Stevia: What's New in 2019? Appetite, Food Intake, Fertility, Metabolism, Microbiome | Plus: Is Your Stevia 'Natural'?

Stevia is available in all forms and combinations... often you don't realize before you take a look at the label that it was literally diluted with fillers and other sweeteners such as erythritol etc. Moreover, no one can reliably tell you if the exclusion of the "bitter stuff" and reliance on Rebaudioside A, exclusively, doesn't nullify some of the previously described health benefits of the whole plant.

I was just about to simply add the results of a recent study to your daily dose of research news on "FB/SuppVersity", when it occurred to me that it has been suspiciously quiet on the sweetener front, lately - specifically when it comes to stevia, a sweetener of which many people claim that it was "natural"... But is that true, is what you can buy at the supermarket or online really still "natural"?

While the former is certainly a question of your definition of natural" (do you think a highly processed, isolated white powder is "natural"?).

You can learn more about sweeteners at the SuppVersity

Aspartame & Your Microbiome - Not a Problem?

Sucralose 2018 Update #1 - Does it Make Us Fat?

Diet Soda Beats Water as Dieting Aid in RCT

Experiments Don't Support AS<>Obesity link

The Case Against Saccharin: Why it may be different.

Other Diet Soda Additives May be the Real Problem

There's one issue with the (often) Rebaudioside A based products from the shelves, no one can seriously question: Whether the results of studies that are done with the real thing, i.e. stevia leaves of which you could rightfully claim that they are "natural" sweetening agents, will almost certainly not translate 1:1 to the effects of consuming 'stevia' from commercial foods and beverages.

• So why is your "stevia" not the real deal? In view of the results of a recent study in the "Journal of Pharmaceutical and Biomedical Analysis" whose authors (Pacifico 2019) report fifty bioactive constituents in stevia leaves (UHPLC-ESI-QqTOF-MS/MS analysis), you cannot seriously expect that the white powder you call "stevia", which usually is water-extracted and chemical processed Rebaudioside A, the steviol with the least bitterness of all, plus all sorts of fillers and anti-caking agents, will have the same physiological effects on your body as this complex mix of phytochemicals.
  
  

  

  If you want to put that #chlorogenic acid that was lost when your "stevia" was produced back in, study my Coffee 101 it has all the details on how to maximize the CGA content of your home-brewed coffee.

  Speaking of compounds, among the fifty the study identified, non-phenol metabolites, such as benzyl primeveroside and roseoside, as well as a lignan polyphenol (5′), were reported for the first time as constituents of the Stevia leaf. Others, such as chlorogenic acid (the good stuff from coffee) have been detected before but few people are aware of their presence in the true natural sweetener, i.e. the stevia leaves.
  Practically speaking, this means: Your "stevia powder" must not boast any of the health-benefits studies ascribe to either stevia leaves or what scientists would call a 'crude extract'.
  
  This "real deal" forms of stevia have been found to blunt the digestion of carbohydrates, have potent anti-oxidant qualities, and can thus even help alleviate diabetes. With other recent studies showing that the whole leaves (including the bitter compounds) seem to prevent liver disease by modulating hepatic inflammation and fibrosis (Ramos‐Tovar 2018 & 2019), fibrosis and )

Ok, now that you've learned the news that you should have known all along: To call the white stuff from the supermarket a 'natural' sweetener is certainly questionable and unquestionably irrelevant...

Latest review confirms what you've read about sweeteners per se at the SuppVersity - Experimental evidence of ill effects = not convincing: If we widen the scope from Stevia to all non-nutritive sweeteners, it's worth  mentioning Ahmad et al. published in the July issue of "Current Opinion in Clinical Nutrition and Metabolic Care" (Ahmad 2019). The scientists pretty much agree with my previous assessment of the literature when they write that "[o]n the basis of the current evidence, we are still incapable of establishing a definite judgment on whether NNS use truly affects glycaemic control". The authors do however highlight the research on sucralose I analyzed in 2018.

