But I love my no-calorie artificial sweetener!

For one brief moment, I lost my perspective. I forgot to wear my magic scientific glasses and take a hefty shot of skepticism before glancing at the news headlines dancing across my computer screen. I suddenly felt compelled to throw my favorite type of diet soda across the room (and I really love Coke Zero), toss out my beloved low-fat yogurt made with non-calorie artificial sweetener, collapse in my kitchen and weep about what in the hell I was going to snack on at 3:00 PM when I got really hungry and a little tired.  

You may know what I mean. You might have seen the headlines sometime over the past 12 days.

Headline news

An article was recently published in Nature about artificial sweeteners, microbiota, and glucose intolerance. Here are just a few of the many news articles that I found covering this topic (all accessed on September 18, 2014): 

• Science20.com
• Esciencenews.com
• National Post 

I was hooked by the topic and the titles. But my interest was piqued because the online articles I initially found did not provide a link or even a reference to Nature where the actual original research article was published on September 17, 2014. Instead, all of the articles provided a link to a place I'd never heard of called the Weizmann Institute of Science. This is, apparently, where the researchers work. It is not common practice for journalists reporting on research to only link to the research institution and not provide a link or at least a reference to the actual published research. 

In hot pursuit of the primary research article, I followed the link to the Weizmann Institute of Science and ended up at institute's home page. After selecting "News and Media," I was able to find some information about the specific research topic at the Weizmann Institute of Science - News & Media - Gut Bacteria, Artificial Sweeteners & Glucose Intolerance (accessed on September 18, 2014 and then again on September 29, 2014). The article I found at the institute's web page was a public relations piece about the research. On September 18th, the posting mentioned that the research paper was published in Nature, but there was no way of actually getting to the journal article from the institute's page. 


Not yet willing to admit defeat, I pushed onward. I marched six blocks over to the public library. Once there, I found out that the current year of Nature is only available in print, and that my local library was a little behind (about a week) getting journals processed and out onto the shelves. 

"San Diego Central Library" by Nserrano - Own work. Licensed under Creative Commons Attribution-Share Alike 3.0 via Wikimedia Commons 




I left the beautiful public library feeling a bit frustrated, but still not defeated. I kept searching and eventually got a copy of the article. I won't say how. As of September 29, 2014, I can report that there is an active link to the peer-reviewed journal article in Nature on the Weizmann Institute of Science website through the News & Media section.

I also came across a promotional article at Nature.com (accessed September 29, 2014). I don't know for sure, but I am willing to guess that this is the post that led to the media frenzy.

What does "microbiota" mean?

• Microbiota refers to microorganisms living in a particular site, such as the gut. 

• Sometimes, microbiota in the gut are referred to as commensal flora or commensal bacteria. 

• Microbiome is a term that refers to the genetic composition of microorganisms in a given environment such as the gut. 

It is an exciting time for scientists involved in the field of gut microbiota research. There is a lot to discover, learn, and explore (in other words, we don't know very much).

They are what we eat. And drink. And otherwise ingest.

What we eat and otherwise ingest influences the profile of our gut mircobiota. This includes food, beverages, air, dietary supplements and drugs. As you might imagine, there is tremendous diversity among people when it comes to intestinal microbiota. The development of microbial diversity starts at the time of birth and continues to develop throughout life. 

Research in this field focuses on understanding how microbiota may or may not impact human health and wellness, metabolism and immunity. Emerging research indicates that some diseases may be associated with decreased microbial diversity in the gut (1,2). It may be that balance of bacteria shifts or becomes skewed in unique ways with different conditions and diseases. Which comes first (the disease or the change in the gut microflora) is unknown. 

I am particularly fascinated by research that investigates whether or not differences in microbial composition influences the risk for over-eating, gaining weight, developing insulin resistance and developing type 2 diabetes. Some research suggests that there may be metabolic consequences associated with changes in the microbial composition of the intestines. Why this happens and what may facilitate these changes is, as I've said, not clear. The Suez article in Nature suggests that high saccharin intake under different dietary conditions (such as in the presence of a high fat diet) is associated with altered gut microbiota and impaired glucose tolerance (3).

Resources:

1) Khanna, S., & Tosh, P. K. (2014). A clinician's primer on the role of the microbiome in human health and disease. Mayo Clin Proc, 89(1), 107-114. doi: 10.1016/j.mayocp.2013.10.011

2) Russell, W. R., Duncan, S. H., & Flint, H. J. (2013). The gut microbial metabolome: modulation of cancer risk in obese individuals. Proc Nutr Soc, 72(1), 178-188. doi: 10.1017/S002966511200288 10.1038/nature13793

3) Suez, J., Korem, T., Zeevi, D. et al. (2014). Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature, advance online publication. doi: 10.1038/nature13793

Will I become glucose intolerant or diabetic because I consume non-caloric artificial sweeteners?

