artificial sweeteners, microbiome, and glucose intolerance, in mice and men (and women)

there have been several blogs i've sent out over the past couple of years on artificial sweeteners. one on 5/13/14 comments on studies showing they are associated with weight gain (though other studies refute this), that their intense sweetness may actually distort taste preferences leading people to eat higher sugar-content foods, and that they may actually increase glucose and insulin responses after a glucose meal. the journal Nature had a really striking article on these sweeteners and their effect on gut flora and glucose tolerance (see microbiome artificial sweeteners nature 2014 in dropbox, or doi.org/10.1038/nature13793). most of the non-caloric artificial sweeteners (NAS) pass through the gut without being absorbed, thereby being directly exposed to the gut microbiota (and prior blogs have shown that alterations of the gut microbiome have been associated with the metabolic syndrome). this Nature study had several components, with results:

    ​--mice fed glucose plus an NAS (either saccharin, sucralose or aspartame) developed marked glucose intolerance, in both lean and obese mice. saccharine was the worst of them.

    --in both lean and obese mice consuming NAS, giving them 4 weeks of broad-spectrum antibiotics (combo of cipro and metronidazole, or with vanco)​ eliminated the glucose intolerance.

    ​--to assess whether the antibiotic effect was from changes in the microbiota, they did fecal transplant from those on saccharin vs glucose (control) into normal, germ-free mice (a special breed with sterile intestines) and, after 6 days, those given the microbiota from saccharin-fed mice developed glucose intolerance.

    --assessing the intestinal bacteria, mice on saccharin had clearly different bacteria (dysbiosis), with more Bacteroides and Clostridiales species and fewer Lactobacillus reuteri among others. of note, just adding saccharin to in-vitro stool cultures, then transferring this to germ-free mice also induced glucose intolerance (ie, seems to be a direct effect of NAS on the gut microbiome)

And now, for the humans: 

    --in 381 nondiabetics (44% male, ave age 43.3) in ongoing nutritional study, there was significant correlation between NAS consumption and metabolic syndrome parameters (increased weight, central obesity, higher fasting  glucose, higher A1c, increased ALT). this was true after controlling for BMI. and there were consistent differences in microbiota between the NAS and non-NAS consumers independent of BMI. note that this was not an intervention study.

    ​--7 healthy volunteers (5 men) aged 28-36, who historically did not eat NAS-containing food, consumed saccharin for one week. 4 of the 7 developed significant glucose intolerance (increase glucose, abnormal glucose tolerance tests). evaluation of the microbiota showed significant changes in these 4 (vs the other 3 who did not develop glucose intolerance). then stool samples were transferred to germ-free mice: those from those who developed glucose intolerance conferred glucose intolerance in the mice, whereas those from the 3 who did not develop glucose intolerance did not do so in the mice

so, to me this is a really interesting, though admittedly preliminary study (esp since the human part was so small, but still pretty impressive changes with only 7 days of saccharin). the totality of the data so far points to a likely deleterious role of NAS in developing diabetes (and, of course, the explosive diabetes epidemic correlates time-wise with increased NAS consumption, from the probably false hope by many of us that NAS would decrease obesity and diabetes). it all goes back to the Michael Pollan's comments (The Omnivore's Dilemma and a slew of other books): don't eat anything that has ingredients that your grandmother would not understand. and, it reinforces that the best liquid to drink is water (which could be flavored with some lemon, or adding some cucumber, etc -- or even small amounts of fruit juices)​.