...unless you're stupid enough to believe that everything that marketing people label "natural" is healthy. With that being said, you got to be careful not to (over)generalize the results of a recent review in Current Nutrition Reports which concludes:

"A growing body of evidence indicates that Stevia rebaudiana Bertoni is protective against malignant conversion by inhibition of DNA replication in human cancer cell growth in vitro. Consumption of Stevia has demonstrated to be generally safe in most reports. Further clinical studies are warranted to determine if regular consumption brings sustained benefits for human health" (Rojas 2018)

The same goes for another rave review from last year, in which Samuel et al. praise the promising research on stevia's effects on metabolism, its safety, impact on blood glucose and insulin concentrations, energy intake and weight management, blood pressure, dental caries, naturality and processing, taste and sensory properties (Samuel 2018), and obviously the research results from the last 12 months I've promised in the intro of this article:

• Artificial and sweeteners, obesity, and (in-)fertility revisited - Stevia sticks out: negatively - even compared to aspartame! You may remember from the good old days of short daily SuppVersity articles that there is evidence (from rodent studies) that stevia may impair female fertility... well, a new study (Cho 2018) that investigated the interaction between obesity, low-calorie sweeteners, and prebiotic oligofructose on reproductive parameters - once again in rats, obviously - reports that...
  
  ... stevia, when delivered at 2-3 mg/kg/d in the drinking water, reduces the rate of successful pregnancies by another -7% over the effects of obesity, alone!
  
  In this context, it will come as a relief to overweight human mothers to be who are already pregnant that those 53 percent of the rats who became pregnant had 100% pregnancy and delivery indexes - in other words: the effect must occur before the fertilized egg nests and starts to divide. With only a handful of studies on potential fertility effects of stevia, we are yet far from being able to say with certainty that a high/regular consumption of the "natural" (and, hence, in way too many people's minds "healthy") sweetener poses absolutely no threat to female fertility ... especially if the latter is already endangered by obesity!
• Do sweeteners just make you hungry? No... and for stevia the opposite may be the case! The former is at least what a recent study from the University of Manchester seems to suggest (Stamataki 2019).
  
  For said study, the authors tested in a randomised controlled double-blind crossover trial, how the energy intake of healthy participants (n = 20, 9 males, mean body mass index 21.8 kg/m²) was affected by having different beverages 30 minutes before an ad-libitum (have as much as you want) lunch condition. The test beverages included (C) 330 mL of water (control-no calories and no taste) and either 330 mL of water containing (1) 40 g glucose or (2) sucrose (sweet taste and calories), (3) maltodextrin (calories and no sweet taste), or (4) 240 ppm all-natural sweetener, stevia (Truvia RA-95-sweet taste and no calories).
  
  The additional questionnaires revealed that the stevia and glucose preloads were rated to have equal sweetness levels, while water and maltodextrin the lowest levels of sweetness. As you would expect, though, "only glucose, sucrose and maltodextrin elevated blood glucose" (Stamatki 2019) - interestingly, both the almost non-sweet maltodextrin and the similarly sweet calorie-containing glucose and sucrose, and the stevia treatment significantly suppressed the participants' (all compared to water). What's more important, though is that these observations also translated to the objective (and actually relevant) study outcome: food intake on the ad-libitum meal:

  "Compared to water preload, food intake was significantly lower after the consumption of each of the sweet or caloric preloads" (Stamatki 2019).

  What about stevia? Well, the conclusion of the study says that the study "found a beneficial effect of a stevia beverage consumed prior to a meal on appetite and subsequent energy intake" (Stamatki 2019) - so where's this benefit?
  
  

  

  Figure 1: The figure depicts the cumulative energy intake for all five intervention groups (Stamatki 2019)

  It appears only in the analysis of the subjects cumulative energy intake (preload and lunch), which showed that total energy intake was lower after the stevia preload compared to the water preload.
  
  The latter, i.e. a significant effect compared to water must yet not make us forget that this advantage did not persist when compared to the caloric preloads, which made up for the extra-calories they delivered by suppressing food intake more significantly.
  
  Needless to say, that 24h follow-ups, habituation effects, and - most importantly - studies in people whose natural ability to self-regulate their body weight seems to be impaired - are warranted before advising people to consume a stevia-sweetened beverage before a meal to reduce their overall energy intake... 'cause, after all, we all know that that is what really counts.
• Like everything you eat, stevia will affect your microbiome - the question is: For good or for bad? Further insights into stevia's effects on the microbiome come from University of Calgary (Nettleton 2019), where researchers conducted a rodent study the results of which are worth reporting despite the somewhat uncertain transferability to human beings.
  
