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Trzeciak, P. Intestinal Microbiome in Depression. Encyclopedia. Available online: https://encyclopedia.pub/entry/8066 (accessed on 20 August 2024).
Trzeciak P. Intestinal Microbiome in Depression. Encyclopedia. Available at: https://encyclopedia.pub/entry/8066. Accessed August 20, 2024.
Trzeciak, Paulina. "Intestinal Microbiome in Depression" Encyclopedia, https://encyclopedia.pub/entry/8066 (accessed August 20, 2024).
Trzeciak, P. (2021, March 17). Intestinal Microbiome in Depression. In Encyclopedia. https://encyclopedia.pub/entry/8066
Trzeciak, Paulina. "Intestinal Microbiome in Depression." Encyclopedia. Web. 17 March, 2021.
Intestinal Microbiome in Depression
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This entry is adapted from the peer-reviewed paper 10.3390/nu13030927

The intestinal microbiota plays an important role in the pathophysiology of depression. As determined, the microbiota influences the shaping and modulation of the functioning of the gut–brain axis. The intestinal microbiota has a significant impact on processes related to neurotransmitter synthesis, the myelination of neurons in the prefrontal cortex, and is also involved in the development of the amygdala and hippocampus. Intestinal bacteria are also a source of vitamins, the deficiency of which is believed to be related to the response to antidepressant therapy and may lead to exacerbation of depressive symptoms. Additionally, it is known that, in periods of excessive activation of stress reactions, the immune system also plays an important role, negatively affecting the tightness of the intestinal barrier and intestinal microflora.

depression mental diseases gut microbiome psychobiotics

1. Introduction

Depression (major depressive disorder, MDD) is a serious medical illness that negatively affects thoughts, behavior, feelings, motivation, and sense of well-being [1]. Nowadays, depression is considered a civilization disease, due to its wide range and frequency of occurrence, especially in highly developed countries. Globally, about 300 million people, i.e., 4.4% of the world’s population, suffer from depression (Global Burden of Disease Study 2015). According to the Diagnostic and Statistical Manual of Mental Disorders (fifth edition; DSM-5), the diagnosis of major depression requires the presence of five or more symptoms within a two-week period [2]. One of these symptoms should be either a depressed mood or anhedonia (loss of interest or pleasure), whereas the others include appetite or weight changes, difficulty sleeping, diminished ability to think or concentrate, fatigue or loss of energy, feelings of worthlessness or excessive guilt and suicidality [3]. The multitude of observed cases of depression pose a challenge for researchers in terms of acquiring a deeper understanding of the etiology and mechanisms of depression. Since it is a disease related to the nervous system, most studies have focused on the search for biochemical and molecular bases of the disease, primarily in the brain structures involved with the onset of symptoms. Many in vivo and clinical studies have demonstrated the significant role of stress in the development of depression [4][5]. In addition to the above, a significant role has also been assigned to the immune system, which, in periods of excessively activated stress reactions, inter alia, negatively affects the tightness of the intestinal barrier and the intestinal microbiota. In turn, the intestinal microbiota has a significant impact on the functioning of the nervous system, including participation in the processes of neurotransmitter synthesis, myelination of neurons in the prefrontal cortex, and involvement in the development of the amygdala and hippocampus [6]. It is also known that there is a constant exchange of nerve and biochemical signals between the gut and the brain [7]. In view of the above, it seems very important to present and link these aspects in the pathomechanism of depression.

The available literature lacks data on simultaneous abnormalities in the functioning of the intestinal barrier, caused by increased activity of the immune system in response to stressors. The literature also lacks data on the influence of the intestinal microbiota on the nervous system as a consideration of the multidirectional factors influencing the manifestation of the depression. A consequence of examining the mechanisms related to the pathophysiology of depression, is the search for new drugs and therapeutic strategies for this disease, since the current treatment methods—although having been slowly supplemented with new drugs in recent years—are still unsatisfactory [8]. Most of the commonly used medications only alleviate the symptoms of the disease and are often ineffective and burdened with numerous side effects. In recent years, research has been conducted on probiotic bacteria (psychobiotics), which—when consumed in appropriate amounts—have a positive effect on mental health, but so far have not been included in the treatment of mental diseases [9]. In the presented work, the role of psychiobiotics in the prevention and treatment of depression will be discussed in detail through their influence on the intestinal barrier, immune processes, and functions of the nervous system.

