Artificial sweeteners were designed to keep food and drinks' sweet taste while doing away with excess sugar's unwanted effects, such as weight gain, diabetes and metabolic syndrome.

Sweet tasting drinks without calories seemed like a win-win.

And off we went on this large-scale experiment, which sounded quite promising. But our body is a very complex machine, and simple calorie counts fail to predict what food inventions will do in our body, especially in the long run.

Obesity rates continued to rise, and studies started to indicate that diet soda might not assist with weight loss .

What was even more alarming was the emergence of evidence showing a connection between the consumption of diet soda and metabolic syndrome and type 2 diabetes ; another study showed that people who drank diet soft drinks on a daily basis were at increased risk of stroke, heart attack, and vascular death.

These counterintuitive results were a total surprise only to people who don't appreciate the intricacy of our biology.

Emerging explanations for the diet soda-obesity connection

Aspartame's downside

A new study helps explain why diet soda hasn't yielded the expected weight loss. The researchers, led by Richard Hodin from Massachusetts General Hospital, hydrated mice with aspartame, a sweetener commonly used in diet soda, and compared them to mice that drank plain water. The mice on the aspartame water gained more weight and developed metabolic syndrome.

Further experiments pinpointed the mechanism for weight gain. Aspartame breaks down to phenylalanine in the body, and phenylalanine interferes with intestinal alkaline phosphatase, a beneficial enzyme that helps prevent diabetes and metabolic syndrome.

The researchers demonstrated that when you add intestinal alkaline phosphatase to diet soda and regular soda in a test tube, the activity of this beneficial enzyme was significantly lower in the diet soda solution.

They then looked at the effect of aspartame in the intestine of living mice, and found the same effect inside the body: The mice given aspartame had low activity of intestinal alkaline phosphatase - the 'good' enzyme that fights obesity and metabolic syndrome.

Microbiome havoc

Another recent study , led by Eran Elinav, fed mice several commercially available sweeteners (saccharin - Sweet-n Low, sucralose - Splenda, and aspartame - Equal) and found that the mice developed glucose intolerance, a condition that is a forerunner of type 2 diabetes.

Further tests implicated an altered gut microbial flora as the reason.

When these sweetener-treated mice were given wide spectrum antibiotics the glucose intolerance went away. When the fecal bacteria of the sweetener-treated glucose intolerant mice were transferred to normal mice, they, too, developed glucose intolerance. Furthermore, the gut bacteria that dominated the sweetener-treated mice's gut are associated with type 2 diabetes in humans, and are involved in digesting and storing carbohydrates.

These are mice studies, though. Is this relevant to people?

The researchers also looked at 381 non-diabetic people, and found that using non-caloric sweeteners was associated with glucose intolerance, high glucose measurements and other signs of the metabolic syndrome. The volunteers that reported using non-caloric sweeteners had the same patterns of altered gut bacteria populations seen in the sweetener-treated mice.

Lastly, 7 people who don't usually use non-caloric sweeteners were fed the maximum recommended amount of Sweet-n Low for 7 days. In this very short time 4 of the 7 developed glucose intolerance, and showed alteration in the gut microbial population. When the gut microbes of these 4 people were transferred to mice, those mice developed glucose intolerance, too.

This study shows quite nicely that non-caloric sweeteners can alter gut microbes in mice -- a change that has negative metabolic consequences -- and provides preliminary evidence that it can happen in humans too.

Unexpected consequences

To further appreciate how complicated our handling of diet soda can be, here's another little example: Our intestine (or bowel) is covered with cells that secrete hormones. These cells react to the presence and composition of food by secreting peptides such as glucagon-like peptide 1 (GLP-1), peptide YY (PYY) and cholecystokinin - these names are not important - that work on the brain, signal satiety and control glucose by influencing the secretion of insulin. Guess what: Artificial sweeteners seem to not affect these hormones the way real food does.

So although at this point we can't be sure that diet soda directly causes obesity and metabolic syndrome, I think it's fair to say the experiment isn't going too well.

These latest studies offer a few fascinating mechanisms that can explain the link between diet soda and untoward outcomes.

An explanation, and perhaps also a lesson.

We have co-evolved with the traditional foods that come from nature; we have survived and thrived on them from the beginning of human time. They combine into endless possibilities - culinary boredom isn't even a possibility.

As much as I like technology, innovation and progress, food might not be the place to experiment with new materials. Replacing soda, a drink with nothing but empty calories, with a drink equally lacking in nutritional value but with calorie-free sugar substitutes, isn't likely to advance our wellbeing - both are silly inventions.

Dr. Ayala

Full disclosure: I co-founded Herbal Water, where we make organic herb-infused waters that have zero calories and no sugar or artificial ingredients. I'm also a pediatrician and have been promoting good nutrition and healthy lifestyle for many years.

This is a crosspost of my blog, Healthy Food & Healthy Living .