Association between major depressive disorder and gut microbiota dysbiosis

Introduction

An estimated 300 million people globally suffer from Major Depressive Disorder (MDD), ¹ a crippling mental condition that is linked to around 800,000 suicide fatalities per year. ² The symptoms of MDD include low mood, low self-esteem, and a loss of interest in once-enjoyable activities. ³ In addition, depression is linked to a higher risk of immunological deficiencies, and metabolic diseases, including type 2 diabetes mellitus, atherosclerosis, heart disease, hypertension, stroke, cognitive decline, and dementia. ⁴ Numerous researchers have tried to use neurotransmission deficits, neurotrophic changes, and abnormalities in neuroanatomical structure to explain the pathophysiology of depression. None of these theories, nevertheless, was able to explain everything.^5,6 Additionally, the importance of gut microbiota in preserving homeostasis in health and in the etiology of numerous diseases is becoming increasingly recognized. This is currently being extended to include central nervous system disorders. ⁷ The term “microbiota” refers to all microorganisms that are present on or in the human body; the gut contains 10¹⁴ different types of microbe cells. ⁸ The study of the microbiome has advanced dramatically over the last 20 years, shedding light on the numerous ways that these microscopic intruders affect our day-to-day existence. It is now clear that the microbiota take part in a major role in regulating host physiology and determining human health and disease. ⁹ There is growing evidence that the gut microbiota is involved in brain function and the development of neuropsychiatric disorders, such as MDD. ¹⁰ Consisting of roughly 40,000 bacterial species and 1800 distinct phyla, the microbiome is a collection of trillions of microorganisms, including bacteria, that live in and interact with human hosts, with effects ranging from beneficial to pathogenic. ¹¹ It has been linked to various aspects of human health and disease. Numerous pieces of evidence support the idea that anxiety disorders and other related behavioral disorders are influenced by the microbiota. Changes in the mice’s microbiota’s structure are influenced by ongoing stress.^12,13 The microbiota–gut–brain axis is the name of the communication pathway that the human gut microbiome uses to exchange communication pathways with the central nervous system (CNS). It is thought that the microbiota-gut-brain axis regulates the vagus nerve, which in turn affects the synthesis of immune mediators and microbial metabolites that alter neurotransmission, neuroinflammation, and behavior.^14-17 Preclinical research continues to imply that microorganism’s impact host behavior and brain development through the microbiota-gut-brain axis. The disruption of the neuroimmune-neuroendocrine system in depression is triggered by the gut microbiota. ¹⁸ The majority of studies on the influence of microbiota on host behavioral patterns have been carried out on mice or rats; the relationship between human depression and microbiota is until now unclear. ¹⁹ Due to the high prevalence of depression and the numerous complications and risks of MDD, especially suicide, the present study aimed to evaluate an association between gut microbiota dysbiosis and MDD.

Materials and methods

Results

The study was accomplished with 35 patients with depression and 35 healthy people. There was no significant difference between healthy and depressed individuals in terms of mean age and sex (P >.05). Based on the qPCR results, the total number of bacteria in the bacterial phyla was different in the depression groups and the control group (Table 1). The relative abundance of bacteroidetes to firmicutes in the control and case groups was .66 and 1.33, respectively (P value <.05).

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Table 1.

The total number of bacteria in the phyla in control and depression groups.

Bacterial phyla	The number of bacterial copies/μL in control group	The number of bacterial copies/μL in MDDa group	P value
Firmicutes	6 ± 2 × 106	3 ± 2 × 106	≤.05
Bacteroidetes	8 ± 2 × 106	2 ± 2 × 106	≤.05
Actinobacteria	3 ± 2.5 × 105	2.8 ± 2.2 × 105	>.05
Proteobacteria	3 ± 2.2 × 105	2.7 ± 2 × 105	>.05

Discussion

The present study found that there was a significant decrease in the level of firmicutes and bacteroidetes phylum, On the other hand, there were no significant differences in actinobacteria and proteobacteria in the MDD group compared to the HC group. As a matter of fact, a variety of intestinal microbiota can significantly contribute to the development of behavioral and psychiatric illnesses by influencing the body’s immunological and inflammatory systems and generating metabolites. This lends credence to the theory that the gut microbiota influences brain activity through the complexes that mediated inflammatory responses (inflammasome signaling platform), which modifies brain function and behaviors associated with anxiety and depression. ²¹