2. The Role of the Intestine Microbiome in Depression

One of the newest theories of the pathophysiology of depression focuses on research into the gut microbiome [10]. It has been observed that the gut and brain work in a bi-directional manner and can affect each other’s functions and significantly impact stress and depression [11]. A healthy gut microflora is known to transmit signals to the brain via pathways involved in neurotransmission, neurogenesis, microglia activation, and behavioral control under both normal and stressful conditions. Studies into the effects of the gut microbiota on behavior and neurobiology, called the microbiome–gut–brain axis (MGBA), began with the observation of patients suffering from inflammatory bowel disease and irritable bowel syndrome (IBS) [12][13][14]. It has been noticed that the composition of the intestinal microflora in patients with depression differs from that in healthy people, as confirmed in animal models of depression [15][16]. The influence of intestinal microflora on depressive behavior was also demonstrated in studies carried out on rats and mice born and raised in a microflora-free environment and in animals with specific pathogen-free (SPF) gut microbiota [17][18][19]. Colonization of pathogen-free animals with SPF intestinal microbiota has been shown to ameliorate their behavior [20][21]. Some bacteria have been observed to produce neuromodulatory substances such as those found in the nervous system of animals: acetylcholine, dopamine, serotonin, GABA, norepinephrine [22][23].

The adult human gut microbiome includes about 1013–1014 microorganisms, including: bacteria, viruses, fungi, archaea, and protozoa [24]. The composition of the microbiota is unique for each individual and is the result of various factors related to changes in the intestinal environment, lifestyle, and dietary habits [25]. The functions of the gut microbiota can be defined in three categories, i.e., metabolic, trophic, and protective functions. The metabolic function is carried out by decomposition of undigested food residues and production of B vitamins and vitamin K [26]. The trophic functions include controlling the tightness of the intestinal epithelium by participating in processes related to the maturation and exchange of enterocytes, while the interaction of the microbiota in terms of activity is another example of gastrointestinal (GI) motor skill functioning [27][28][29].

Intestinal bacteria are also a source of vitamins, including vitamin K-2 and B vitamins (niacin, biotin, folic acid, and pyroxidine) [30][31][32]. Studies have shown low levels of folate in the blood serum of patients with depression. This deficiency is believed to be related to the response to antidepressant therapy and may lead to exacerbation of depressive symptoms [33]. In turn, pyroxidine is an essential cofactor of enzymes that are altered in people with depression. Such enzymes are involved in the kynurenine pathway and depressed individuals have increased susceptibility to pyroxidine deficiency, which is demonstrated by disease-free animals [34].

Despite the significant role attributed to microorganisms that make up the microbiota, it is believed that this environment also affects the immune and nervous system. Each permutation in the composition of the gut microbiome results in the production of lipopolysaccharides (LPS) by the microorganisms, which in turn activates inflammatory responses. The produced cytokines send signals to the vagus nerve, thus, connecting to the HPA axis. Behavioral effects are a consequence of these processes. It has also been shown that GI inflammation can lead to inflammation of the nervous system, which in turn drives the action of microglia, triggers the kynurenine pathway and, consequently, may contribute to the development of depression [35]. Most importantly, this influences the production of pro-inflammatory cytokines and the functioning of the nervous system through participation in the synthesis of neurotransmitters. The synthesis of GABA, serotonin, glutamate and BDNF is important in affecting the nervous system [6]. Over the course of several years, it has been determined that the microbiota influences the shaping and modulation of the functioning of the gut–brain axis. Studies carried out with germ-free (GF) mice and rats (animals kept in sterile conditions, without intestinal microbiota) have shown that the intestinal microbiome has a significant influence on the formation of neural networks of the enteric nervous system (ENS), as well as the neuronal connections between the ENS and the central nervous system (CNS) [36]. In the early stages of life, a lack of specific microbes in the gut results in an overactive stress response later in life. [37]. Importantly, the intestinal microbiota is involved in the processes of myelination of neurons in the prefrontal cortex and is involved in the development of the amygdala and hippocampus [38].

