The gut microbiome is a complex and dynamic ecosystem that is crucial for the normal functioning of the organism. There is a continuous bidirectional communication between the gut microbiome and the host, and many bioactive compounds or metabolites synthesized by the gut microbiome can have positive effects on the human body. These microbial metabolites can cross the blood-brain barrier (BBB) or have significant effects on the brain, playing a key role in the microbiome-gut-brain axis.
Modulating the microbiome-gut-brain (MGB) axis is a major regulatory approach for many neurological diseases, including major depressive disorder (MDD). This article will explain some physiological and pathological features of MDD from the perspective of the signaling pathways and functions of microbial metabolites (short-chain fatty acids, bile acids, amino acids, tryptophan derivatives, etc.).
Microbiome-gut-brain (MGB) axis
The gut is considered the 'second brain.' The gut microbiome is the main representative element located in this organ, which has multifunctionality and important functions at both local and systemic levels, thus leading to the MGB axis to handle the complex relationships between these elements.
The MGB axis mainly works through the following three mechanisms.
01. The digestive system is innervated through its connection with the central nervous system (CNS) and the enteric nervous system (ENS) within the gastrointestinal wall.
The ENS and CNS control the interactions between gut activity and the microbiome. Conversely, the microbiome and gut cells may also influence the neural networks of the ENS and CNS. For example, some neurotransmitters released by efferent neurons from the central nervous system may be utilized by certain types of bacteria, determining the growth of these microbial populations; at the same time, some microbes produce or regulate the release of certain neurotransmitters from the gut to the central nervous system.
02. The immune system is an important mechanism.
The interaction between the gut microbiome and the immune system involves various mechanisms, including microbial products, inflammatory cytokines, and appropriate bacterial metabolites. A rich gut microbiome can positively regulate immune responses. In contrast, changes in the microbiome (dysbiosis) are accompanied by exacerbated immune responses and impaired gut barriers. This may ultimately lead to bacterial translocation and endotoxemia, enhancing systemic inflammation and negatively affecting the brain.
03. The dissemination of various elements (including hormones, metabolites, or neurotransmitters) in the blood.
The gut microbiome is a major source of various metabolites, playing roles in the MGB axis through multiple pathways, including stimulating the vagus nerve, regulating gut, systemic, and neuroinflammation, central nervous transmission, and the integrity of the gut microbiota.
Microbial metabolites in MDD
Through the intake of different nutrients and components in the diet, the gut microbiome produces various metabolites. Current research has identified a large number of microbial metabolites that have significant effects on health. Below, we will describe some of the most relevant microbial metabolites involved in the development of MDD.
01. Short-chain fatty acids
Short-chain fatty acids (SCFAs) are a subtype of fatty acids primarily produced in the colon (i.e., large intestine), mostly generated from the fermentation of undigested food residues by anaerobic bacteria in the colon, mainly including acetate, propionate, and butyrate.
SCFAs have been shown to be a core mechanism of gut-brain communication. SCFAs may interact with enteroendocrine cells and promote the release of indirect signals to the brain through systemic circulation or the vagus nerve pathway, thereby inducing the production of various hormones and neurotransmitters in the gut, such as γ-aminobutyric acid (GABA) and serotonin.
Lactic acid is an important metabolite produced by some microbes (including lactobacilli, bifidobacteria, or proteobacteria) and is often converted into SCFAs by some microbes. Studies have shown that under physiological conditions, this metabolite can cross the blood-brain barrier to meet the energy needs of the brain and affect many neuronal functions.
The gut microbiome is not the only source of lactic acid; it can also be produced by astrocytes in the brain, which serve as a local lactic acid reservoir that can transfer this metabolite to neurons (some studies suggest that neurons preferentially utilize lactic acid as an energy substrate).
Lactic acid is also produced by muscle cells during exercise, and physical activity may be a strong link between lactic acid and antidepressant effects, influencing not only muscle production of lactic acid but also the MGB axis.
New evidence reveals the mechanisms by which the gut microbiome regulates tryptophan metabolism.
Tryptophan (Trp) is one of the essential amino acids in the human body, exerting biological activity through its various metabolites. The gut microbiota is a key mediator in regulating Trp metabolism, and the gut microbiome can convert Trp into a large number of active substances, among which the most relevant to the MGB axis are:
(1) Trp is converted into the neurotransmitter serotonin (5-hydroxytryptamine), which is beneficial for brain and gut function.
(2) Trp can be metabolized into kynurenine, indole, and tryptamine.
Glutamate and phenylalanine are some amino acids that show significant changes in the body fluids of patients with depression.
The gut microbiome plays a key role in the regulation of these two amino acids. Regarding glutamate, on one hand, some microbes can consume it to generate energy or form their structural components, while on the other hand, some bacteria can produce glutamate or convert it into GABA; phenylalanine, which can be synthesized by microbes, is a precursor to catecholamines such as epinephrine, norepinephrine, and dopamine.
Bile acids (BA) are important physiological factors and key regulators of the composition of the gut microbiota, which in turn metabolizes BA, determining the size of the bile acid pool. Primary BA is produced by the liver and secreted into the small intestine, while secondary BA is produced by the metabolism of the gut microbiota. Studies have supported that secondary BA is a key molecule involved in the MGB axis.
Vitamin deficiencies are often observed in patients with MDD, especially deficiencies in vitamin D and B complex vitamins. Research has clarified the effects of combined supplementation of probiotics and biotin (vitamin B7) for 4 weeks in MDD patients.7Compared to groups receiving only vitamin B with placebo or probiotics with placebo, patients receiving both probiotics and vitamins showed increased synthesis of vitamin B6and B7with improved clinical outcomes.
Choline is a nutrient found in meat, milk, grains, eggs and their derivatives, and fish. Choline can be converted into various related metabolites, such as trimethylamine (TMA), betaine, phosphocholine, and acetylcholine. The gut microbiota plays a key role in choline metabolism, significantly participating in the production of TMA, which is then converted into trimethylamine-N-oxide (TMAO) in the liver. Studies have found a positive correlation between TMAO levels and the severity of depressive symptoms in both women and men.
References:
Miguel A. Ortega.etc.Gut Microbiota Metabolites in Major Depressive Disorder—Deep Insights into Their Pathophysiological Role and Potential Translational Applications.[J]Metabolites:2022,12(1).
(The article is excerpted from popular science literature and does not provide any medical guidance.)
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