Depression and The Gut Microbiome – The Unresolved Chicken and Egg Question?

Depression is one of the most common mental disorders experienced worldwide with an average lifetime prevalence of 11–15%. As I discussed in The Gut Immune Connection, about 160 million people suffered from major depressive disorder in 2017, young people being the highest risk group. A Blue Cross Blue Shield report showed that in 2016, 2.6% of youths between twelve and seventeen years of age were diagnosed with major depression, a 63% increase from 2013. In addition to these disturbing numbers, the prevalence of depression has doubled and, in some countries, even tripled during the COVID-19 pandemic, suggesting a strong role of environmental factors (the so called “exposome”) in its pathogenesis. The importance of the exposome which includes lifestyle, diet, and exposure to chemicals is further supported by the low to moderate heritability and the small effects of genetic variants identified in large genome-wide association studies of depression.

“…the prevalence of depression has doubled and, in some countries, even tripled during the COVID-19 pandemic…”

Despite a wealth of preclinical and clinical knowledge published during the past decades, pharmacologic treatment options, based primarily on the prevalent disease model implicating an imbalance of monoamine neurotransmitters like serotonin, dopamine, and norepinephrine, are sub-optimal with most antidepressants performing only marginally better than placebo. In the hope to overcome these limitations, researchers have expanded the traditional narrow focus on these monoamine neurotransmitters and strategies (in particular reuptake inhibitors for serotonin, like SSRIs and norepinephrine (NSRIs), to other disease mechanisms and treatment strategies, such as diet (nutritional psychiatry), psychedelic compounds (like ketamine or psilocybin) and the microbiome.

“…animal studies suggest that the gut microbiota might have impact on the neurobiological features of depression.”

Based on a series of paradigm shifting preclinical studies in mice, the gut microbiome has emerged as another promising candidate in the pathophysiology of human depression. Several animal studies suggest that gut microbiota might have an impact on the neurobiological features of depression. For example, a study showed that transferring gut microbiota from depressed human patients to “germfree” rats without a gut microbiome showed that the recipient animals developed depression-like behaviors suggesting (but not proving) that gut microbiota may be causally involved in the development of depression. However, there have been very few studies systematically exploring the association between gut microbiome and depression in humans. Further, the existing studies are based on very small samples, lacking statistical power to detect robust and reproducible associations. The majority of published studies in humans did not adjust for confounding lifestyle factors and medication use, which are known to modify the gut

“Two large recent studies have confirmed the association of a group of gut microbes with symptoms of depression.”

In a recent study, published in the prestigious journal Nature Communications, a team of European investigators aimed to overcome limitations of earlier studies by investigating the association of fecal microbiome diversity and composition with depressive symptoms in 1,054 participants from a large existing data set (the Rotterdam Study cohort) and validate these findings in another data set of 1,539 subjects (the Amsterdam HELIUS Cohort). In this impressive study, the investigators identified an association of thirteen microbial taxa with depressive symptoms. These microbes are known to be involved in the synthesis of butyrate, an anti-inflammatory short chain fatty acid, and the central neurotransmitters glutamate, serotonin, and gamma amino butyric acid (GABA), which are molecules long implicated in the pathophysiology of depression. Based on their findings, the author suggested that the gut microbiome composition may play a key role in depression.

In a companion paper, the same group of investigators analyzed samples from 3211 individuals from the same HELIUS cohort, with the aim to characterize gut microbial changes and their associations with depressive symptoms in 6 ethnic groups (Dutch, South-Asian Surinamese, African Surinamese, Ghanaian, Turkish, Moroccan), living in the same urban area. While gut microbial diversity predicted depressive symptom levels, these associations did not differ between ethnic groups. Bacterial genera associated with depressive symptoms belonged to multiple microbial families. In summary, analyses of a large and ethnically diverse population demonstrated robust associations between features of the gut microbiome and depressive symptoms. These associations were largely invariant across ethnic groups and withstood adjustment for a uniquely large set of potential confounders, including demographic, behavioral, and medical factors.

“Is current evidence enough to establish some of these microorganisms as causing or contributing to depression?”

When viewed together, a growing number of well-designed high-quality studies in large human data sets have demonstrated a significant association of a group of gut microbes with known functions and symptoms of depression. Is it enough to establish some of these microorganisms as causing or contributing to depression? The answer is yes and no.

The preclinical and clinical evidence published over the past few years is certainly highly suggestive of a causal relationship. The identification of microbes capable of producing neurotransmitters involved in depression, and in anti-inflammatory butyrate provides plausibility of the findings. But the proof can only come from longitudinal intervention studies showing that an intervention-related change in the gut microbial alterations in patients with depression is associated with an improvement of clinical symptoms. For ethical reasons, it is obviously not possible to use the same strategy used in animal models, in which the transplant of fecal material from a donor mouse with depression-like behavior results in depression symptoms in the recipient. If the altered gut microbiome does play a clinically relevant change in depression, the question is why has the prevalence of depression increased in the last 10 years, particular in younger patient groups, and most dramatically during the pandemic? Which lifestyle changes that have a strong influence on the gut microbial ecosystem may be underlying this increase in symptoms? Is it the same diet-related systemic immune activation that has been implicated in the different diseases of the chronic non-communicable disease epidemic?

On the other hand, well characterized brain changes in animal models of depression and in human patients are associated with well-studied changes in the top-down influences of the brain on the gut and its microbiome. In my opinion, it is equally likely that these brain to gut influences, mediated by the autonomic nervous system and the central stress system are responsible in part for the observed microbiome changes.

In my personal view, there is still a long way to go before we can say for sure that the gut microbiome plays a role in depression which is causative and clinically relevant, and that interventions targeted at the gut microbiome are effective enough to be clinically meaningful, and don’t simply represent a placebo response.

Dr. Emeran Mayer is a Distinguished Research Professor in the Departments of Medicine, Physiology and Psychiatry at the David Geffen School of Medicine at UCLA and the Executive Director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience at UCLA.