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Sweeteners and the Gut–Brain Axis

Sweets provide a quick rush but may lead to depression.

Key points

  • Sugar affects our gut microbes by promoting pathogens.
  • Pathogenic microbes can create a “leaky gut” leading to inflammation, which can lead to depression and anxiety.
  • Artificial sweeteners also have a negative effect on our gut microbes.

I love to eat Kit Kats or cookie ice cream. I need sugar like five times a day. –Kim Kardashian

If you're eating sugar throughout the day, you're spiking your blood sugar level and you're becoming a fat storing machine. –Jackie Warner

We’ll let social media queen Kim Kardashian and nutrition coach Jackie Warner fight this one out. One thing is for sure: There is a lot of conflicting information about sugar on the Internet.

 RossHelen/iStock
Sweets can evoke mixed feelings.
Source: RossHelen/iStock

Here’s the latest science: Sugar is delicious but sadly unhealthy in large doses. It has been implicated in type-2 diabetes, metabolic syndrome (also called insulin resistance), obesity, and cardiovascular diseases. It isn’t just sitting in the sugar bowl either. It’s in spaghetti sauce, breakfast cereal, sports drinks, and even supposedly healthy foods like yogurt and kefir.

Food manufacturers have mastered the art of adding sugar to everything, delighting our tongues but, it turns out, disturbing our gut microbes. By virtue of altering our microbiota, sugar—via the gut–brain axis—may contribute to depression and anxiety.

Our intestines are efficient at splitting sugar into its components, glucose and fructose. Sugar causes the pancreas to release insulin, which shepherds the glucose into our cells for energy. Excess glucose is stored as glycogen (the animal version of starch) and fat.

If we consume a large amount of sugar, it will overcome our pancreatic attempts to deal with it, and glucose levels will rise in our blood, as measured by the glycemic index. Foods that raise our glycemic index too high can damage our metabolism and microbiota. For instance, sugar promotes the growth of pathogenic bacteria such as the barely pronounceable Erysipelotrichaceae, a microbe associated with colorectal cancer and metabolic disorders.

Sugar and Fat

A study by Ivaylo Ivanov, Yoshinaga Kawano, and colleagues found that sugar can change our gut microbes, starting a chain reaction that leads to fat gain.

The story starts with beneficial microbes that attach directly to our gut lining and stimulate special immune cells called Th17. Besides their immune duties, Th17 cells also prevent lipids from being absorbed by our gut, helping to prevent metabolic disease, weight gain, and type-2 diabetes. But when we eat sugar, other bacteria come to dominate, and that interferes with the Th17 effect. We then start to absorb more lipids, neatly explaining how fat can be accumulated in response to sugar consumption.

Disruptions in the gut microbiota and Th17 cells can lead to “leaky gut,” where the gut becomes permeable enough to allow toxins and even bacteria to breach the lining and reach the bloodstream. From there, gut microbes can infect every organ in the body, leading to systemic inflammation. Almost every chronic disease can start like this, including heart disease, dementia, arthritis, type-2 diabetes, colon cancer, Alzheimer’s, and Parkinson’s. Scientists are starting to appreciate Hippocrates’s maxim that “all disease starts in the gut.”

So, if sugar isn’t good for us, what are our options?

Artificial Sweeteners

Up to half of Americans consume artificial sweeteners (the most widely used food additives in the world), specifically to regulate weight and lower their blood sugar levels. That sounds like a good idea, but is it borne out by research? The Food and Drug Administration has approved these common artificial sweeteners after thorough testing; however, it doesn’t consider their effect on the microbiome, and that effect may not be benign.

Small and sometimes conflicting studies over the years have linked artificial sugars to weight gain and inflammation. These studies are typically observational, so it can be tough to tease out cause and effect. It makes sense that people who are overweight may try to cut calories with lo-cal sweeteners, so do sweeteners cause overweight, or does overweight lead to sweetener consumption?

