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Written by Yu Yu, edited by Wang Sizhen Microglia are inherent immune cells in the central nervous system, which are involved in the regulation of astrocyte development, synaptic pruning, and removal of myelin debris [1]
.
Previous studies have shown that the intestinal flora plays an important role in maintaining the maturation and function of microglia under steady-state conditions and subsequent disordered conditions.
For example, under sterile conditions, the morphology and number of microglia Will change, and its antiviral function will be weakened.
Short-chain fatty acids (SCFAs) play a vital role in this process, and SCFAs will also aggravate the disease process of Parkinson’s disease[2, 3 ]
.
In the Alzheimer's disease (Alzheimer's disease, AD) mouse model, the lack of intestinal flora can lead to the reduction of β-amyloid (Aβ) deposition [4]; in the multiple sclerosis (MS) model, SCFAs are involved Regulate the function of mitochondria in Treg cells [5]
.
Based on these research advances, scientists came up with the constructive concept of the gut-brain axis
.
Studies have shown that many immune responses are accompanied by changes in the metabolic state of cells, but the specific mechanism of the regulation of immune metabolism by the flora is still unclear
.
On November 2, 2021, the Marco Prinz team of the University of Freiburg in Germany published an article titled "Microbiota-derived acetate enables the metabolic fitness of the brain innate immune system during health and disease" on Cell Metabolism, which clarified the microorganisms The source of acetate promotes the maturation of microglia and regulates their metabolism under steady-state conditions, and regulates the mechanism of microglia phagocytosis in the case of neurodegenerative diseases [6]
.
First, the researchers compared the bulk RNA-seq (Figure 1A) and ChIP-seq data (Figure 1 D, E) of microglia under sterile (GF) and specific pathogen-free (SPF) conditions, and Ingenuity pathway analysis (ingenuity pathway analysis, IPA) was done on differential genes
.
The results of IPA analysis showed that in the GF group, pathways such as immune cell proliferation and cell survival were activated, and pathways such as macrophage development, cytokine quantity, neuroinflammatory signal transduction pathway, and STAT3 pathway were inhibited (Figure 1 B) , C), these results are consistent with the view that the function of microglia in the GF group is immature
.
In addition, the results of IPA also enriched pathways related to metabolism such as lipid concentration, number of mitochondria, and macrophage reactive oxygen species (ROS) production (Figure 1 B, C)
.
These results suggest that there may be changes in the proliferation, activation, and metabolism of microglia in the GF group (Figure 1)
.
Figure 1 RNA-seq, ChIP-seq difference and IPA results between GF group and SPF group
.
(Source: Erny D et al.
, Cell Metab, 2021) Next, the researchers focused on the metabolism of microglia.
They conducted a comprehensive metabolomics analysis of microglia in the SPF and GF groups.
107 significantly different metabolites were found.
Among them, the tricarboxylic acid cycle, purine metabolism, and nicotinate and nicotinamide metabolism of microglia were changed due to the lack of microorganisms (Figure 2)
.
The author further applied flow cytometry to detect the number of mitochondria, lipid droplets, lysosomes and ROS production in microglia under two conditions.
Among them, the number of mitochondria in microglia in the GF group was significantly increased.
Production has also increased significantly (Figure 3)
.
Figure 2 Targeted metabolomics analysis results of microglia in GF and SPF groups (Source: Erny D et al.
, Cell Metab, 2021) Figure 3 Flow cytometry observation of microglia in GF and SPF groups The content of the various components
.
(Source: Erny D et al.
, Cell Metab, 2021) So what exactly changed the function of microglia in the GF group? Previous studies have shown that SCFAs, acetate, propionate, and butyrate are essential for the maturation and function of microglia under steady-state and pathological environments [2], However, it is unclear whether these different SCFAs work together or individually on microglia
.
Therefore, the researchers added the SCFAs mixture and acetate, propionate, and butyrate to the drinking water of the GF group mice.
The results showed that the SCFAs mixture group and the acetate group mouse brain microglia The density (Figure 4 A, B), morphology (Figure 4 D) and DDit4 (DNA damage-inducing transcript 4) gene expression (Figure 4 C) are similar to those in the SPF group, but the propionate and butyrate groups are smaller The condition of murine microglia has not improved (Figure 4 AC)
.
In addition, the number of mitochondria in the microglia of the SCFAs and acetate treatment groups also returned to the level of the GF group (Figure 5)
.
This shows that acetate plays a vital role in regulating the maturation and metabolism of microglia
.
Figure 4 Changes in the number and morphology of microglia after treatment with SCFAs (Source: Erny D et al.
, Cell Metab, 2021) Figure 5 Changes in mitochondria in microglia after treatment with SCFAs (Source: Erny D et al.
, Cell Metab, 2021) Since acetate plays such an important role in regulating the function of microglia under normal physiological conditions, does it have the same mechanism in disease conditions? Previous studies in Marco Prinz's laboratory found that Aβ deposition was reduced in the GF group AD mouse model (5xFAD), but it is not clear whether SCFAs are involved in regulating the changes in Aβ deposition [4]
.
So they experimented with the 5xFAD mouse model
.
The 5xFAD mice in the GF group were fed drinking water containing acetate, and the Aβ deposition in their brains was observed
.
The results showed that the Aβ deposition and the number of microglia in the brain of the GF+acetate group were close to those in the SPF group (Figure 6 AD), but the Aβ deposition in the brain of the 5xFAD mice in the GF group was significantly less than that of the other two groups.