The short answer - no. At the time of this blog post, nothing in the scientific literature proves that consuming non-caloric artificial sweeteners causes obesity, weight gain, insulin resistance, glucose intolerance, or type 2 diabetes. Scientists specializing in this area of research are diligently working to understand about gut microbiota. With the publication of their manuscript, Suez et al. (2014) contributed their novel and unique findings to this growing body of knowledge regarding the microbiome, diversity, and metabolic health. These are still early days in this field of research. 



Insulin resistance and type 2 diabetes


The factors behind the development of insulin resistance (glucose intolerance) and type 2 diabetes are complex. Research supports the role of excess body weight and particularly excess body fat as important factors that contribute to what is known as low-grade inflammation. This type of inflammation differs from the kind that produces swelling and fever. Low-grade inflammation results in the production of small but significant amounts of specific proteins and chemicals that can act in local areas or travel throughout the entire body to exert their inflammatory effects. Some of these molecules lead to the inability of cells to respond properly to the hormone insulin. Over time, this leads to insulin resistance and, in genetically susceptible people, contributes to the development of type 2 diabetes.

After we eat a meal (particularly one that contains carbohydrates), this is what happens when everything is working properly.

• Insulin is produced in the pancreas by cells called beta cells. 
• Beta cells release stored insulin as well as newly made insulin. Insulin travels from the pancreas out into the blood. 
• Meanwhile, in the small intestine, the body breaks down bigger carbohydrates into smaller units.
• Insulin binds to insulin receptors on cells throughout the body.
• The action of insulin binding to the insulin receptor triggers a signal within the cell.
• This signal tells the cell glucose is available for pick-up and use.
• To pick-up glucose, glucose receptors (called glucose transporters) move to the surface of the cell so that it can “grab” glucose from the blood and bring it into the cell.
• Cells will use the glucose for energy right away or store it for later. 
• Muscle and liver cells can store glucose as glycogen.
• Other cells, mostly fat cells called adipocytes, store excess glucose as triglycerides (fat).

In insulin resistance (glucose intolerance), the process gets messed up because cells become desensitized to the insulin signal. The insulin signal is blocked and this is what happens:

• Cells don't get the message that glucose is in the blood.
• Glucose transporters fail to migrate to the surface of the cell. Without glucose transporters present at the cell surface, glucose is unable to enter the cell.
• Cells become "hungry" because they are running low on energy. Cells that can't pick up glucose have to start using alternative fuel sources for energy.
• Meanwhile, the blood is "stuffed" with glucose. Blood glucose levels are rising because not enough cells are picking up glucose.
• Over time, elevated glucose in the blood damages blood vessels, capillary walls, etc. 

Scientists do not yet understand the role of gut microbiota with regard to insulin resistance and type 2 diabetes. That is why Suez and colleagues (2014) conducted their research. Other researchers have found that people with type 2 diabetes have a different microbial balance than people without type 2 diabetes.

Non-caloric artificial sweeteners

These sweeteners were originally developed and marketed to enhance the diet of those individuals who, for medical reasons, needed to restrict their intake of carbohydrates. These sweeteners add flavor to food without contributing carbohydrates and calories. Non-caloric artificial sweeteners do not require carbohydrate digestion, so consuming them does not raise blood glucose levels and therefore does not require insulin to trigger the removal of glucose from the blood. This is why these sweeteners are an appealing alternative for people with diabetes.

It was not expected that the use of non-caloric artificial sweeteners would coincide with increased prevalence of obesity. To be fair, lots of things track with increasing obesity rates in the United States including decreased physical activity, suburban sprawl, sedentary lifestyles, fast-food consumption, portion-distortion (increased portion sizes), etc. 

At this time no evidence exists to support the assertion that consuming artificial sweeteners causes obesity, glucose intolerance, or type 2 diabetes. 

«Tab can» de lokate366 - originally posted to Flickr as tab can. Disponible bajo la licencia Creative Commons Attribution-Share Alike 2.0 vía Wikimedia Commons.

The research article about non-caloric artificial sweeteners, microbiota and glucose tolerance

The authors of this paper (Suez J, et al. 2014) investigated how artificial sweeteners impact the gut microbiome and how this may contribute to the development of glucose intolerance (insulin resistance). The researchers conducted a variety of interesting experiments with mice and humans (a very, very small group of humans). They also examined preliminary data from an ongoing clinical trial and found that people with metabolic health issues also reported using non-caloric sweeteners.  

Below are links to two well done articles that summarize and discuss this research study:

•  Steven Novella, NeurlologicaBlog wrote a good article about the research, its strengths and limitations, and the importance of keeping these results of this work in perspective (accessed September 29, 2014). 