With this caveat in mind, a recent study by Charlotte Debras and colleagues discovered a correlation between artificial sugar and heart disease. The extra cardiac hazard these researchers found is less than 10 percent. Smoking, on the other hand, can double the risk of cardiovascular disease, so some perspective is warranted. A small extra risk might be tolerable if these sweeteners could minimize metabolic syndrome.

Sweeteners and Metabolic Syndrome

So, it is sadly ironic that a new study by Jotham Suez, Eran Segal, Eran Elinav, and colleagues has found artificial sweeteners may exacerbate metabolic syndrome via gut microbes.

For this study, they gave volunteers artificial sweeteners at a rate lower than typical usage. The researchers found certain (but not all) artificial sweeteners alter the populations of gut bacteria and enhance their pathogenic potential. In particular, saccharin and sucralose alter gut microbes negatively, significantly impairing the glycemic response. This left many of the subjects with stubbornly high blood-sugar levels. Over time, this can lead to metabolic syndrome and, ultimately, type 2 diabetes.

Not everyone in the study was affected equally. Those with the least change in glucose response also had the least change in microbiota. That means that for some people, artificial sweeteners are just fine. When it comes to the microbiome, we’ve come to expect this kind of person-to-person variation, which is vexing for statisticians.

The effect was likely causal, as demonstrated by a fecal microbial transplant from the human subjects to mice. After the transplant, the mice had glycemic responses largely reflecting those of their human donors. In other words, metabolic syndrome can be transmitted by gut microbes. Studies like this, although fairly small (120 adults), are fascinating because they show microbes can transmit a trait and that it can work across species.

Sweeteners and Depression

Similar studies have shown that fecal microbes can transmit depression from humans to mice as well. Depression is often a fellow traveler with metabolic syndrome, obesity, and diabetes. So, if artificial sugars are affecting glucose response and metabolism, they may contribute to depression as well.

Metabolic syndrome is a neuroendocrine disorder, with involvement by both the brain and hormones. It involves the hypothalamic–pituitary–adrenal (HPA) axis, which kicks in when you’re stressed, like when running from a lion. It dials down other lesser concerns, like our sex drive, while we’re trying to avoid becoming lunch. Depression, with its rejection of enjoyment, is thus a reasonable response to stress.

But chronic stress, as with an overbearing boss, can become pathological. Our gut microbes can affect our HPA axis with various secretions both hormonal and neuronal. That gives them a shocking amount of leverage over our biology, and artificial sweeteners appear to manipulate that leverage.

This is pretty bad news, but all is not gloom. My next post will explore some new alternatives to sugar and artificial sweeteners that may actually be good for you. Don’t lose hope!

References

Kaakoush, Nadeem O. “Insights into the Role of Erysipelotrichaceae in the Human Host.” Frontiers in Cellular and Infection Microbiology 5 (2015).

Kawano, Yoshinaga, Madeline Edwards, Yiming Huang, Angelina M. Bilate, Leandro P. Araujo, Takeshi Tanoue, Koji Atarashi, et al. “Microbiota Imbalance Induced by Dietary Sugar Disrupts Immune-Mediated Protection from Metabolic Syndrome.” Cell 0, no. 0 (August 29, 2022).

Debras, Charlotte, Eloi Chazelas, Laury Sellem, Raphaël Porcher, Nathalie Druesne-Pecollo, Younes Esseddik, Fabien Szabo de Edelenyi, et al. “Artificial Sweeteners and Risk of Cardiovascular Diseases: Results from the Prospective NutriNet-Santé Cohort.” BMJ 378 (September 7, 2022): e071204.

Suez, Jotham, Yotam Cohen, Rafael Valdés-Mas, Uria Mor, Mally Dori-Bachash, Sara Federici, Niv Zmora, et al. “Personalized Microbiome-Driven Effects of Non-Nutritive Sweeteners on Human Glucose Tolerance.” Cell 185, no. 18 (September 1, 2022): 3307-3328.e19.

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