Stevia Kills Good Gut Bacteria - One Study Enough to Stop Using the Natural Sweetener? Probably Not in View of its Anti-Diabetes, Anti-LDL, Anti-Viral & Anti-Cancer Effects

Study indicates stevia kills healthy gut bacteria. So, how bad is it? Are the effects significant, will they have an impact on your overall health and does this mean you must not use stevia any longer?

A recent study from the Institute of Microbiology and Biotechnology at the University of Latvia in Riga shows the impossible: Stevia, the "natural" sweetener that's everybody's darling, could mess up your gut microbiome by killing large numbers of the beneficial Lactobacillus Reuteri bacteria in your tummy - exactly those bacteria of which several studies have shown that supplementing will help cure acute diarrhea in young children (Shornikova. 1997), is capable of reducing frequency and intensity of antibiotic-associated side-effects during eradication therapy for H. pylori. (Lionetti. 2006), confers broad-spectrum protection against disease in humans and animals (Casas. 2000), has cholesterol lowering effects (Jones. 2012) and much much more.

You can learn more about the gut & your health at the SuppVersity

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The Macrobiotic MaPi2.0 Diet

In view of the fact that it would appear as id Lactobacillus reuteri was clearly one of the "good guys" it seems that the results I. Denin a, P. Semjonovs, A. Fomina, R. Treimane and R. Linde report on their latest study in Letters in Applied Microbiology (Denin. 2014) were really bad news:

Figure 1: Influence of stevioside (a) and rebaudioside A (b) on biomass formation in Lactobacillus reuteri strains (24 h | Denin. 2014).

"In samples supplemented with stevia glycosides, the growth of all Lact. reuteri strains was slightly inhibited – however, a statistically significant concentration-dependent inhibitory effect was not observed for all strains (Fig. 1).

Comparing both the glycosides, the inhibitory effect of stevioside was more pronounced for strains 44 and 16, while the effect of rebaudioside A was more pronounced for strains 16 and 19. Statistically significant concentration-dependent inhib itory effect was observed for lactic acid and acetic acid synthesis. The decrease in lactic acid and acetic acid production was observed for both stevioside and rebaudioside A. [...] Although the inhibitory effect of stevioside on pH was observed at different stevioside concentrations, the effect was evident for all strains. Rebaudioside A had a more pronounced inhibitory effect on pH values of certain strains including Lact. reuteri 12, 16, 43 and 44" (Denin. 2014 | my emphasis).

The good news, however, is in the details: The inhibitory effect was "slight" (see quotation above) and the design of the study leaves it open, whether similar effects would occur in vivo and thus outside of a glycoside, stevioside and rebaudioside laden Petri dish.

Previous studies seem to refute significant effects of stevia on the human microbiome! In 2003, Gardana et al. found no effect of stevia on the make-up of human fecal cultures when they were incubated with either stevioside or rebaudioside A. Only the fact that bacteroides, i.e. the "enemies" of lactobacilli, were the most efficient in hydrolyzing Stevia sweeteners to steviol would suggest that there may be an overall effect on the human microbiome form stevia (ab-)use.

And while we have little in vivo evidence that stevia is bad for you, a brief review of the contemporary scientific literature on Stevia yields the following "proven" (mostly only in a handful, if not just a single study) benefits:

• Stevia has been implicated in diabetes and hyperlipidemia treatment and its effects on blood glucose levels are not a mere result of the corresponding reduction in sugar intake.

  

  Figure 2: Effects of stevia vs. diabetes drug Glibenclamide on blood glucose and lipid levels in diabetic rodents; data expressed relative to healthy control (Singh. 2014)

  In a recent rodent study that compared the effects of stevia against those of the often-prescribed diabetes-drug Glibenclamide, the natural sweetener outperformed the drug in many in its ability to reduce LDL and blood sugar and was not far off of what the Glibencamide did for the diabetic lab animals in terms of its effects on HDL and VLDL (see Figure 2).
  
