Microbiome-gut-brain axis

The gut and brain are connected through bidirectional pathways involving nerves, endocrine, and immune systems, forming the gut-brain axis, which closely links emotional cognition in the brain with the functions of the peripheral gut. The gut-brain axis mainly includes structures such as the central nervous system, the enteric nervous system, the autonomic nervous system, and the hypothalamic-pituitary-adrenal axis, with all systems participating in the regulation of the gastrointestinal tract and emotions. Numerous studies have proven the mutual regulatory effects between gut microbiota and the brain and gut, together forming the microbiome-brain-gut axis. As the core of the microbiome-brain-gut axis, gut microbiota can influence the central nervous system through various pathways while also being regulated by the central system.

Ways gut microbiota influence the central system

1. Vagus nerve

The enteric nervous system, composed of nerve components within the gastrointestinal wall, is referred to as the 'second brain.' Its communication with the central nervous system is mainly mediated by the vagus nerve. The vagus nerve is the most direct intermediary pathway between the gastrointestinal tract and the brain. The enteric nervous system forms synaptic connections with the vagus nerve, creating the 'gut microbiota-enteric nervous system-vagus nerve-brain' information transmission pathway. A related study found that the improvement of abnormal behavior in the brain by probiotics is mediated by the vagus nerve. After mice consumed lactic acid bacteria, their anxiety improved, but this improvement weakened or even disappeared after cutting the vagus nerve. Moreover, gut microbiota can produce a series of important components involved in neural activation, including gamma-aminobutyric acid, histamine, serotonin, and dopamine. Among them, peripheral serotonin acts as a neurotransmitter in the brain, influencing the central nervous system through the bloodstream, with about 90% produced in the gut by enterochromaffin cells, a special type of immune cell, and neurons. Researchers found that in germ-free mice, the serotonin level produced by enterochromaffin cells was only 40% of that in normal microbiota mice. Transplanting normal gut microbiota into germ-free mice can restore their serotonin levels. Further analysis of their gut microbiota structure revealed that 20 species of spore-forming bacteria are involved in regulating serotonin levels, and the survival and reproduction of these bacteria depend on the abundant secretion of serotonin.

2. Immune system

Since gut microbiota can influence the immune system, immune activation may be a pathway of the microbiome-brain-gut axis. In fact, it has been confirmed that immune signals can lead to or promote the occurrence and development of certain neurological diseases, such as degenerative diseases, anxiety disorders, and depression. Microbial-related compounds such as peptidoglycan, phospholipids (characteristic components of Gram-positive bacterial cell walls), lipopolysaccharides (characteristic components of Gram-negative bacterial cell walls), bacterial lipoproteins, and flagellin can activate various immune cells, especially innate immune cells like macrophages, neutrophils, and dendritic cells. Once activated, these cells produce a large number of pro-inflammatory cytokines, such as TNF-α, IL-1, and IL-6, which can diffuse and enter the brain through transport proteins, acting on neurons and glial cells, especially on receptors expressed by microglia (innate immune phagocytic cells originating in the brain), altering their activity and physiological functions. In the peripheral nervous system, these cytokines can act on receptors of afferent nerves, changing the long-distance regulatory signals sent from peripheral organs to the central nervous system, thereby affecting central nervous system function.

3. Tryptophan metabolism

Tryptophan is an essential amino acid commonly found in protein-rich foods such as eggs, fish, and meat. The metabolism of tryptophan in the gastrointestinal tract has three basic pathways: (1) the kynurenine pathway, where most tryptophan is metabolized, enzymatically generating kynurenine; (2) in enterochromaffin cells, tryptophan is hydroxylated by tryptophan hydroxylase 1 and decarboxylated to form serotonin (5-hydroxytryptamine); (3) gut microbiota can metabolize tryptophan into ligands for aryl hydrocarbon receptors (AhR), including indole-3-aldehyde, indole-3-acetic acid, indole-3-propionic acid, indole-3-aldehyde, and indole propionic acid. Ligands for AhR can cross the blood-brain barrier and activate AhR in astrocytes (resident macrophages in the brain and spinal cord, serving as the main source of immune defense in the central nervous system) and microglia. Multiple studies have found that the severity of neurological diseases such as schizophrenia and bipolar disorder is related to AhR-related genes.

4. Short-chain fatty acids

The main source of short-chain fatty acids (SCFAs) in the human body is microbial fiber fermentation, while fermented foods can be a secondary source. The endogenous sources of SCFAs include host metabolism of long-chain fatty acids, conversion of pyruvate to acetate, and the breakdown of proteins by the microbiota. SCFAs influence the central nervous system mainly through the following four pathways: (1) binding to G protein-coupled receptors Gpr41 and Gpr43, acting as signaling molecules to stimulate the sympathetic and autonomic nervous systems; (2) activating Gpr41 and Gpr43 receptors on the surface of intestinal epithelial cells and immune cells, causing inflammatory responses or immune responses. This process participates in acute infections, but if the regulatory mechanism is abnormal, it may lead to excessive responses, increasing intestinal permeability and the absorption of neuroactive metabolites; (3) directly activating the sympathetic nervous system through Gpr41 receptors located on sympathetic neurons; (4) crossing the blood-brain barrier to influence neural signals and neurotransmitter products.

The central nervous system and the enteric nervous system influence each other through nerves, immunity, metabolism, etc., and the role of gut microbiota is crucial. Gut microbiota affect the stability and development of the central nervous system through the microbiome-brain-gut axis, thus the study of the microbiome-brain-gut axis is also of great significance for research on neurological diseases.

Microbiome-gut-brain axis and neuropsychiatric diseases

1. Alzheimer's disease

Alzheimer's disease is an irreversible form of dementia that triggers brain disorders and leads to memory and cognitive issues, ultimately affecting daily life activities. In an exploratory intervention study on supplementing probiotics for Alzheimer's patients, researchers found that various probiotic treatments could influence the composition of the gut microbiota and serum tryptophan metabolism in patients. After treatment, patients receiving probiotic therapy showed lower intestinal permeability and a richer variety of gut microbiota compared to the control group. In summary, this suggests the potential effectiveness of probiotics in improving cognitive function in Alzheimer's patients.

2. Bipolar Disorder

In fecal microbiome analysis, compared to healthy controls, patients with bipolar disorder showed a decrease in the number of Firmicutes and Bacteroides, and the degree of reduction was also related to the severity of the patients' symptoms. A recent clinical study confirmed that interventions with Lactobacillus and Bifidobacterium significantly reduced the rate of psychiatric readmission in discharged patients.

3. Schizophrenia

Recent findings indicate differences in the gut microbiota composition between chronic schizophrenia patients and healthy controls. Compared to healthy controls, schizophrenia patients had lower levels of Proteobacteria, Haemophilus, and Clostridia, while levels of Anaerococcus were higher. Additionally, mice that received fecal transplants from schizophrenia microbiota had lower levels of glutamate in the hippocampus, higher levels of glutamine and gamma-aminobutyric acid, and exhibited behaviors associated with schizophrenia.

Conclusion

Currently, the interaction between gut microbiota and the central nervous system has been confirmed, and the pathways of their interaction, namely the microbiota-brain-gut axis, are also basically clear. Although some regulatory mechanisms of the microbiota-brain-gut axis have been confirmed, further in-depth research is needed to clarify the details.

Note: This article is for informational purposes only and should not be considered medical guidance.