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Click on the blue word to focus on our gut microbiota disorders are closely related to inflammatory bowel disease, obesity, cardiovascular disease, depression, anxiety and other diseases
.
Animal experiments have shown that the gut microbiota modulates the brain's production of neurotransmitters such as dopamine, norepinephrine, serotonin, and gamma-aminobutyric acid, which in turn affects brain development and myelination, as well as social, emotional, and anxiety-like behaviors
.
Gut microbiota transplantation based on long-term interactions between gut microbiota and brain ameliorates multiple sclerosis and depressive-like behavioral disorder in mice
.
4-Ethylphenyl sulfate (4EPS), a metabolite of gut microbiota, is elevated in autism serum
.
Intestinal flora can convert tyrosine to 4-ethylphenyl (4EP) by tyrosine ammonia lyase (encoded by BACOVA_01194 gene), phenolic acid decarboxylase (encoded by PAD gene), etc.
, and then sulfated to 4EPS
.
In 2013, Sarkis K.
Mazmanian of Caltech found that 3 weeks of continuous intraperitoneal injection of 4EPS induced obvious anxiety-like behavior in mice, leaving the suspense of how 4EPS is produced in the body and how it causes anxiety behavior
.
After 9 years, on February 14, 2022, Sarkis K.
Mazmanian's research team found the answer: the gut microbial metabolite 4EPS regulates anxiety behavior by acting on oligodendrocytes
.
Bacteroides ovale and Lactobacillus plantarum can convert p-coumaric acid to 4EP, but the conversion rate is not high
.
The researchers then genetically modified these bacteria, inserting both the BACOVA_01194 and PAD genes into
B.
At the same time, they constructed a mutant of the BACOVA_01194 gene of Bacteroides ovale that hardly transformed p-coumaric acid
.
Figure 1: Functional Ultrasound Imaging Reveals Brains of 4EP-Positive Mice Germ-free Mice Receiving Bacteroides ovale symbiosis with BACOVA_01194 Gene Mutants After symbiosis, called 4EP Negative Mice, Receiving Bacteroides ovale with Two BACOVA_01194 and PAD Gene Insertions After symbiosis, they were called 4EP-positive mice
.
A series of behavioral experiments showed that 4EP-positive mice exhibited anxiety-like behavior disorder and stereotyped behavior disorder
.
Compared with 4EP-negative mice P mice, 4EP-positive mice had significantly higher levels of 4EP in urine, feces, and brain tissue, and almost no 4EP was found in blood
.
Functional ultrasound imaging technology found abnormal functional connections in the hippocampus, hypothalamus, thalamus, and amygdala of 4EP-positive mice
.
In order to further explore the molecular mechanism of 4EP in the brain, they performed mRNA sequencing technology in the above-mentioned brain regions associated with elevated 4EP levels.
Among them, the paraventricular nucleus (PVT) region of the thalamus has the largest number of differentially expressed genes, and the cell types with down-regulated gene expression.
For neurons, newly formed oligodendrocytes and mature oligodendrocytes
.
Figure 2: Reduced maturation of oligodendrocytes in 4EP-positive mice.
Immunofluorescence experiments further found that (compared with 4EP-negative mice) the number of immature oligodendrocytes in the PVT region of 4EP-positive mice increased, and the number of mature oligodendrocytes increased.
The number has decreased
.
Electron microscopy also showed that 4EP-positive mice had a reduced proportion of neuronal myelination in the PVT region and reduced oligodendrocyte-neuron contact, suggesting that 4EP could reduce oligodendrocyte maturation.
.
Clemastine fumarate is a drug that promotes the maturation of oligodendrocytes
.
4EP-positive mice treated with clemastine fumarate ameliorated anxiety-like behavioral disorders while promoting oligodendrocyte maturation
.
Overall, this paper reveals the pathway of 4EP biosynthesis in mice.
4EP in the peripheral system can enter the brain through the blood-brain barrier, specifically act on the paraventricular nucleus of the thalamus, reduce neuronal myelination, and ultimately cause anxiety.
such behavior
.
[Reference] 1.
https://doi.
org/10.
1038/s41586-022-04396-82.
Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders The pictures in the text are from the reference
.
Animal experiments have shown that the gut microbiota modulates the brain's production of neurotransmitters such as dopamine, norepinephrine, serotonin, and gamma-aminobutyric acid, which in turn affects brain development and myelination, as well as social, emotional, and anxiety-like behaviors
.
Gut microbiota transplantation based on long-term interactions between gut microbiota and brain ameliorates multiple sclerosis and depressive-like behavioral disorder in mice
.
4-Ethylphenyl sulfate (4EPS), a metabolite of gut microbiota, is elevated in autism serum
.
Intestinal flora can convert tyrosine to 4-ethylphenyl (4EP) by tyrosine ammonia lyase (encoded by BACOVA_01194 gene), phenolic acid decarboxylase (encoded by PAD gene), etc.
, and then sulfated to 4EPS
.
In 2013, Sarkis K.
Mazmanian of Caltech found that 3 weeks of continuous intraperitoneal injection of 4EPS induced obvious anxiety-like behavior in mice, leaving the suspense of how 4EPS is produced in the body and how it causes anxiety behavior
.
After 9 years, on February 14, 2022, Sarkis K.
Mazmanian's research team found the answer: the gut microbial metabolite 4EPS regulates anxiety behavior by acting on oligodendrocytes
.
Bacteroides ovale and Lactobacillus plantarum can convert p-coumaric acid to 4EP, but the conversion rate is not high
.
The researchers then genetically modified these bacteria, inserting both the BACOVA_01194 and PAD genes into
B.
At the same time, they constructed a mutant of the BACOVA_01194 gene of Bacteroides ovale that hardly transformed p-coumaric acid
.
Figure 1: Functional Ultrasound Imaging Reveals Brains of 4EP-Positive Mice Germ-free Mice Receiving Bacteroides ovale symbiosis with BACOVA_01194 Gene Mutants After symbiosis, called 4EP Negative Mice, Receiving Bacteroides ovale with Two BACOVA_01194 and PAD Gene Insertions After symbiosis, they were called 4EP-positive mice
.
A series of behavioral experiments showed that 4EP-positive mice exhibited anxiety-like behavior disorder and stereotyped behavior disorder
.
Compared with 4EP-negative mice P mice, 4EP-positive mice had significantly higher levels of 4EP in urine, feces, and brain tissue, and almost no 4EP was found in blood
.
Functional ultrasound imaging technology found abnormal functional connections in the hippocampus, hypothalamus, thalamus, and amygdala of 4EP-positive mice
.
In order to further explore the molecular mechanism of 4EP in the brain, they performed mRNA sequencing technology in the above-mentioned brain regions associated with elevated 4EP levels.
Among them, the paraventricular nucleus (PVT) region of the thalamus has the largest number of differentially expressed genes, and the cell types with down-regulated gene expression.
For neurons, newly formed oligodendrocytes and mature oligodendrocytes
.
Figure 2: Reduced maturation of oligodendrocytes in 4EP-positive mice.
Immunofluorescence experiments further found that (compared with 4EP-negative mice) the number of immature oligodendrocytes in the PVT region of 4EP-positive mice increased, and the number of mature oligodendrocytes increased.
The number has decreased
.
Electron microscopy also showed that 4EP-positive mice had a reduced proportion of neuronal myelination in the PVT region and reduced oligodendrocyte-neuron contact, suggesting that 4EP could reduce oligodendrocyte maturation.
.
Clemastine fumarate is a drug that promotes the maturation of oligodendrocytes
.
4EP-positive mice treated with clemastine fumarate ameliorated anxiety-like behavioral disorders while promoting oligodendrocyte maturation
.
Overall, this paper reveals the pathway of 4EP biosynthesis in mice.
4EP in the peripheral system can enter the brain through the blood-brain barrier, specifically act on the paraventricular nucleus of the thalamus, reduce neuronal myelination, and ultimately cause anxiety.
such behavior
.
[Reference] 1.
https://doi.
org/10.
1038/s41586-022-04396-82.
Microbiota Modulate Behavioral and Physiological Abnormalities Associated with Neurodevelopmental Disorders The pictures in the text are from the reference