Research on the intestinal microbiota has brought a new perspective on the pathomechanism of many diseases. In the context of depression, it has become a topic of interest for determining the composition of the microbiota in those suffering from this disorder. Indeed, many studies have indicated that people with depression are disturbed by both the composition and the number of strains that make up the gut microbiome [39].

Liu et al. evaluated the gut microflora of 90 young American adults by comparing the intestinal microflora of 43 participants with (MDD) and 47 healthy individuals in the control group. The study found that people with MDD had significantly different gut microbiota compared to the control group. People suffering from MDD had lower levels of Firmicutes and higher levels of Bacteroidetes, with similar trends in class (Clostridia and Bacteroidia) and row (Clostridiales and Bacteroidales). At the genus level, the MDD group showed lower levels of Faecalibacterium and other related members of the Ruminococcaceae family, which were also lower compared to healthy controls. In addition, participants with MDD enriched the Gammaproteobacteria class. The study authors conclude that the difference in the abundance of these bacterial strains resulted in a reduced ability to produce short-chain fatty acids (SCFA) in people with MDD [40].

In a separate study, Huang et al., using rRNA 16S sequencing and bioinformatics analysis, assessed the composition of the gut microbiota. The study material consisted of fecal samples taken from 54 people (27 patients with MDD). The results showed that patients with depression have a serious disorder of the composition of the intestinal microbiota. The authors observed a significant decrease in the amount of Firmicutes [41]. Analysis of the results of the two above studies led to the conclusion that reducing the amount of Firmicutes results in a decrease in SCFA. Firmicutes bacteria contribute to the fermentation of carbohydrates into SCFA [42]. It is claimed that SCFA deficiency may weaken the function of the intestinal barrier [43]. It is noteworthy that the leakage of the intestinal barrier contributes to pathogens and their metabolites crossing the barrier This process induces an immune response, which may be linked to the occurrence and development of depression [44]. To confirm this relationship, a separate study was carried out. This study eventually showed a significant correlation between stress-induced behavioral changes in mice and Firmicutes disorder in the gut microflora [45]. With the decline of Firmicutes, the protective factors of the intestinal barrier weaken and the body is additionally exposed to the risk of inflammation [41].

The comprehensive meta-analysis in patients with MDD has indicated that several taxa at the family and type level were reduced, particularly within the Prevotellaceae, Corprococcus and Faecalibacterium families compared to the control group. The study also confirmed the beneficial aspect of using probiotics, which improved the symptoms of depression [46]. A separate meta-assessment of adults over 18 years of age suffering from MDD and healthy adults, reviewed disorders in the composition of the microbiota. Differences in α and β microbiota occurred in people with depression compared to healthy control subjects at the level of the Bacteroidetes, Firmicutes and Proteobacteria. The high abundance of Fusobacteria and Actinobacteria was observed in people suffering from depression. In patients with depression, the high abundance of Actinomycineae, Bifidobacteriaceae, Clostridiales incertae sedis, Clostridiaceae, Eubacteriaceae, Fusobacteriaceae, Lactobacillaceae XI, Nocardiaceae, Porphyromonadaceae, Streptomycetaceae, Thermoanaerobacteriaceae and low abundance of Bacteroidaceae, Chitinophagaceae, Marniabilaceae, Oscillospiraceae, Streptococcaceae, Sutterellaceae and Veillonellaceae at the family level was observed. In turn, at the genus level, a high abundance of Actinomyces, Anaerofilum, Anaerostipes, Asaccharobacter, Atopobium, Blautia, Clostridium IV, Clostridium XIX, Desulfovibrio, Eggerthella, Erysipelotrichaceae incertae sedis, Eubacterium, Gelria, Holdemania, Klebsiella, Olsenella, Oscillibacter, Parabacteroides, Paraprevotella, Parasutterella, Parvimonas, Streptococcus, Turicibacter, Veillonella, and low abundance of Clostridium XlV, a Coprococcus, Dialister, Escherichia/Shigella, Lactobacillus, Howardella, Pyramidobacter and Sutterella was found in depressed patients [47].

