artificial sweeteners: microbiome1

as mentioned in prior blogs, I think that the microbiome represents a very important mediator between the external environment and health/disease. A few recent articles supplement and strengthen this understanding. The first in a series of two is a study reinforcing the potentially deleterious effects of non-caloric sweeteners on the microbiome and health outcomes. The second (to be sent tomorrow) is a broader description of our understanding of the microbiome overall and its potential relationship to health.

​Non-caloric artificial sweeteners (NAS) were developed from the biological perspective that these potent sweeteners (more than 100 times sweeter than sucrose) are non-caloric and  are excreted unchanged; they should therefore be an important sugar alternative to help people lose weight and control glucose intolerance. Although a study done in the 1980s, prior to DNA sequencing capabilities, did show that saccharin could alter the rat microbiome, it is only relatively recently that we understand the fuller effects of NAS on both the microbiota as well as clinical outcomes. Many of the clearest studies were done on animals, since it is easier to control the environment completely and isolate the effects attributable to NAS. A recent study looked further into the relationship between NAS, the microbiome, and the clinical effects (see artificial sweeteners and microbiome gutmicrobes2015 in dropbox, or Suez J. Gut Microbes 2015; 6(2), 149). This is an update of a prior article in Nature (see prior blog: http://gmodestmedblogs.blogspot.com/2014/10/artificial-sweeteners-microbiome-and.html ​ )

Background:
-- the human weight control studies here are a bit mixed. However it should be noted that most of the comparisons were between individuals consuming NAS to those consuming caloric sweeteners, with very few comparing NAS consumption to avoiding all sweeteners.
-- Several studies have shown NAS leads to weight gain in rats (including saccharin, sucralose, aspartame and Stevia), and are associated with increased adiposity
-- NAS can also induce hyperinsulinemia, impaired insulin tolerance, impaired glucose homeostasis, and worsened atherosclerosis in genetically susceptible mice
-- it should be noted that there are some genetically-altered mice where there are some discordant defects: some with decreasing glucose and insulin levels but increasing adiposity, and in some cases hyperinsulinemia

 Details of the current study: 
-- mice drinking water supplemented with high doses of commercial saccharin, sucralose, or aspartame, after 11 weeks had marked glucose intolerance, as compared to controls drinking water, sucrose, or glucose.
-- Further studies of saccharin showed that mice on different baseline diets (e.g. high-fat or other) and at different doses of saccharin had increased glucose intolerance
-- the glucose intolerance induced by NAS was ameliorated by prior dosing with antibiotics (ciprofloxacin and metronidazole, in an attempt to sterilize the gut)
-- there were specific changes in the microbiome associated with NAS, including enrichment of Bacteroides and some Clostridiales and decreases in Lactobacilli and some other members of Clostridiales, several of the microbiota changes previously associated with type II diabetes in humans
-- fecal microbiomes from mice consuming either water or commercial saccharin were then transplanted into germ-free mice, finding that those germ-free mice receiving the saccharin-associated microbiome developed glucose intolerance
-- in 381 nondiabetic humans, NAS consumption was associated with increases in BMI, blood pressure, hemoglobin A1c, and fasting glucose levels. Also there were changes in microbial taxa in the microbiome: more Actinobacteria, Enterobacteriales, and certain Clostridiales.
-- A preliminary small-scale human study found that supplementing the regular diet with higher doses of saccharin led to elevated glycemic responses in four of the seven volunteers, those 4 had microbiome alterations. And when these microbiomes were transplanted into germ-free mice, these mice also developed the same abnormal glycemic responses. Of note, in two of these 4 volunteers, their microbiome changes reverted to normal within 2 to 8 weeks.

Commentary:
-- NAS is consumed by approximately 32% of adult Americans.
-- The microbiome can be rapidly altered by diet, as noted in diets rich in fat (for example, see http://gmodestmedblogs.blogspot.com/2014/10/heart-failure-microbiome.html  )
-- there are a remarkable number of largely unregulated food additives in the current food supply, many added for purely commercial ends, such as preservatives to extend the shelf life of some foods. I believe this NAS data challenges the concept that even those ingredients that are not absorbed and internalized could conceivably adversely affect the human microbiome. The main point here is not that all additives or chemicals are necessarily bad, but that we should be very circumspect about assuming that they are probably benign based on our often incomplete models (i.e. It did make intuitive sense at the time that a non-absorbed sweetener would lead to less obesity and diabetes; but as our understanding and models have expanded/become more complex, our "intuitive" sense has changed). But, I think all of this reinforces what Michael Pollan (author of many books, including The Omnivore's Dilemma) has suggested: it really does make sense to eat natural foods, especially ones which our bodies have evolutionarily adapted to, and avoid foods with ingredients that your grandmother would not know.

in my practice, i have focused on trying to get patients to decrease their consumption of sodas, and with some reasonable success. i think this is often the low-hanging fruit (though less healthy than other fruits), and at least most of my patients say they have dramatically decreased or eliminated sodas by either substituting water (best) or water slightly flavored by fruit juice.  For regular sodas, the attempt is to decrease the consumption of high-fructose corn syrup (a bad actor with multiple bad effects, including increasing uric acid levels), was well as "diet" sodas (commenting on the fact that they really are not benign, non-sugar alternatives, as above). i think my patients have been able to change this soda habit by our regularly and repeatedly targeting this issue (with motivational interviewing) over the past several years, especially with my patients who are overweight, glucose intolerant/diabetic or hyperuricemic.