How diet and gut bacteria may point to new treatments for depression

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A diet high in the amino acid proline has been linked to a higher prevalence of depression. Guillermo de la Torre/Stocksy
  • Antidepressants are often one of the first lines of treatment for depression, but they may have side effects or may not work for many people.
  • Research has attempted to establish whether modifying one’s diet may have an effect on combating depressive symptoms.
  • New findings suggest that some people with high levels of the amino acid proline in their diet may experience more severe depression, but much of that depends on a person’s microbiome.

Around the world, some 280 million people, or 5% of the adult population, suffer from depression. The World Health Organization has called it a “leading cause of disability in the world”. Currently available treatments such as antidepressants and behavioral therapies are effective for many people but are not suitable or accessible to everyone.

Some research has suggested that diet can have an impact on depression. A diet high in processed foods has been associated with more severe symptoms, while eating more fresh, plant-based foods may reduce symptoms.

However, a study published in Cell metabolismsuggests that the severity of depression can be influenced by a specific amino acid – proline.

Research also indicates that a person’s gut bacteria can affect how this amino acid is processed and how it can counteract its depressive effects in some people.

The researchers used a multi-omics analysis approach – an integrated analysis of many different molecules. They controlled for antidepressants and anxiolytics in their sample.

First, they analyzed the type and amount of amino acids in the diets of people taking part in the study. They also analyzed blood plasma and feces samples from the participants.

Those who had a higher level of proline in their diet reported more severe depression.

Proline can be metabolized into GABA, a neurotransmitter thought to help fight depression. However, high levels of proline can disrupt GABA production.

Participants who reported more severe depression also tended to have higher plasma proline levels, suggesting that the proline in their diet was not metabolized efficiently.

Some people with high proline intake have not reported worsening of symptoms. The researchers found that these people had lower plasma proline levels.

By analyzing their gut bacteria, they found that their microbiota was similar to that of participants reporting low levels of depression.

Gut bacteria in people with high proline intake and low levels of depression contained species involved in proline transport and metabolism.

“Without a doubt, the microbiome affects proline levels, but what levels and how it affects mood/depression or other aspects of the body needs to be determined.”

– Dr. John Tsai, Austin Gastroenterology Board Certified Gastroenterologist

To test their theory, the researchers transplanted fecal samples from study participants into mice. Mice that received the microbiota of more depressed participants with high levels of proline showed behaviors associated with depression.

To further test the effect of proline, the researchers isolated the gut bacteria they thought might make a difference.

They found higher levels of Bifidobacterium in participants with fewer depressive symptoms as well as certain strains of Lactobacillus. Another intestinal bacterium, Enterobacterwas associated with more severe depression.

They gave food containing Lactobacillus or Enterobacter to fruit flies (Drosophila melanogaster). The flies given the Lactobacillus were much more motivated to eat and climb than those who Enterobacter.

In their latest experiment, the researchers genetically modified flies so that proline could not be transported to the brain – these flies were found to be highly resistant to depression.

Dr. Tsai, however, said he was unconvinced by the study’s findings.

“I think this study is interesting but has many limitations in the study design as well as extrapolation of the results from mice/flies to humans. There may be a correlation, but this study falls far short of proving the causation,” he said.

“I think the most interesting aspect of this study came from the fruit flies and how the proline channels in their brains adapted. The use of proline-rich or proline-depleted foods in the man and functional PET of the brain (especially the prefrontal cortex and hippocampus) can be a very interesting study to consider,” he added.

Researchers suggest that proline-restricted diets may be effective in reducing depressive symptoms.

Alternatively, they suggest that adjusting the microbiome to contain higher levels of bacteria that metabolize proline, thereby reducing the amounts reaching the blood plasma, may be a route to treating depression without altering diet.

“I don’t think there’s enough here to directly link dietary proline levels to depression based on this study. It’s worth investigating more diligently with a randomized, controlled, prospective human experiment and double-blind,” Dr. Tsai concluded.


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