Many of you will recall my interview last October (2013) with Dr. Susan Swithers on the metabolic derangements caused by artificial. So it is fitting that a year later that “opinion” piece was given major support from a recent paper out of Nature. Researchers from several institutions contributed to a series of step-wise studies, each building on the previous. This paper is an example of science at its finest, and ultimately paints a picture that is pretty damning. What I intend to do is clarify some of the issues surrounding what constitutes an artificial sweetener, address some of the criticisms surrounding research like this, and then highlight each of the major findings of the paper.
Artificial vs Natural: just because its made from sugar doesn’t make it natural
Anyone who has seen a Splenda commercial will recognize that tag line. The fact is, just because its natural, doesn’t mean it’s safe. Cobra venom is all natural, as is crude oil. Would you drink either? So based on all the available information, when we talk about “artificial” we actually mean any non-caloric sweetener (NCS), including the much beloved Stevia. However, as I’ll note below, the most recent paper indicates that all non-caloric sweeteners have a similar impact on gut microbiota, but saccharin appeared to have the greatest impact, and thus was used as the representative NSC for the final series of studies. I imagine, that future work will reexamine the others in detail.
Of microbiota, mice, and men
The key players in this research are gut microbiota, microorganisms that live in our intestines that are in many ways companions from our early evolutionary development. How cool is it that an alien life form lives in us that so impacts our health? They’re also the reason why yogurt is supposed to be so good for us. We now know that these microbiota are strongly implicated in obesity and possibly autism; actually, certain groups are good, and others are not good, at least for our current environment, and they in turn influence overall health. The other player, mice, have long been an intricate and essential animal model for human research. While I am not a huge fan of animal research, we cannot overlook the value of what they bring to us, including the wealth of knowledge we have in exercise related research. I accept this, and the humane treatment of animal’s value to our own benefit. PSA aside, mouse models are actually robust in comparison to humans and much of the data is very applicable. So do not be fooled into naysayers of this research using mice, not people.
Chronic NAS consumption exacerbates glucose intolerance
Quoting from the paper’s titles, the first experiment compared three solutions of saccharin, sucralose and aspartame plus sugar, with water and water plus glucose. After 11 weeks, all the artificial sweeteners significantly increased glucose intolerance. Sub-analysis showed that saccharin had the largest effect, so for all subsequent studies the researchers used pure saccharin at the same relative dose as is acceptable in humans. Using a high fat diet combined with either glucose or saccharin, they found that the NCS induced glucose intolerance in as little as 5 weeks. When taken together, the researchers found that compared to high fat or normal diets, the addition of NCS resulted in metabolic derangements. This term is interesting because it is exactly what Susan Swithers discussed in her Opinion piece last year. The mice data is actually filling in the circumstantial epidemiological data in humans.
Gut microbiota mediates NAS-induced glucose intolerance
It is well established that microbiota play a key role in health, including obesity, so it is not surprising that this would be a possible causal link. As the researchers noted:
“Since diet modulates the gut microbiota, and microbiota alterations exert profound effects on host physiology and metabolism, we tested whether the microbiota may regulate the observed NAS effects.”
In a fascinating examination to determine if gut microbiota, the researchers continued their mouse model by providing broad spectrum antibiotics. The premise is simple, if bad microbes are at play, then knocking out microbes would have a positive effect. Within 4 weeks, the intolerance was abolished. They then went a step further to establish whether microbiota were the causal link, they performed a fecal transplant, an effective treatment for several bowel related diseases, between glucose intolerant mice and normal mice. In other words, they took bad microbes and transferred them to healthy mice and induced glucose intolerance. These data provide strong evidence that intestinal microbiota mediate the glucose intolerance.
NAS mediate distinct functional alterations to the microbiota
If all that wasn’t enough to get you to throw out that diet soda, the rest of the paper surely will. Moving beyond just experimental response, the authors examined the genetic sequences of the microbes present in the different group. Here is where things really get interesting.
we mapped sequencing reads to the human microbiome project reference genome database. In agreement with the 16S rRNA analysis, saccharin treatment induced the largest changes in microbial relative species abundance…changes in relative abundance were observed across much of the length of the bacterial genomes, as exemplified by one overrepresented (Bacteroides vulgatus, BAD) and one underrepresented species (Akkermansia muciniphila, GOOD).