  Previous human studies indicate that stevia extracts will also increase the increased 16 healthy human volunteers whose plasma glucose levels during an oral glucose tolerance tests were significantly lower after having consumed 5 grams of aqueous leave extract at regular 6-h intervals for 3 days (Curi. 1985).

  

  Figure 3: Effects of stevia and aspartame replacement of sucrose in test meals that were fed to obese and normal-weight volunteers on postprandial blood glucose levels (Anton. 2010)

  Moreover, in a more recent study by Anton et al. where stevia was compared to aspartame, it had the same beneficial effects on total energy intake and let to statistically significant reductions in postprandial glucose levels of both obese and lean study subjects (see Figure 3) that did not reach significance when the sucrose content of the test meal was replaced by aspartame.
• In-vitro stevia appears to have anti-cancer effects, as well. That's at least what studies by  Jayaraman et al. (2008) observed with stevia extracts. An effect that may be related to both it's anti-microbial, as well as its potent anti-oxidant activity (Tadhani. 2007) of the whole leaves and leave extracts of which Tahani et al. found that they contain significant effects of folic acid (52.18 mg/100 g) and vitamin C, as well as 130.76 μg catechin and 15.64 μg quercetin for leaves and 43.99 μg catechin and 1.57 μg quercetin for cellus at mg of water extracts, respectively.
  
  Furthermore, Tadhani et al.'s results showed that the leaf extracts contained higher amounts of free radicals, hydroxyl radicals and superoxide anion radical scavenging activities than those of the callus extracts or the anti-mutagenic effects Cariño-Cortés et al. report in their 2007 study. Whether anything similar can be observed with the white "stevia" powder that is used by most people to sweeten their foods is yet questionable - it's after all pure steviosid and thus devoid of all of the previously mentioned compounds.

  

  Figure 1: Several natural constituents of the stevia plant, including steviosides, which are the naturally sweet agents in stevia have potent anti-viral activity against Epstein-Barr virus; values in brackets
  represent % of untreated control dish (Konoshima. 2002)

  Another possible anti-cancer mechanism may be related to stevia's ability to kill viruses like the Epstein-Barr virus that has been implicated in the pathogenesis of Burkitt’s lymphoma, Hodgkin’s disease, non-Hodgkin’s lymphoma, nasopharyngeal carcinoma, and lymphomas, as well as leiomyosarcomas arising in immunocompromised individuals.in humans (Thompson. 2014).

Against that background it seems questionable that the new evidence of negative effects on allegedly healthy gut bacteria (just want to remind everyone that we have no clue what the optimal gut microbiome would look like) is significant enough to have us all reconsider our use of tiny amounts of stevia as a sweetener in our foods.

Read more about the effects artificial sweeteners have on the microbiome in a prevoius article | go ahead!

Interim conclusion: While I am not all too scared that stevia will mess with my gut microbiome in a way that makes me sick, fat and what not, I truly believe that the effects of artificial sweeteners on the make-up and density of the human gut microbiome is still massively under-researched - and that in spite of the fact that it could have a significant effect on the health of us all.

As s SuppVersity reader you will also be aware that this is not a stevia-specific effects. Only recently I have written about similar effects for a bunch of artificial sweeteners - an article I can only recommend to anyone who hasn't read it yet | Comment on Facebook.

References:

