Gut microbiota and depression

Authors: Haiyang Wang, Xueyi Chen, Yangdong Zhang, Hanping Zhang, Peng Xie

Full Article:


Major depressive disorder (MDD) is one of the most disabling mental disorders, affecting over 35 million people worldwide. MDD is characterized by significant and persistent low mood and is driven by a combination of genetic and environmental factors. The recent pandemic has added a marked depressive burden to this situation; the 2020 Global Burden of Disease (GBD) data from 204 countries indicates that, throughout 2020, the COVID-19 pandemic and associated lockdowns led to a 27.6% increase in MDD cases.

The trillions of microorganisms that inhabit our guts, including bacteria, viruses, archaea, and fungi, play roles in human health. Recent studies have demonstrated the effects of the gut microbiome on distal organs, such as the brain. A pivotal role of gut microbiota in the pathogenesis of MDD has long

 However, a clear cause-effect relationship has not been definitively shown. MDD is associated with microbial dysbiosis, which is defined as an alteration in microbial diversity owing to the disrupted balance of microbiota and corresponding functional changes.

Circumstantial evidence comes from an observed increased risk of severe mental disorders (e.g., depression, anxiety, and psychosis) following antibiotic use, even 5–10 years after use.

A recent systematic review indicated the association between antibiotics use and subsequent development of depression.

Although increasing evidence has suggested a role of gut microbiota in MDD pathogenesis, the definitive role of dysbiosis remains unclear. So far, it is unclear whether microbial dysbiosis is intrinsically causal or merely a consequence of depression-related pathological changes. In addition, over decades of observational research, the gut microbiome field is shifting from association to modulation.

The ultimate goal of researches is to promote the development of microbiota-based interventions in depression. However, there is still a long way to go to realize the clinical application of microbial therapy. Before this, antidepressants are still the therapeutic mainstays in depression. So, in the current stage, we should not only pay attention to the development of microbiota-targeted interventions, but also to the influence of gut microbiome on efficacy of antidepressant drugs. Thus, in this review, we fully describe the association between dysbiosis and MDD, drug–microbiota interactions in antidepressant treatment, and the potential clinical transformations of microbial-targeted therapeutics for MDD.

Microbiota-gut-brain (MGB) axis in depression

Microbiota-gut-brain (MGB) axis in depression Communication between the gut and the brain is bidirectional and involves various routes including neural, endocrine, and immune pathways. The microbiota and their derived metabolites act as key modulators in gut-brain signaling, leading to the concept of an MGB axis.

The role of the routes involved in the MGB axis in depression has been well delineated (Fig. 2). The microbial composition and metabolites change in MDD patients results in a disrupted homeostasis of

the gut microenvironment, affecting the function of the gut epithelium and causing intestinal barrier dysfunction and inflammatory responses.

The increased systemic translocation of gut metabolites, microbial cell components, or even the microbiota via the damaged intestinal barrier (the “leaky gut”) heightens systemic inflammatory responses (e.g., Th17/regulatory T cell (Th17/Treg) imbalance, interleukin [IL]-6, IL-1β, and tumor necrosis factor-alpha (TNF-α)) that have been implicated in the pathogenesis of depression.

The enteric nervous system (ENS), referred to as the “second brain”, has been reported to be involved in the development of brain disorders. Abnormal ENS activity arising from intestinal pathology aggravates depression-related pathological changes by altering gut secretion, immune defenses, motility, and permeability.

Besides the ENS, the vagus nerve also plays an important role in transmitting microbial signals from the gut to the brain in depression.

Preclinical studies have verified that subdiaphragmatic vagotomy blocked the development of depression-like behaviors in rodents after LPS injection or fecal microbiota transplantation (FMT) from Chrna7 knock-out mice with depression-like behaviors.

In clinical, vagus nerve stimulation has long been approved for treatment-resistant depression.

The microbial cell components, e.g., LPS produced by gram-negative bacteria, and peripheral inflammatory signals reach the brain by crossing the blood–brain barrier resulting in neuroinflammation, subsequently induce neuropathological changes through chronic activating specific cells, including synaptic defects, demyelination, abnormal neurogenesis and neurotransmitters release,

that are involved in the pathogenesis of depression. Microbial signals, pathological neurobiological changes, and depressive emotions can activate the HPA axis, increasing the synthesis and release of cortisol. As a part of the brain-gut axis, excessive levels of cortisol promote gut pathology by modulating intestinal barrier function and inflammatory responses, resulting in a leaky gut

this process is a key component of the MGB axis in depression. Beyond these routes, various signal transduction systems and metabolic pathways are also implicated in the MGB-based pathogenesis of depression, such as the endocannabinoid system, CAMKII-CREB and MAPK signaling, and glycerophospholipid metabolism.

In addition, mitochondria are reported to be potential key mediators of the gut microbiota dysbiosis and depression relationship.

These routes in gut-brain bidirectional communication form a complex network of mechanisms; their interactions complicate investigations of mechanisms involved in gut microbiota regulation of depression.

Summary and prospects

Gut microbiota plays a vital role in regulating human health. In recent years, abundant research has uncovered the effects of gut microbiota and its metabolites on the pathogenesis of depression. Microbiota-based diagnostics and therapeutics for depression are the future directions of research. In moving the field forward, many key challenges need to be addressed and some recommendations provided might be useful: (1) Exploring the causal relationship between gut microbiome and depression. More prospective studies are required to analyze the interplay between the development of dysbiosis and depression, and drug–microbiota interactions, to uncover the causal relationships between dysbiosis, depression, and treatment. In particular, we need to better understand if the antidepressant effects of drugs can be enhanced by modulating gut microbiota; (2) Elaborating the pathological mechanism in MGB axis and identifying the key strains.

Growing preclinical and clinical evidence suggests that microbiota-based therapies can result in the remission of depression, but little is known about their mechanisms of action, the key microbiota, and how these bacteria interact; (3) Isolating the bacteria to construct the disease-based gut microbial biobank. More studies are required that utilize high-throughput sequencing, multi-omics approaches, and microbial culture technology to isolate the pathogenic and beneficial strains involved in depression, identify the exact functions of these strains, and uncover the underlying mechanisms involved in the gut-brain axis, to build a disease-based strain resource database; (4) Analyzing the confounding effects to promote the development of microbiota-based diagnostics and therapeutics.

The effects of various confounding factors should not be ignored when analyzing the changes of microbial structure and function in depression. We must better understand how the composition, proportion, and abundance changes of gut microbiota contribute to various cases of MDD. This will build a foundation for targeted therapeutic manipulation and finally impel the uptake of microbiota-based personalized precision medicine for depression; (5) Developing new tools. New methodological tools such as isotope tracing, engineered and CRISPR-edited strains are instrumental to moving the development of microbiota-based treatment strategies forward in depression, and this is a next frontier in microbiome research.