  You've read about a putatively negative effect of stevia and "un-"natural sweeteners on the SuppVersity before. You are also well-informed about the under-researched and overhyped role of the gut microbiota as an "important environmental factor that can mediate metabolism and subsequent obesity and disease risk" (Nettleton 2019). To further our insights into what is a much more complex relationship than the NY Times article you may have read (and trusted) suggests, Nettleton et al. didn't just want to confirm and further analyze the stevia-mediated changes in gut microbiota, they also wanted to know if they could be prevented or reserved by the provision of pre-biotics, i.e. food for the allegedly good bacteria. To this ends, they conducted the following experiment:

  "Three-week old male Sprague-Dawley rats were randomized to consume: (1) Water (CTR); (2) Rebaudioside A (STV); (3) prebiotic (PRE); (4) Rebaudioside A + prebiotic (SP) (n = 8/group) for 9 weeks. Rebaudioside was added to drinking water and prebiotic oligofructose-enriched inulin added to control diet (10%). Body weight and feces were collected weekly and food and fluid intake biweekly. Oral glucose and insulin tolerance tests, gut permeability tests, dual X-ray absorptiometry, and tissue harvest were performed at age 12 weeks" (Nettleton 2019).

  With 2-3mg/kg Rebaudioside A, the rodents were fed the human equivalent of approximately 14-15mg which is way below the ADI set by the Health Canada (which is  4 mg/kg bw/day for adults). It is thus not 100% surprising that the study did not reproduce the weight loss effects some previous studies using 30-50-fold higher dosages observed. In a similar vein, the rodents glucose tolerance seemed to be pretty stable - and that's despite the fact that ...

  "[...] the administration of Rebaudioside A did, however, alter gut microbiota composition and reduce nucleus accumbens tyrosine hydroxylase and dopamine transporter mRNA levels compared to CTR" (Nettleton 2019).

  Now, while this may sound pretty bad, it's where the actual news comes in, as the scientists found that the ill effects on the microbiome was attenuated by the provision of prebiotics in the rodents' diet. Moreover, both the prebiotic, alone, as well as the prebiotic + Rebaudioside A group, had reduced fat mass, food intake, gut permeability and cecal SCFA concentration - all four well-known 'side effects' of probiotics.

While the changes in dopamine availability may suggest that the provision of stevia increases the risk of overeating, the rodents intake of the (albeit blatant) diet was unaffected (top); much in contrast to the composition of the microbiome (bottom).

Whut? Stevia reduces dopamine? This is exactly what the Nettleton study shows. If you scrutinize what the scientists analyzed, though, you will realize that their data relates exclusively to the dopamine production and uptake in the mesolimbic reward circuit, where RebA reduced tyrosine hydroxylase (TH | p = 0.044) and dopamine transporter (DAT | p = 0.044) mRNA levels in the nucleus accumbens. In previous studies, similar changes have been linked to food overconsumption - an effect that was, as the figure on the left goes to show you, yet not observed in the study at hand. In view of the fact that the rodents were fed a rather blatant diet the lack of dopamine (~reward) has been linked specifically to the overconsumption of highly palatable food, in particular, any form of definite all-clear signal seems to be unwarranted - especially in view of the fact that these (anti-)dopaminergic effects may well be a downstream effect of the "natural" sweetener on the microbiome (that would also explain its attenuation by prebiotics in the ventral tegmental area,  a group of neurons located close to the midline on the floor of the midbrain).

• What the study adds, though, is that these benefits were not abolished by the coadministration of Rebaudioside A ... well, ok, if you like to poop, you may complain that 'stevia' triggered a significant reduction in cecal weight.
  
  

  

  SIBO-sufferers beware of pre- and probiotics. While they may counter some of the potentially 'bad' effects of stevia, they may mess you up big time | more.

  If you're a stevia junkie it would thus seem prudent to make sure that you get your daily dose of probiotic fiber in your diet ... but wait: if you're already suffering from dysbiosis and or SIBO the 10% FODMAP diet (oligofructose-enriched inulin), the rodents in the study at hand received may actually do more harm than good - as an avid SuppVersity reader you knew that all along, though, right (learn more about SIBO and pro/prebiotics)? If you experience abdominal pain, bloating or the previously discussed brain fog in response to adding inulin rich foods to your diet, you're thus better off with stevia alone.

