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You Are What You Eat: How Gut Health May Correlate with Depression

by Riya Sharma

The gut has more nerve cells than anywhere else, second only to the brain. An evolutionary perspective highlights that the gut and brain are closely interconnected because our survival has long depended on consuming nutrient-rich foods while avoiding toxic substances. Although there is no doubt that it’s beneficial to us, there may be another result of our gut and brain’s crosstalk.   

Depression affects 264 million people worldwide, making it one of the leading causes of disability. Symptoms include difficulty focusing, loss of interest, appetite, and impaired sleep. Although the exact cause is unknown, research suggests that there are lots of contributing factors that could be biological, psychological, or social. Some studies think it is low levels of brain-derived neurotrophic factor. Some believe it may be hypothalamic-pituitary axis (HPA) malfunction. Others hypothesize that it’s serotonin system dysregulation or structural brain abnormalities. The list could go on, but more recently, the gut has been considered another potential cause.  

The enteric nervous system (ENS) operates from the gastrointestinal tract as the third division of the autonomic nervous system. The ENS carries out bidirectional communication, and is considered the second brain because of its 500 million neurons. However, your gut microbiome, composed of billions of bacteria, is just as important because it is responsible for your ENS development. One study by Dr. Yuuki Obata provided evidence that germ free mice—those that are lacking a microbiome—have fewer ENS neurons than control mice with microbiomes (Obata). These microorganisms are quick to inhabit your digestive tract, taking residence within days of birth (Obata). Together, the microbiota and ENS play an influential role on the brain: modulating sympathetic neurons, maturing the endocrine system, and influencing neurotransmitter synthesis.  

The result of this ENS influence could tell us more about depression. One of the first promising findings was a study, conducted by Dr. Jane Foster, connecting the gut to the proper HPA axis function (Foster). The HPA axis is responsible for your stress response. The hypothalamus releases corticotropin releasing hormone (CRH), which triggers adrenocorticotropic hormone (ACTH) release in the anterior pituitary. ACTH then signals for cortisol release from the adrenal glands, which affect your appetite, sleep, and blood pressure—functions also disrupted by depression, which is why stress is often added to the suspect list. A dysregulated HPA axis has been associated with depressive symptoms that resolve once homeostasis is restored. The scientists conducting this study tied in the gut bacteria by measuring ACTH response in germ-free mice placed under stress. Results showed that following a stressor, there was a greater release of ACTH in the germ-free mice compared to the healthy mice. Dr. Foster also found that elevated levels of corticosterone, a hormone involved in stress response, returned to baseline after treatment with probiotics. The combination of these findings— along with the fact that the mature stress response develops at the same time as the bacterial colonization of the gut— supports the idea that the gut microbes are necessary for proper HPA development and therefore healthy stress responses (Foster).  

An even more well-known theory is that decreased serotonin is associated with depression. Adding to the evidence in support of the connection between the gut and depression, it is important to note that epithelial cells in the gastrointestinal tract produce a majority of the body’s serotonin (Legan). Germ-free mice also have had an increased rate of serotonin turnover and expression of serotonin receptors in the brain (Foster). In the past ten years, there has been an increase in skepticism surrounding this theory (Moncrieff); though, selective serotonin reuptake inhibitors (SSRIs) remain one of the most common medications used to treat depression.  

In addition, intestinal permeability is increased during stress due to hormonal interactions. This allows bacteria to travel across the membrane and directly interact with the ENS, and by association, the brain. This pathway further implicates them as a potential cause of depression (Foster). The electrophysiology of the ENS is also altered in germ-free mice; electroencephalogram recordings show decreased excitability until the germ-free mice are inoculated with the microbiota of the healthy mice or are fed probiotics (Foster).  

More physical evidence is found in microbiota composition, which varies in those with depression. There are five prominent phyla of bacteria in the gut, but the two most common are Bacteroidetes and Firmicutes. These are found in elevated levels in those with irritable bowel syndrome (IBS), a comorbidity of depression (Zhu). Another study from Dr {BLANK} Zhu showed that transferring the feces from depression patients into healthy mice causes depression-like behaviors: increased anxiety activity, metabolism dysfunction, and decreased happiness (Zhu). 

Following the results of these animal studies, researchers have moved on to conducting studies in human subjects. A double blind and placebo controlled study found that the consumption of probiotics by healthy patients for at least three weeks resulted in improved scores on depression questionnaires (Foster).  Assuming healthy patients’ scores differ from those with depression, the results are still promising and give researchers some direction on developing treatments.  

Current treatments for depression include therapy and medications, often SSRIs or monoamine oxidase inhibitors. This doesn’t help the 35% of patients who have treatment-resistant depression, and even the ones who can take the medications are only offered symptom alleviation. In fact, patients can build tolerance and medication can become less efficacious with long-term use (Zhu). Overall, the effectiveness of SSRIs varies person to person, highlighting the need for new treatment options. Seeing how the gut bacteria potentially play a huge role, diet changes as a treatment for depression are being considered. More research is needed to validate whether the differences are significant, but patients have reported antidepressant effects of prebiotics. Another option is engineering bacteria that produce antidepressant-like metabolites. Both of these are promising options, but there is another potential treatment that is starting to be tested: fecal microbiota transplants (FMT) (Zhu).  

Although we’ve spent this article discussing how the gut microbiome could play a role in causing depression, FMTs can provide the  microscopic bacteria a chance for redemption. The principle behind it is that we know healthy people have a good gut microbiome, and those bacteria may also be present in their feces. By transplanting the fecal matter to the gut of someone without a healthy microbiome composition it could induce the flourishing of healthier bacterial populations. There are a few different ways in which FMTs can be done: enemas, endoscopies, or capsules.  

In an animal study, a FMT from healthy to stress-induced depressed rats resulted in decreased depressed behavior and increased serotonin. One case study from Dr. Jessica Doll discusses two patients with depression who received fecal matter transplant pills. Both had reduced scores on the Hamilton Depression Rating Scale (HAMD), categorizing them as having mild depression within two weeks. These effects remained until eight weeks without further treatment, and patients also reported decreased GI symptoms. Both patients reported no side effects and the positive effects of the treatment were quicker than most antidepressants. The patients who received a placebo only had reduced HAMD scores for the first two weeks. Analysis showed increased bacterial diversity, although the most common phyla in each patient varied. The sample of this case study is limited, nonetheless, FMT is a promising treatment for depression.  

Overall, there is a lot of evidence supporting a correlation between gut health and depression, giving “you are what you eat,” a whole new meaning. More research and dedicated trials are necessary; however, the potential treatments that could be derived from the gut brain connection are promising and could offer much needed relief to those facing depression.