Two newly published studies build on a compelling growing body of evidence linking depression with mechanisms in our gut. A fascinating study led by researchers at the Columbia UniversityIrving Medical Center found that low levels of serotonin, a neurotransmitter associated with depression, can directly result in gastrointestinal distress such as constipation, while a second study, from the Children's Hospital of Philadelphia, discovered that transplanting gut bacteria from a mouse with depressive behavior to a healthy mouse, can also result in the transfer of those depressive behaviors.

Inside our gastrointestinal tract is a massive mesh of neurons.It's the largest collection of neurons found in the body outside of the brain, and because of its ability to operate entirely independently it has often been referred to as our "second brain." These gut neurons are thought to produce up to 90 percent of the serotonin used in the body.

Gastrointestinal disorders are commonly reported by patients suffering major depression. While we know that low levels of serotonin can affect a person's mental health, it is unclear whether this important neurotransmitter also plays a role in our digestive system. A new study suggests low serotonin levels could be causing both gut and brain disorders.

"The gut is often called the body's 'second brain,'"says study leader Kara Gross Margolis. "It contains more neurons than the spinal cord and uses many of the same neurotransmitters as the brain. So it shouldn't be surprising that the two conditions could be caused by the same process."

To study this connection between serotonin and the gut, researchers examined a mouse model engineered with a genetic mutation that results in major depression by impairing serotonin production. It was discovered depleting serotonin production caused notable disruptions to the animal's gastrointestinal tract, including a reduction in gut neurons and a slowing in the movement of contents through the gut.

"Basically, the mice were constipated and they showed the same kind of GI changes we see in people with constipation," says Margolis.

Even more importantly, it was revealed that a new experimental treatment, originally developed to target depression, also worked to raise serotonin levels in the gut and improve constipation symptoms.The drug is a new slow-release formulation of 5-HTP, a precursor molecule that is converted into serotonin when ingested.

GI contractions in mice with a serotonin deficiency in their neurons; untreated (left) and treated with slow-release 5-HTP (right) Kara Margolis

This intriguing connection between depression and the gut has also been affirmed in a different study, recently published in the journal Molecular Psychiatry. This research set out to examine whether microbiome changes in the gut could alter an animal's mental health. Compelling prior work has found interesting associations between certain species of gut bacteria and major depression. In fact, one strange study from earlier this year suggested symptoms of schizophrenia could be transferred from oneanimal to another simply through a fecal transplant.

In a collaboration between the PerelmanSchool of Medicine at the University of Pennsylvania and the Children's Hospital of Philadelphia, the new study explored how chronic exposure to stress can alter an animal's microbiome,causing depressive behavior, and how these behavioral characteristics can then be transferred to healthy animals via a microbiome transplant.

"In rats that show depressive-type behavior in a laboratory test, we found that stress changes their gut microbiome – the population of bacteria in the gut," explains study leader Seema Bhatnagar, from the Children's Hospital of Philadelphia. "Moreover, when we transplanted bacteria from those stress-vulnerable rats into rats that had not been stressed, the recipient animals showed similar behavior."

This study also found that brain inflammation increased in the healthy animals following the transplantation of a microbiome from astressed donor. This suggests certain gut bacteria has the ability to modulate inflammatory reactions in the brain.

Interestingly, it was observed that the microbiome transplants only induced depressive-type behaviors in the recipients and not anxiety-type behaviors. The researchers hypothesize this result points toward a mechanistic distinction between the causes of depression and the causes of anxiety, and that depression may be more influenced by gut bacteria.

"Although much more research remains to be done, we can envision future applications in which we could leverage knowledge of microbiome-brain interactions to treat human psychiatric disorders,"says Bhatnagar.

While both studies are still only proven in animals, there are plans to move forward with human trials for the serotonin research, exploring whether the new 5-HTP formulation effectively treats both depression and constipation.It's early days, and much more work is needed before these discoveries are translated into clinical treatments, however, the growing consensus seems to be that mental health issues such as depression may not be just in your head, and the second brain in your gut may play a big role in future treatments.

The serotonin/5-HTP study was published in the journalGastroenterology.

The microbiome transplant study was published in the journalMolecular Psychiatry.

Sources: Columbia University Irving Medical Center, Children's Hospital of Philadelphia