• Salynn Boyles at MedPageToday provides a thoughtful, insightful and informative article about this research paper.
• Boyles' article also underwent a review process.
• I appreciate that this article was not posted until September 22, 2014 and revised once on September 23, 2014. This reflects that time and care went into researching and writing it. 

Since the links above provide detailed summaries of the research, I am gong to highlight a few aspects about this study that I find important to keep in mind.

• Non-caloric artificial sweeteners:
• The researchers started out investigating the effect of three different non-caloric sweeteners (saccharin, sucralose, and aspartame). The bulk of the research, however, only focused on saccharin.
• After the first set of experiments, the authors choose to continue with only one sweetener. They selected saccharin because mice drinking saccharin supplemented water had the poorest glucose response of the three sweetener supplemented groups. 
• I understand the need to scale back a larger project to a more manageable one for logistic and/or financial reasons. This was an interesting study with some pretty involved experiments. 
• That said, I disagree with the decision to deviate from the original study design. The difference that informed their decision to use saccharine was based on data that were were statistically significant but perhaps not biologically relevant. 
• It is not unreasonable to expect different responses with different sweeteners as they chemically differ from one another.
• From a dietary perspective, I question the choice of saccharin (i.e. Sweet 'N Low) over aspartame (i.e. NutraSweet) and/or sucralose (i.e. Splenda), because saccharin containing products are less common among ready-to-eat foods and beverages compared to the other choices. 

• These researchers used the FDA acceptable daily intake (ADI) values to calculate safe dosage levels for all three non-caloric artificial sweeteners. 
• ADIs are determined through laboratory research.
• An ADI is a level deemed safe to consume every day throughout one's lifetime. ADIs are not recommendations or goals to achieve.
• In the research world, the work presented in this paper provides some evidence of what may happen in extreme conditions. These are not real-world conditions: 
• The ADI for saccharin is 5 mg of saccharine for every kg of body weight. An adult weighing about 150 lbs (68 kg) would need to consume around 9-12 packets of saccharin (powdered form) to come close to reaching the ADI. That is a lot of saccharin.
• To reach the ADI for aspartame  (50 mg/kg body weight), a 68 kg adult would have to drink about 14-19 cans of aspartame containing diet soda or use 80 packets of Equal before reaching the ADI. There are not enough hours in the day for that.
• The ADI for sucralose is 5 mg/kg body weight. Estimates for this intake are a bit more conservative and it may take about 6 cans of diet soda made with Splenda for our 68 kg adult to reach the ADI.
• When thinking about the real-world impact of these results, keep in mind that it is incredibly unlikely that anybody is ever going to consume that much artificial sweetener. 

• Diet design
• Whenever a diet study is conducted, the details of the diet should be provided in the paper or supplementary material. 
• The type of fat used in rodent diets can strongly influence metabolic outcomes. Some types of fat promote inflammation while other types of fat are less inflammatory or even anti-inflammatory. After reading this paper, I do not know what type of fat was used to make the high fat diet.
• Control diets and experimental diets require careful design to make sure that the parts that are adjusted or are different are the dietary components of interest. The differences that exist between control and experimental diets should be specific, explainable, and designed to test the researchers' hypothesis. 

Resources:

Suez, J., Korem, T., Zeevi, D. et al. (2014). Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature, advance online publication. doi: 10.1038/nature13793

Pollard JM and Bielamowicz MK. Sugar Substitutes - Weight loss, diabetes, safety, nutrition? Health Hints. April/May 2010; Vol. 14, No. 4, 5. htttp://fcs.tamu.edu/health/healthhints/2010/may/  (Accessed September 29, 2014).

Final comments

The results of this study did not lead to an immediate cure for any type of cancer, an invention that will stop world hunger or resolve a war. Nothing late-breaking, earth-shattering, blow-your-mind amazing, or change the world immediately comes out of this one study. I don't want to diminish, minimize or marginalize the quality and quantity of work that went into this study. It is a lot and overall, I think that they did it well. 

I am, however, baffled by the onslaught of attention this one study received. This one study that focused on the impact of saccharin on gut microbiota. Within minutes to hours of this paper first being published, online writers posted about it. It took me a long time to get through this paper and I'm still not clear on a few points. There is simply no way that the majority of people who initially reported on this research could have attempted to read the paper. I have a problem with that. Many people who wrote news articles about this research did not try to find a citation for the primary published source. 

I still struggle to understand why this particular article received so much attention. Really, only scientists working on gut microbiota should get excited and worked up over this paper at this time. Maybe nutrition students in graduate school should discuss this article during journal club. But that is it. My third cousin on my mom's side of the family who recently started working out and watching what she eats should not suddenly start panicking about her use of non-caloric artificial sweeteners and focusing on what is living in her intestine. Well, unless of course she a tapeworm infection.