• Anton, Stephen D., et al. "Effects of stevia, aspartame, and sucrose on food intake, satiety, and postprandial glucose and insulin levels." Appetite 55.1 (2010): 37-43.
• Casas, Ivan A., and Walter J. Dobrogosz. "Validation of the probiotic concept: Lactobacillus reuteri confers broad-spectrum protection against disease in humans and animals." Microbial ecology in health and disease 12.4 (2000): 247-285. 
• Curi, R., et al. "Effect of Stevia rebaudiana on glucose tolerance in normal adult humans." Brazilian journal of medical and biological research= Revista brasileira de pesquisas médicas e biológicas/Sociedade Brasileira de Biofísica 19.6 (1985): 771-774.
• Deniņa, Ilze, et al. "The influence of stevia glycosides on the growth of Lactobacillus reuteri strains." Letters in applied microbiology 58.3 (2014): 278-284. 
• Gardana, Claudio, et al. "Metabolism of stevioside and rebaudioside A from Stevia rebaudiana extracts by human microflora." Journal of agricultural and food chemistry 51.22 (2003): 6618-6622. 
• Jayaraman, Sathishkumar, Muthu Saravanan Manoharan, and Seethalakshmi Illanchezian. "In-vitro antimicrobial and antitumor activities of Stevia rebaudiana (Asteraceae) leaf extracts." Tropical Journal of Pharmaceutical Research 7.4 (2008): 1143-1149.
• Jones, M. L., C. J. Martoni, and S. Prakash. "Cholesterol lowering and inhibition of sterol absorption by Lactobacillus reuteri NCIMB 30242: a randomized controlled trial." European journal of clinical nutrition 66.11 (2012): 1234-1241.
• Konoshima, Takao, and Midori Takasaki. "Cancer-chemopreventive effects of natural sweeteners and related compounds." Pure and applied chemistry 74.7 (2002): 1309-1316.
• Lionetti, E., et al. "Lactobacillus reuteri therapy to reduce side‐effects during anti‐Helicobacter pylori treatment in children: a randomized placebo controlled trial." Alimentary pharmacology & therapeutics 24.10 (2006): 1461-1468.
• Shornikova, Aino-Vieno, et al. "Lactobacillus reuteri as a therapeutic agent in acute diarrhea in young children." Journal of pediatric gastroenterology and nutrition 24.4 (1997): 399-404.
• Singh, Sunanda. "Antidiabetic, Antidyslipidymic and Antioxidative potential of methanolic root extract of Stevia rebaudiana (Bertoni) on Alloxan induced Diabetic Mice Sunanda Singh and Veena Garg Department of Bioscience and Biotechnology, Banasthali Vidyapeeth, Banasthali, Rajasthan, India." (2014). 
• Tadhani, M. B., V. H. Patel, and Rema Subhash. "In vitro antioxidant activities of Stevia rebaudiana leaves and callus." Journal of Food Composition and Analysis 20.3 (2007): 323-329. 
• Thompson, Matthew P., and Razelle Kurzrock. "Epstein-Barr virus and cancer." Clinical Cancer Research 10.3 (2004): 803-821.

Stevia Increases Satellite Cell Recruitment and Ameliorates Insulin Resistance by Reducing NF-KappaB Mediated Inflammatory Response to Muscle Damage & High Fat Diet

Image 1: If you take a look at the number of studies on production and processing techniques related to stevia and stevia products, it becomes evident that the production of the traditional South American "sweet leaf" has already been seized by the usual subjects from the "food industry"

"Rats would buy Stevia rebaudiana!" I don't know about you, but personally, I would not advertise my product with this slogan, but if I did, I would at least have valid scientific data to support this claim... well, sort of, because I am not 100% sure where or even that rats even buy any sweeteners. Be that as it may, although Sclafani et al. were able to show that the preference their lab animals showed for stevia over saccharine was related to the activation of the sweet taste receptors (Sclafani. 2010), you could also make a point that the rodents might have "tasted" that there is more to Stevia rebaudiana than its insanely sweet taste (personally, I have been using stevia for ~6months, now, and had to get used to the taste initially), if you take a closer look at some of the more recent data on the potential health benefits of (allegedly large amounts of) steviosids, the major steviol glycosides from the leaves of the stevia plant.

Steviosids work via NF-kappaB by reducing inflammation

Assuming that you have followed the Intermittent Thoughts on Building Muscle series, you will be familiar with the notion that the recruitment of so-called satellite-cells, i.e. muscle-specific stem-cells, is an essential part of the repair process after exercise (or otherwise) induced muscle damage. You will also be aware that inflammation plays an important, albeit hitherto not fully elucidated role in this process and that it is after the initial inflammation is abating, when the macrophages start the actual (re-)construction process (cf. "Inflammation & Hypertrophy"). You will thusly maybe even less surprised than a group of Malayan scientists from the Mahidol University in Bangkok (Bunprajun. 2012), when they found that 10mg/kg of pure steviosids, of which previous studies had already shown that they are able to ameliorate stress-induced NF-kappaB (which is believed to be one of the master regulators of inflammatory responses) expression, did not only lead to the expected amelioration in NF-kappaB expression in cardiotoxin injected tibialis muscles of male rodents, but also increased the post-recovery increase in myo-D positive, i.e. newly recruited satellite cells.