In very simple terms, NCS appear to be altering the type of microbiota to one overrepresented by lead to glycan (compounds consisting of a large number of monosaccharides linked glycosidically) degradation into short-chain fatty acids (SCFA). These SCFA then signal an increase in glucose release and fat creation. These data also support research in humans with type 2 diabetes that show over abundance of the “bad” glucose and fat production pathways, and an under representation of glucose transport pathways.
NAS directly modulate the microbiota to induce glucose intolerance
Finally, this research team took gut fecal material (and all those microbes) from normal mice, treated it with saccharin and transplanted it back in; yeah, this is getting pretty wild! The treated mice again had an over abundance of the bad microbes, and far less of the good microbes. Likewise, the glycan degradation pathways were also highly enriched (i.e., they increased a lot). Additionally, pathways involved in sphingolipid metabolism, present in non-obese diabetic mice, were also prevalent. There data collectively show that saccharin has a direct impact on the composition and function of the gut microbes, and leads to a cascade of alterations in glucose tolerance.
NAS in humans associate with impaired glucose tolerance
The obvious question, despite my primer at the beginning, is what does this really mean to us humans. Well, if you’ve read Susan Swithers’ review and listened to her interview, you should realize that these studies fill in a lot of mechanistic gaps. However, these researcher also asked and attempted to answer the question buy examine the impact of chronic NCS (or NAS) among 381 non-diabetic people. Without boring you with a lot of stats, here’s the summary:
- significant positive correlations between NAS consumption and several metabolic syndrome-related clinical parameters, including increased weight and waist-to-hip ratio (measures of central obesity); higher fasting blood glucose, HbA1C% and glucose tolerance test.
- HbA1C%, were significantly increased when comparing a subgroup of high NAS consumers (40 individuals) to non-NAS consumers. These users also had similar disruptions in their gut flora as cohort mice.
- results are independent of body fat
Artificial sweeteners were ubiquitously introduced into our food system to reduce calories and satisfy our sugar craving, without influencing blood sugar. However, the data are clear, that this introduction, while not solely to blame, coincides slowly to American’s ever expanding waste line and epidemic obesity rates. The present paper directly implicates the causal role that such sweeteners have at exacerbating obesity and diabetes. It also highlights the need for individualized obesity and diabetes treatments, including examination of the gut microbiota, which have a significant impact on how we process nutrients.
The above paragraph is a paraphrase from the authors, which I believe accurately summarizes the state of the research. However, I am already imagining the response from the food industry, with sugar and Stevia lining up touting its “natural” benefits, and the artificial sweeteners claiming its just one study, and its inconclusive. However, in a court of law, not to mention recent wars, far less evidence has propelled us to action. I admit, I still consume some NCS, however, not regularly, and not in large doses. I hold no illusions about their relative safety, which accord to Dr. Swithers is less than one diet soda per day. In my opinion, reduction of sugar in our diets is imperative, but an overall reduction in sweetness is really the issue. If you want natural sweet goodness, eat fruit. I also believe American’s have been hyper focused on cancer concerns. I am quite certain than someone will say that they never touched saccharin anyway, because it causes cancer. The fact is that your risk from cancer is minuscule compared to diabetes, which is influenced by saccharin (apparently) and lack of exercise. So I say gain, throw out the diet soda and get off your ass and exercise!
Following this posting, I heard from Dr. Swithers with her thoughts on the paper. Here are her insights:
“They did a number of really elegant studies and while it doesn’t prove that the same outcomes actually occur in most people, it provides more evidence for another mechanism that could mediate a causal association between artificial sweeteners and negative health outcomes like type 2 diabetes. We still have little data about the so-called natural sweeteners, especially over the long-term. But depending on the mechanisms involved, they may not prove any more helpful than their more lab created cousins.”