Artificial Sweeteners Mess W/ Gut Biome & Induce Insulin Resistance in Rodents - What about Man? Plus: Sucralose & Saccharin, Not Aspartame Induce the Effect

Could diet coke really be more obeso- genic than regular coke? There is no evidence to prove that and still the mainstream interpretation of the latest rodent study in Nature says just that.
In contrast to some other experts, I believe in the usefulness of rodent studies as preliminary, easily available way to investigate general physiological processes. Still, when I look at a study that has to use germ-free mice to produce an effect, I begin to doubt that the results are relevant for someone with an intact gut microbiome (no matter if it's "perfectly healthy", or not).

Before I go on with my criticism of a recently published study in Nature (Suez. 2014), I would suggest we'll first take a look at study design and outcome, to make sure not just Steven and Conor, both of whom asked my opinion on the study on Facebook, know what we are talking about.
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Suez et al. claim that their study, a 10-week study in the course of which germ-free mice (no bacteria in the gut at the onset of the study) were fed standard chow and supplied with unlimited access to
  • saccharin (artificially), sucralose or aspartame sweetened drinking water,
  • naturally sweetened drinking water with either sucrose or glucose as a sweetener, or
  • plain water as a control,
would demonstrate that the consumption of commonly used non-caloric artificial sweeteners (NAS) formulations, in this case , drives the development of glucose intolerance through induction of compositional and functional alterations to the intestinal microbiota. In that, they probably rightfully point out that
"[...t]hese 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," (Suez. 2014)
but they don't tell the reader without full-text access that the negative effects occurred only in four of the animals, were saccharin- and sccralose exclusive and did not occur with the often (falsely) derided sweetener aspartame (see Figure 1, right hand side).
Figure 1: Changes in the bacterial make-up (left) and consequences for the glycemic response after 11 weeks on regularly or artificially sweetened drinking water and antibacterial treatment (Suez. 2014).
Scientific fraud? No, I would rather say a clever way to draw everyone's freakin' attention to a problem that (even if it exists), is not one of all artificial sweeteners and maybe not even be one everyone is susceptible to.
You, as a SuppVersity reader know that this is not the first study to show significant effects of alternative sweeteners on the gut microbiome of the host.
Previous experimental evidence shows that NAS promote, not hinder weight loss | learn more
Experimental evidence vs. observational statistics: As a SuppVersity reader you will also remember that experimental evidence from human studies shows that "Artificial Sweetened Foods Promote, Not Hinder Fat(!) Loss. 1.2kg Body Fat in 70 Days By Eating Artificially Sweetened Products." In the corresponding study by Sørensen et al. I wrote about in May 2014, the artifical sweetener group also had lower hunger ratings, and higher fat oxidation rates compared to the subjects on sucrose sweetened diets. Similar results have been reported by Chen et al. in a study, where subjects replaced part of their regular SSB consumption with diet drinks (Chen. 2009) and de Ruyter et al. who recorded sign. reductions in fat and weight gain in youths after masked replacement of regular SSBs with diet coke & co (de Ruyter. 2012).
In April 2014, I already wrote about a corresponding study by Daly et al. which found that "[d]ietary supplementation with lactose or artificial sweetener enhances swine gut Lactobacillus population abundance," and shows that this effect can be beneficial, as well (at least atm, we still believe that lactobacilli were among the "good guys").
Table 1: Human gut-associated microbial species capable of metabolizing fructose, sugar alcohols, artificial sweeteners (left) and rare sugars and host metabolism and potential implications of consuming various dietary sugar compound (right; HFCS = high fructose corn syrup | Payne. 2014)
Likewise earlier this year, Payne et al. (2014) published a review on the gut microbial adaptation to dietary consumption of fructose, artificial sweeteners and sugar alcohols and the implications for host–microbe interactions contributing to obesity (see Table 1), which suggests both, positive and negative effects depending on the type of sweetener that's used. In this context, it's yet worth mentioning that previous reviews of the literature clearly indicate that the role of artificial sweeteners in the gastrointestinal tract in humans vs. rodents may be fundamentally different (Brown. 2012).

