Humans are eating more fructose than ever and it’s becoming problematic — not just for our widening waistlines but for our brains, mounting research suggests.
Through most of human history, honey and fruits provided the primary source of fructose. Both were scarce: honey harvesters braved buzzing colonies of stinging bees, while many of our favorite fruits did not exist in their current sugary forms.
However, many people cannot properly digest this now-all-too-common sugar – and consumption has increased. Historically, we consumed less than 5g of fructose a day, but current consumption levels are in the 50-80g per day range in developed countries. More alarming still, over the past few decades numerous human studies and animal experiments have suggested an association between fructose malabsorption and anxiety and depression symptoms. Yet this essential gut-brain axis remains enigmatic.
Now, a unique new study published in Brain, Behavior and Immunity, has again explored the effects of fructose malabsorption in both humans and mice and provided a possible explanation for the link between the sugar and emotional states.
Of mice and men
On the human side, the study followed a group of 55 healthy male volunteers, aged 18 to 35, with a BMI below 25 and without gastrointestinal, psychiatric, or neurological conditions.
Participants ingested 35 grams of fructose and underwent a breath test. Exhaled hydrogen and methane concentrations in their breath revealed that 60% were fructose malabsorbers. The participants then kept a seven-day food diary at home, documenting all food sources consumed during that week.
They also completed two questionnaires to evaluate potential mood disorders. The State-Trait Anxiety Inventory (STAI) assessed anxiety traits like nervousness and apprehension, while the Hospital Anxiety and Depression Scale (HADS) measured pathological anxiety and depression.
The researchers then collected stool samples from the participants to perform a microbiota (gut microbe) analysis, as well as blood samples to analyze proteins and other compounds linked to bodily inflammation.
In parallel, this work featured a mouse model. It included normal mice and mice that were genetically engineered to exhibit fructose malabsorption. The engineered mice were further split into two groups: one group received a fructose-laden diet, while the other did not.
The mice were put through two physical tests to study stress. First, they spent 5 minutes in the elevated plus maze (EPM), a plus-shaped maze with two open arms and two enclosed arms — a common laboratory assay for measuring anxiety-like behavior in animals.
Subsequently, the researchers conducted a 6-minute forced swim test (FST), placing the mice in a tank of water and recording how much time they spent swimming versus floating. Finally, the researchers extracted brain samples as well as DNA from the large intestines of the mice.
Analyzing gut-brain changes
The human participants and the mice both showed physical and biological signs associated with increased anxiety symptoms. In both cases, the researchers found, anxiety was associated with an unbalanced intestinal bacterial ecosystem and the presence of inflammation
Notably, the human malabsorbers displayed “significant differences” in the relative abundance of five types of gut bacteria: agathobacter, bifidobacterium, prevotella, enterococcus, and zhenpiania.
They also displayed a “slight but significant increase in anxiety state,” as measured by the STAI questionnaire, without reaching pathological levels.
Intriguingly, the researchers found that the abundance of certain microbes was positively associated with different fructose sources, such as dairy products, beverages, or the added sugars from sweets.
Other microbe populations were negatively correlated with fructose sources, such as those from fruits and vegetables. These microbes may also be associated with anxiety-like symptoms, perhaps by producing inflammation-inducing metabolites.
The mouse-based findings seemed to support these trends, as fructose-malabsorbing mice had noticeably different gut microbe abundances. These changes seemed to correlate with inflammation and changes in inflammation-modulating genes in microglia, the brain’s immune cells.
The overall gut-brain mechanism may hinge on “metabolites released from the microbiota which would reach the brain to impact microglia physiology,” corresponding author Xavier Fioramonti, a metabolism and cognitive sciences researcher at French National Institute for Agriculture, Food, and Environment (INRAE), told Refractor.
“Whether it induces neuroinflammation per se, we cannot say. We can only say that microglia seem impacted.”
New avenues for alleviating anxiety-like symptoms
“Clinical and pre-clinical data from this study show that fructose malabsorption is associated with alterations in gut microbiota, elevated markers of systemic inflammation and increased anxiety-like behavior,” the researchers conclude, though they note some study limitations.
First, the small study size and its inclusion of only male participants and male mice. Second, the study was observational rather than interventional, so the researchers could not exclude fructose from the human cohort, as they did for mice.
Overall, these findings hint that determining a “definitive microbiome signature” for anxiety and depression, if possible, could help guide therapeutic strategies.
“One future direction is to study the possible direct effect of fructose on the brain to determine whether the combination of a direct and indirect impact of high fructose intake can impact the brain to trigger anxiety-like symptoms,” Fioramonti told Refractor.
It may also be prudent to explore the nature of “bad fructose,” Fioramonti adds, in order to “determine whether consuming fructose from soda is more deleterious than consuming fructose from fruit.”
