow of Science Friday had a 12-minute interview with study co-author Eran Elinav yesterday on NPR, which I was fortunate to accidentally catch while out and about. It’s a really good overview of the whole thing and gives added detail into the two human trials conducted, one observational and one controlled.
A previous study showed that sucralose can alter the rat gut microbiome—specifically, by decreasing beneficial bacteria—but this latest work pinpoints a microbe-mediated mechanism by which artificial sweeteners might influence glucose metabolism, said Yanina Pepino, who studies how non-caloric sweeteners influence glucose metabolism at the Washington University in St. Louis School of Medicine.
Elinav and Segal’s team observed that mice given a 10 percent solution of one of three types of commonly consumed commercial artificial sweeteners—saccharin, sucralose, or aspartame—in place of regular drinking water had elevated blood-glucose levels after 11 weeks compared to mice given either a 10 percent glucose solution or water alone. The researchers used saccharin for subsequent experiments as this artificial sweetener showed the most pronounced effect on glucose levels in preliminary trials. Mice fed a high-fat diet plus the 10 percent saccharin solution showed the same effect on glucose metabolism as animals given an even higher saccharin dose—comparable to the US Food and Drug Administration’s (FDA’s) upper limit for safe human consumption. [emphasis added]
You catch that?
- Artificial sweeteners produced worse glucose metabolism than if they were fed the same dose as plain glucose (or water). Kinda strikes me like my exercise analogy. You know: couch potato climbs flight of stairs, heart races to 200+ bpm; he concludes he can’t handle any exercise at all. So, perhaps to have a physiologically normal glucose metabolism, you need to ingest some glucose. Use it or lose it?
- A high fat diet didn’t help any. In fact, it was as bad as mice given even higher doses of saccharin (presumably as part of a normal chow diet).
Four weeks of treatment with gut bacteria-depleting antibiotics reversed the glucose intolerance in mice that continued to receive saccharin. This led the team to examine whether the microbiomes of the mice were somehow altering glucose metabolism. Transplantation of feces from non-antibiotic-treated mice that consumed saccharin- or glucose-containing water into germ-free mice within six days induced the same blood-sugar elevations in animals that were never themselves exposed to the sweeteners.
There’s a bit of an ambiguity there—”mice that consumed saccharin- or glucose-containing water“—so hopefully someone with access to the full text can clear that up. But the takeaway here is that it looks like the NAS are causing a gut dysbiosis either in terms of increased bad bacteria, decreased good bacteria, or both (that antibiotics corrects—probably as a general reset or “weeding” deal); a high fat diet (LC) doesn’t help, or actually makes things worse.
You know what that last sentence in the quoted text means, don’t you? That’s causality.
Using shotgun metagenomic sequencing on the fecal samples, the researchers showed that mice given saccharin or those that received a fecal transplant from saccharin-fed mice had a different microbiome composition compared to mice given sugar or no sweeteners. [emphasis added]
Perhaps it’s because we evolved with a taste for sweet and there’s a reason behind it; that in reasonable doses, it could not only be not harmful, but beneficial?
The team also found similar glucose metabolism and gut microbiota changes in humans.
In a cohort of 381 non-diabetic volunteers who answered diet questionnaires, those who regularly consumed artificial sweeteners—particularly those who consumed the highest amounts—showed higher fasting glucose levels, poorer glucose tolerance, and different gut microbe profiles compared to those who did not consume such sweeteners. The difference between the two populations remained even after correcting for body mass index.
Further, the team exposed seven young, healthy volunteers who did not have a history of artificial sweetener consumption to one week of the FDA’s maximum acceptable daily saccharin intake, and continuously monitored their glucose levels. Four of the seven volunteers showed a poorer glycemic response at the end of the week compared to their baseline responses. Those who showed no metabolic response to the sweetener had no change in their gut microbiomes, while those who exhibited the worst glycemic responses at the end of the week showed a different gut microbiota profile after sweetener exposure. Fecal transplants from two artificial sweetener-responder volunteers into germ-free mice resulted in a similar gut microbe profile and glucose intolerance as did transplants from saccharin-consuming mice. But the same transplants from two non-responder volunteers had no such effect in germ-free mice. [emphasis added]
Wow. I mean, that’s pretty compelling stuff, to me. Everything aligns consistently: mouse-to-mouse, human-to-human, and even human-to-mouse. What would be interesting to further explore is the actual diets of those seven participants. It looks like the only variable that changed was everybody got the same amount of saccharin and otherwise kept their same diet (nice control of confounders). So, knowing the differences in baseline diet might give clues as to why four of the seven got compromised guts and glucose intolerance, while the other 3 did not. I’m placing my bet on: beans!
…Although, it might also be sugar, leading to a most ironic finding: ‘eating sugar is protective against the negative effects of artificial sweeteners in sugar metabolism!’
Hey, maybe Pay Peat was right all along about sugar. I’ve been having some interesting results with daily orange juice consumption of about 10-12 oz—half in the morning, half at night—typically taken in a 50/50 mix with water or club soda. So, now that we’re increasingly establishing the healthfulness of starches in rational doses, what’s next: Safe Sugar! May we live in interesting times.
…Oh, one more thing. The 14 comments so far in that The Scientist article are really laughable. Not one single commenter get the point: it’s the microbiome, stupid.