Accordingly, the results Suez et al. present in their latest paper would hardly be considered significant evidence of the existence of a similar problem in human beings, if there weren't the results of an on-going study the scientists are doing. A study that clearly indicates that "similar NAS-induced dysbiosis and glucose intolerance in healthy human subjects." (Suez. 2014)
Alright, but there is one caveat: The previously mentioned human study, the data of which has unfortunately not yet been published has a built-in selection bias with the subjects that meet the criterion of long-term NAS consumption usually being those who have all the reason, namely weight problem, to avoid sugar-sweetened products.

Table 2: Data from the unpublished ongoing observational human study by the same researchers -- Correlates of chronic sweetener (ab-)use; In red: parameters directly related to glycemic control (Suez. 2014)
Still, the significant positive correlations between NAS consumption and several metabolic-syndrome-related clinical parameters (Table 1), including increased weight and waist-to-hip ratio (measures of central obesity); higher fasting blood glucose, glycosylated haemoglobin (HbA1C%) and glucose tolerance test (GTT, measures of impaired glucose tolerance), and elevated serum alanine aminotransferase (ALT, measure of hepatic damage that is likely to be secondary, in this context, to non-alcoholic fatty liver disease) are unquestionably disconcerting and should make us all revisit the amount and frequency with which we are using artificial sweeteners, if the results are eventually corroborated by experimental, not observational, evidence.

Ah, and did the other Internet sources you looked at mention that only saccharine and sucralose, but no allegedly worst of all artificial sweeteners, aspartame, lead to changes in glucose homeostasis? No, well I thought so and I guess they didn't mention either that less than 50% of the mice even developed measurable decreases in insulin tolerance, right? In that case, the fact that stevia has anti-microbial properties (Goyal. 2010; Subudhi. 2010) and could thus also mess with the gut microbiome, wasn't mentioned either, right? Comment on Facebook!
  • Brown, Rebecca J., and Kristina I. Rother. "Non-nutritive sweeteners and their role in the gastrointestinal tract." The Journal of Clinical Endocrinology & Metabolism 97.8 (2012): 2597-2605.
  • Chen, Liwei, et al. "Reduction in consumption of sugar-sweetened beverages is associated with weight loss: the PREMIER trial." The American journal of clinical nutrition 89.5 (2009): 1299-1306.
  • Daly, Kristian, et al. "Dietary supplementation with lactose or artificial sweetener enhances swine gut Lactobacillus population abundance." British Journal of Nutrition 111.S1 (2014): S30-S35.
  • de Ruyter, Janne C., et al. "A trial of sugar-free or sugar-sweetened beverages and body weight in children." New England Journal of Medicine 367.15 (2012): 1397-1406. 
  • Goyal, S. K., and R. K. Goyal. "Stevia (Stevia rebaudiana) a bio-sweetener: a review." (2010).
  • Payne, A. N., C. Chassard, and C. Lacroix. "Gut microbial adaptation to dietary consumption of fructose, artificial sweeteners and sugar alcohols: implications for host–microbe interactions contributing to obesity." obesity reviews 13.9 (2012): 799-809.
  • Sørensen, Lone B., et al. "Sucrose compared with artificial sweeteners: a clinical intervention study of effects on energy intake, appetite, and energy expenditure after 10 wk of supplementation in overweight subjects." The American journal of clinical nutrition (2014): ajcn-081554. 
  • Subudhi, E., et al. "In vitro antimicrobial study of plant essential oils and extracts." Int. J. Microbiol 8.1 (2010): 1-6.
  • Suez et al. "Artificial sweeteners induce glucose intolerance by altering the gut microbiota." Nature (2014). Ahead of Print.
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