3. The Role of Metabolites of the Intestinal Microbiome in Depression

Nutrients derived from food can be metabolized into small-molecule compounds such as SCFA, indoles and its analogues, or acortic acids. The above compounds do not only elicit local actions, but also affect distant tissues and organs [48]. Metabolites of the intestinal microbiota are a source of energy for colonocytes and, by acting as nuclear receptors, modulate a number of immune processes and affect the course of inflammatory reactions and the synthesis of neurotransmitters. There is a great deal of evidence that the above products have a potential association with the occurrence of depression [49][50][51]. Products of metabolism of the intestinal microbiota also include SCFA. With the participation of bacteria in the GI tract, acetate, butyrate and propionate are formed, which—according to research—yield promising benefits. These compounds are linked to the occurrence of pain, depression or neurodegenerative diseases. The above action is realized through the participation of SCFA in anti-inflammatory processes. SCFA interact with NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflamasome cells in the intestinal epithelial cells. This relationship increases the production of IL-8 and improves the tightness of the intestinal barrier [52][53]. The cells of the immune system are also targeted by SCFA. Butylan and propionate have been shown to inhibit the formation and differentiation of dendritic cells, which are responsible for immune dysfunctions [54]. The study of transplantation Bacterioides thetaiotaomicron (manufacturer of acetate) to GF mice can promote the production of mucin and affect the integrity of the intestinal barrier. SCFA may reduce the production of pro-inflammatory cytokines from neutrophils and lipopolysaccharide activated macrophages (LPS) by inhibiting HDAC (histone deacetylases) [55]. Such a broad effect of SCFA affects their involvement in eliminating pain reactions and depressive states. In addition, butylan has the potential to maintain the integrity of the BBB. It should be emphasized that colonization with a bacterium producing buttermilk (Clostridium tyrobutyricum) and oral administration of sodium buttermilk (1000 mg/kg for 3 days) can fix the BBB leak. These changes are related to increasing the expression of proteins with close connections [56]. Based on new research determining the role of buttermilk, it is claimed that this compound affects the behavior, memory and levels of neurotrophic factors in a rat model of chronic mild stress. This study shows antidepressant effects [57]. In addition to the effect on the regulation of neurotrophic factors, butyric acid usually inhibits the deacetylation of histones and prevents activation in the hippocampus. Butyrate, which is a by-product of the metabolism of intestinal bacteria modulates the synthesis of dopamine and norepinephrine. Butyrate affects the change in the expression of the gene that encodes tyrosine hydroxylesis [58].

One of the fine-particle products of microbiota metabolism is secondary bile acids. Bile acids are synthesized from cholesterol in the liver and then metabolized into other bile acids by colon bacteria through numerous enzymatic pathways [59]. Secondary, cholic acids formed by the use of intestinal bacteria include lithocholic acid, deoxycholic acid and ursodeoxycholic acid. These compounds are formed by decoumination and 7α-dehydroxylation [60][61]. Over the years, scientific studies have shown that bile acids have extensive physiological effects, elicited by activating specific receptors in the nucleus and cell membrane [60]. These receptors can mediate various pathophysiological processes, including glucose homeostasis, and inflamed and sensory transduction. Bile acids can affect nuclear receptors (farnezoid X receptor (FXR), preganate X receptor and vitamin D receptor) and surface receptors (for example, bile acid receptor coupled with G protein—GPBAR1 (G-Protein Coupled Bile Acid Receptor 1)) or TGR5, sphingosine phosphate receptor 2 and musculature receptors 2 and 3). In the case of pathogenesis of depression, activation of the FXR ligand is particularly important. A recent study showed that over-expression of hippocampal FXR causes depression-like symptoms and reduces BDNF expression in the hippocampus in naïve rats [61]. Similarly, treatment with tauroursodeoxycholic acid could prevent the depressive behavior caused by LPS. This possibly occurs through weakening neural system inflammation and oxydonitrozative stress [60]. In this regard, it has been shown that the inhibition of nuclear glycelic factor-κB (NF-κB) and the activation of TGR5 in microglial mediates the effect of tauroursodeoxycholic acid on the production of pro-inflammatory cytokines [62].