Figure 1: Inflammatory response (left) and satellite cell recruitment (right) after cardiotoxin injection in tibialis muscle in rodents after pre treatment (7 days) and concomitant (7 days after the injury) treatment with vehicle (control) or 10mg/kg steviosids (data adapted from Bunprajun. 2012)

The initial NF-kappaB response, three days after the injection of a cardiotoxin into the tibialis muscles of the rodents was identical (cf. figure 1). After seven days, however, the NF-kappaB levels in the steviosid group, who received their daily dose of stevia 7 days before and in the 7 days after the injury, are significantly lower than in their vehicle (control) treated peers and correspond well with the profoundly increased number of myoD positive (fresh) nuclei in the stained tissue samples of the treatment group.

The same effects on NF-kappaB also help ameliorate diet-induced insulin resistance

With the increased recruitment of satellite cells being only part of a very complex repair process, and given the fact that the scientists did not find any significant difference in tibialis anterior mass, myofibrillar protein content, the number of central located nuclei, it is actually not surprising that the contractile function of the injured legs was still identical 7 days after this profound injury. For an athlete or any active individual this would probably mean a few weeks away from the gym, the court, the green, or the stadium and this in turn could precipitate weight gain, which brings up another nice "side effect" of the NF-kappaB suppressing effects of high dose stevia supplementation that has been recently established by Wang et al. (Wang. 2012).

Figure 2: Body weight gain, fasting blood glucose and insulin levels and glucose infusion response in rats after 4 months on regular or high fat diet (49%fat / 36%carbs / 15% protein) with or without 2x10mg/kg steviosids per day (data calculated  based on Wang. 2012)

As the data in figure 2 goes to show, the oral administration of stevisoids as 2x10mg/kg was able to ameliorate the negative effects 4 months of "high fat" feeding (49% fat / 36% carbs / 15% protein) exerted on body weight and glucose metabolism of previously healthy rats. With a +36% increase in serum insulin and a -19% reduced glucose infusion response (GIR) the rats in the HFD+stevia group were yet still significantly more insulin resistant than their peers on the regular diet - and the results also show that an increase in insulin sensitivity does not translate into a decrease in weight gain. As we are going to see in the course of the current Intermittent Thoughts series on insulin sensitivity, "ideally" the exact opposite should be the case.

Pounding stevia to stay healthy and gain muscle? Probably not the best good idea.

If we get back to my introductory remarks and the not really advertisable slogan "rats would buy stevia rebaudiana", the question that has to be answered now is: Would you buy stevia? I already told you that I do, but certainly not because of the aforementioned effects. I guess, I would probably die from over-sweetening (if there was such a thing), if I took the corresponding one to two "servings" of 1.6mg/kg (human equivalent of 10mg/kg for a rat) of pure steviosids on a daily basis... but all jokes aside, if you are looking for a healthy sweetener, there probably is no better option than stevia.

If you want to ward off insulin resistance, on the other hand, a "clean" diet with a reasonable amounts of carbs (unless you are diabetic ~100g, which as Beth /thx/ rightly pointed out would be way less than 30% of your total energy intake, is something everyone should be able to handle - and what's more, can help you perform better, keep energy levels and metabolism up and contrary to the contemporary anti-carb paradigm, eventually improve weight- and fat-loss), fats and protein in it should be your main concern. This is particularly important, because a combination of the latter with a reasonable workout routine, sufficient time to recover and a decent amount of quality sleep, will also make the use of stevia as a means to increase muscle repair obsolete,... at least as long as you are not attacked by mad Malayan scientist with a syringes full of myotoxins ;-)