The 2 main bacterial phylotypes that inhabit a healthy human gut are firmicutes and bacteroidetes. Firmicutes comprise between 40% and 65% of the colon or fecal microbiota. ²² Reduced intestinal barrier function can result from the firmicutes in the gut microbiota fermenting carbohydrates into a range of short-chain fatty acids (SCFAs).^23,24 Acetate, propionate, butyrate, and valerate are examples of SCFAs. Low SCFA has been connected to gut inflammation, an inflammatory state associated with depression, and has been linked to feelings of decreased energy and altered neurotransmission. ²⁵ According to the previous reports, SCFAs can reduce colonic inflammation, increase the expression of IL10, activate regulatory T cells (Tregs), and prevent the generation of pro-inflammatory cytokines. ²⁶ Faecalibacterium prausnitzii is a member of the firmicutes family of bacteria that is found in very small amounts. A reduction in the proportion of bacteria has been linked to a decline in the protective function of the intestinal mucosa. These results imply that firmicutes may function as a helpful and protective agent within the gut microbiome. The consequences of the “microbiota-gut-brain axis” have been the subject of numerous prior investigations. According to the study by Huang et al, ²² firmicutes significantly decreased in the MDD group as opposed to the control group, which is in line with our findings. However, Jiang et al ²⁷ found that while firmicutes significantly decreased, bacteroidetes levels significantly increased in patients with major depressive disorder. Furthermore, Zheng et al ²⁸ discovered that while there were no significant variations in the total relative abundances of firmicutes between MDD patients and healthy controls, there was a significant decrease in bacteroidetes in the MDD patient group. They also showed that mice exhibit depressive-like behaviors when their gut microbiome is absent. Depletion of gut microbiota (by antibiotic administration) during adulthood causes an increase in depressive-like behaviors, reduced visceral hypersensitivity, and impaired cognition, according to a study by Hoban et al. ²⁹ The CNS serotonergic system and regular tryptophan availability depend on healthy gut bacteria. The gut microbiota’s diversity was significantly decreased by prolonged antibiotic usage during adulthood, especially in terms of firmicutes and bacteroidetes.

Prior research by Liu et al ³⁰ showed that whereas bacteroidetes levels considerably rose in the MDD group. Firmicutes levels significantly decreased. Firmicutes exhibited a statistically significant decrease in the study by Kovtun et al, ³¹ while bacteroidetes showed a substantial rise in the MDD group. Overall, the synthesis of short-chain fatty acids, the metabolism of tryptophan, and the induction of cytokines are just a few of the ways the gut microbiota can impact the central nervous system and result in a variety of neurological and behavioral disorders. ¹⁰ The synthesis of active neurotransmitters, that pass from the gut to their target organs, including the brain, is mediated by the gut bacteria. Feces contain 2 neurotransmitters including glutamate and GABA. The CNS’s excitatory neurotransmitter is glutamate. The CNS’s most prevalent inhibitory neurotransmitter is GABA. There are other routes via which microbial GABA may transfer from the gut to other organs, such as the vagal or blood pathways. ³² The gut bacteria are likely responsible for the 400 μg of glutamate that accumulated in the colon. Then, the GABA producing bacteria converted a portion of the glutamate pool to GABA. The presence of bacteria that can decarboxylate glutamate to GABA can result in the production of a novel therapeutic agent for the treatment of psychiatric illnesses, especially those involving an imbalance between glutamate and GABA levels and stress relief.^32,33 In our study, bacteroidetes significantly decreased in MDD group. In the previous studies have shown that bacteroidetes, perhaps the major bacterial producers of gamma-aminobutyric acid (GABA) in the human gut, were associated with clinically diagnosed MDD. It has been reported that mental disorders, such as depression, are negatively correlated with the abundance of GABA-producing bacteroidetes. Bacteria that produce GABA aid in the treatment of mental diseases like depression. A changed GABAergic profile has been linked to a number of diseases, including depression and psychiatric disorders linked to decreased fecal GABA.^34,35 Furthermore, a reduction in GABA production ³² was seen in the majority of firmicutes bacteria, which were GABA producers, in our study. Due to all the reasons mentioned above, the gut microbiota dysbiosis presumably can be effective in causing psychiatric and behavioral disorders, including MDD, through the gut-brain axis, which was also observed in our study. This underlines the prospect of the gut microbiota as a novel treatment target for depression. Accumulating evidence supports the efficacy of several microbiota-target treatments in treating depression, including dietary interventions, fecal microbiota transplantation (FMT), probiotics, prebiotics, synbiotics, and postbiotics. In fact, based on current research and potential connections between gut microbiota and depression, MDD patients may benefit from improving their gut’s microbial balance. This can be achieved with the aid of the FMT method, and further research in the form of clinical trials is recommended. ³⁶

Conclusion

The firmicutes had a significant decrease in the depression group and are the main producers of SCFAs in the human gut, which may be the physiological basis for inflammation in depression. In conclusion, our research indicates that gut microbiota dysbiosis may contribute to the onset of depression or the increasing intensity and progression of MDD. So, the modified microbiome and its metabolites may be useful for the management of MDD. The causative links between depression and gut microbiota may be clarified by future research examining microbiome metabolomics, and more investigation is required to look into how to restore the microbial balance.