The metabolism of the intestinal microbiota is associated with the existence of many pathways, metabolic processes and assumes the activity of many enzymes. A wide range of biochemical metabolites, formed by transformation, affects the functioning of the human body. In addition, the wide role of the microbiota also assumes its involvement in the processes of modification of amino acids. Many scientific publications indicate that tryptophan (TRP) is a key amino acid associated with the metabolism of the gut microbiota. Bacteria of the Firmicutes, Clostridium sporogenes and Ruminococcus gnavus families convert TRP into a biogenic amines after birth. These amines are structurally similar to serotonin. It is worth noting that this reaction occurs using the tryptophan decarboxylase enzyme [63]. Ruminococcus gravus is a common bacterium and is common in adults [64] and infants [65]. Tryptamine is a product of metabolism that maintains normal intestinal homeostasis [66].

Nevertheless, the most important metabolite of the intestinal microbiota is indole, which is wiped out by many Gram-positive and negative bacteria [67]. Indole and its derivatives are produced by the bacterial enzyme tryptophanase [68][69][70]. The above compound is a signaling molecule that stimulates enteroendocrine L cells to “separate” glucagon-like peptide 1 (GLP-1). GLP-1 in turn stimulates the aferent activity of the vagus nerve in the colon [71][72]. Indole also regulates the permeability of the intestinal barrier [73]. In the context of behavioral disorders, excessive amounts of indole cause a negative effect, increasing anxiety and depressive behaviors in rats. In addition, indole is associated with the sensitivity of mice exposed to chronic stress and interferes with the biosynthesis of catecholoamins in the adrenal core [74]. Jaglin et al. determined the effect of indole on physiology and behavior in rats [75]. Following acute administration, there was a significant reduction in the mobility and accumulation of indole metabolites in the brain. This study suggests a possible effect of indole on central receptors. Chronic exposure to indole, achieved by the colonization of GF rats by E. coli, increased anxiety and helplessness behavior (i.e., depressive behavior). On the other hand, separate studies have shown that indole and its derivatives (e.g., Indoxyl-3-sulphate (I3S), indole-3-propionic acid (IPA) and indole-3-aldehyde (IAld)) are capable of activating the aryl hydrocarbon receptor (AhR). This action has a subsequent inhibitory effect on the nervous system [76]. Rothhammer et al. demonstrated that neural system inflammation was reduced by activating AhR on astrocytes in mice. These mice were either supplemented with indole or related compounds [77]. These activities described above make it difficult to understand the physiological and pathological role of indole. The reason for this, is the existence of a large number of indole derivatives with diverse and dynamic effects [78].

Studies on animal models have shown that the gut microbiota affects the levels of amino acids in the blood. This also has an impact on the occurrence of depression. Analysis of the fecal metabolome in rats exhibiting depressive behavior revealed changes in AA levels of L-treonine, isoleucin, alanine, serine, tyrosine and oxidized proline. Changes in amino acid levels in the plasma—correlated with both the phylogenetic composition of bacteria and changes in amino acid levels—were observed in fecal metabolomy [79]. In view of the above, it is considered that metabolites of arginine catabolism have an effect on depression. Many studies have highlighted the antidepressant and anxiolytic effects of putrescin and agmatine. These compounds naturally occur as a result of arginine decarboxylation [80].

Additionally, a product of microbiota metabolism is lactate, which is formed by the fermentation of dietary fiber by lactic acid bacteria (e.g., Lactobacillus lactis, Lactobacillus gasseri and Lactobacillus reuteri), Bifidobacteria and Proteobacteria. [81] Lactate is used as an energy substrate by neurons in the brain because it crosses the BBB [82]. In addition, its ability to convert into glutamine contributes to the formation of synaptic plasticity. This plasticity is crucial in the formation of memory pathways [83][84][85]. In the context of depression, both animal model studies and clinical trials have determined that there is an apparent relationship between lactate disorders and the onset of symptoms of depression. Thus, elevated levels of lactate in urine were observed in patients suffering from severe MDD compared to the control group [86]. Carrard and others (2018) have also demonstrated the antidepressant effects of acute and chronic intraitoneal L-lactate injections in a mouse model of depression with corticosterone. These behavioral effects followed an increase in L-lactate concentrations in the hippocampus and were dependent on changes in the expression of several genes associated with depression pathophysiology [87].

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