Suggested read from the SuppVersity Archives: "Can Stevia Help You Ward Off Type II Diabetes? A Review" | Read the full article and/or all posts tagged with stevia from the archives

Stevia, the microbiome and... your teeth! While I suppose that the previous elaborations already gave you more than enough input to think about, there's still one study from early 2019 I would like to mention as it (re-)emphasizes something we tend to overlook over all the hype about the intestinal microbiome: our digestive tract starts in our mouths. In fact, the mouth was the first place where we realized the (in-)direct effects of certain bacteria on our health - the effects of bacteria in the plaque on our teeth on our oral hygiene, the structure of our teeth and, as more recent studies suggest (Noble 2013; Tonsekar 2017; Maldonado 2018), downstream effects of ill oral hygiene and rotten teeth on our dementia (including Alzheimer's) risk.

Said study by Siraj et al. (2019) reports that rinsing for 1 minute with 0.2% aqueous solution of Stevia leaf extract at night reduces the number of acid-producing bacteria on the subjects' teeth to an extent that abolishes the pH decrease in response to the consumption of their favorite food: sugar. What is interesting here is that similar effects were observed for the full-spectrum stevia extract and a commercially available stevioside-based sweetener the scientists used as a comparison in their study ... Why's that interesting? Because it suggests that major microbial effects of stevia remain intact when the sweet compounds are isolated, packaged with fillers and sold as a sugar-alternative, exactly those products of which I initially warned you that they are not identical to the actually "natural" sweetener stevia rebaudiana | Comment!

References

• Ahmad, Samar Y., et al. "Recent evidence for the effects of nonnutritive sweeteners on glycaemic control." Current Opinion in Clinical Nutrition & Metabolic Care 22.4 (2019): 278-283.
• Cho, Nicole A., et al. "Impact of Food Ingredients (Aspartame, Stevia, Prebiotic Oligofructose) on Fertility and Reproductive Outcomes in Obese Rats." Obesity 26.11 (2018): 1692-1695.
• Nettleton, Jodi E., et al. "Low-Dose Stevia (Rebaudioside A) Consumption Perturbs Gut Microbiota and the Mesolimbic Dopamine Reward System." Nutrients 11.6 (2019): 1248.
• Noble, James M., Nikolaos Scarmeas, and Panos N. Papapanou. "Poor oral health as a chronic, potentially modifiable dementia risk factor: review of the literature." Current neurology and neuroscience reports 13.10 (2013): 384.
• Pacifico, Severina, et al. "New insights into phenol and polyphenol composition of Stevia rebaudiana leaves." Journal of pharmaceutical and biomedical analysis 163 (2019): 45-57.
• Ramos‐Tovar, Erika, et al. "Stevia rebaudiana tea prevents experimental cirrhosis via regulation of NF‐κB, Nrf2, transforming growth factor beta, Smad7, and hepatic stellate cell activation." Phytotherapy Research 32.12 (2018): 2568-2576.
• Ramos‐Tovar, Erika, et al. "Stevia prevents experimental cirrhosis by reducing hepatic myofibroblasts and modulating molecular profibrotic pathways." Hepatology Research 49.2 (2019): 212-223.
• Rojas, Edward, et al. "Stevia rebaudiana Bertoni and its effects in human disease: emphasizing its role in inflammation, atherosclerosis and metabolic syndrome." Current nutrition reports 7.3 (2018): 161-170. 
• Samuel, Priscilla, et al. "Stevia leaf to Stevia sweetener: Exploring its science, benefits, and future potential." The Journal of nutrition 148.7 (2018): 1186S-1205S.
• Siraj, E. Saira, K. Pushpanjali, and B. S. Manoranjitha. "Efficacy of Stevioside sweetener on pH of plaque among young adults." Dental research journal 16.2 (2019): 104.
• Stamataki, Nikoleta, et al. "Beneficial Effects of Consuming a Natural Zero Calorie Sweetener Preload Prior to Lunch on Energy Intake: A Double-blind Randomised Crossover Study (FS18-01-19)." (2019): nzz041-FS18.
• Tonsekar, Pallavi P., Shuying S. Jiang, and Gang Yue. "Periodontal disease, tooth loss and dementia: is there a link? A systematic review." Gerodontology 34.2 (2017): 151-163.