There were more plasma cells than the other two groups (Figure 6 BD), and more microglia gathered around Aβ plaques in the brains of 5xFAD mice in the GF group (Figure 6 C, E)
.
The researchers further observed the phagocytic ability of Aβ plaques and the metabolism of microglia in 5xFAD mice that were given acetate drinking water, and found that the phagocytic ability of microglia in the acetate group and the metabolism of microglia ROS are all increased (Figure 7 F, H), which indicates that acetate is also involved in regulating the phagocytosis and metabolism of microglia under neurodegenerative diseases
.
Figure 6 The number of microglia and Aβ in the brain of 5xFAD mice treated with acetate were the same as those in the SPF group (Source: Erny D et al.
, Cell Metab, 2021) Figure 7 Microglia of 5xFAD mice in the acetate group Both phagocytic capacity and ROS are increased (Source: Erny D et al.
, Cell Metab, 2021) Conclusion and discussion of the article, inspiration and prospects In short, this work combines transcriptomics technology, epigenetics technology, and metabolomics Technology and other means clarified the regulation of the intestinal flora on the metabolic state of microglia, and found the most critical component that regulates the metabolic function of microglia under physiological and pathological conditions-microbial source acetate, Reveal the mechanism of intestinal microbes regulating the brain immune system
.
However, this study also has some problems to be solved
.
For example, the Aβ deposition in the brain of 5xFAD mice in the GF group was significantly less than that in the SPF group.
In this case, how does the behavior of the 5xFAD mice in learning, cognition, and memory compare to the SPF group? Is it worse or better? Or is there no change? In addition, the infiltration of peripheral immune cells often occurs in AD mice.
Is the intestinal flora also involved in the function of peripheral immune cells that infiltrate the brain? These issues are worth exploring in the future
.
Original link: https:// Selection of previous articles [1] Sci Adv︱ Is it beneficial to eat more? 7 kinds of amino acid nutrients can improve neurodegenerative dementia dysfunction [2] Nat Metab︱ Tang Qiqun/Qian Shuwen team found that M2 macrophages promote thermogenesis of adipose tissue through sympathetic nerves [3] Nature︱ Behind the practice and performance of bird singing Neural dynamics-stereotyped singing but with heartbeat signals [4] PNAS︱ Chen Sijie’s research group developed a new type of aggregation-inducing luminescence probe for three-dimensional myelin fluorescence imaging of sciatic nerve and brain tissue [5] Sci Adv | Adolescent High Glucose Ingestion is a potential risk factor for the development of mental illness [6] Nat Biotechnol | Li Yulong's laboratory develops a new fluorescent probe to detect the spatiotemporal dynamic changes of endocannabinoids [7] Discovered by Nat Aging︱ Wang Guohao/Lu Wei/Hou Xianyu and others Neurons accumulate lipid peroxides to activate the microglia NLRP3 inflammasome to promote demyelination and neuronal degeneration [8] Cell Rep︱ for the first time! A new mechanism by which the axon guide molecule Robo2 affects the function of the hippocampal circuit [9] A new discovery from the Neuron︱ Nobel Prize Laboratory! The olfactory landmarks and paths are integrated to form a cognitive spatial map [10] Nat Neurosci︱ breakthrough! Corticospinal neurons transmit complex motor signals to the spinal cord and striatum loops.
Recommended high-quality scientific research training courses [1] Discount countdown ︱ EEG data analysis introductory class (online: 2021.
12.
4~12.
16) [2] Online Brain Electrical Data Analysis Full Course (2021.
12.
19~2022.
1.
9) Lectures/Conferences/Seminars/Forums [1] Review of the second phase of the Brain Talk Academician Forum: Axon Regeneration and Neural Stem Cell References (Slide up and down to view) [ 1]Baaklini CS, Rawji KS, Duncan GJ, et al.
Central Nervous System Remyelination: Roles of Glia and Innate Immune Cells [J].
Frontiers in molecular neuroscience, 2019, 12(225.
[2]Erny D,
.
Previous studies have shown that the intestinal flora plays an important role in maintaining the maturation and function of microglia under steady-state conditions and subsequent disordered conditions.
For example, under sterile conditions, the morphology and number of microglia Will change, and its antiviral function will be weakened.
Short-chain fatty acids (SCFAs) play a vital role in this process, and SCFAs will also aggravate the disease process of Parkinson’s disease[2, 3 ]
.
In the Alzheimer's disease (Alzheimer's disease, AD) mouse model, the lack of intestinal flora can lead to the reduction of β-amyloid (Aβ) deposition [4]; in the multiple sclerosis (MS) model, SCFAs are involved Regulate the function of mitochondria in Treg cells [5]
.
Based on these research advances, scientists came up with the constructive concept of the gut-brain axis
.
Studies have shown that many immune responses are accompanied by changes in the metabolic state of cells, but the specific mechanism of the regulation of immune metabolism by the flora is still unclear
.
On November 2, 2021, the Marco Prinz team of the University of Freiburg in Germany published an article titled "Microbiota-derived acetate enables the metabolic fitness of the brain innate immune system during health and disease" on Cell Metabolism, which clarified the microorganisms The source of acetate promotes the maturation of microglia and regulates their metabolism under steady-state conditions, and regulates the mechanism of microglia phagocytosis in the case of neurodegenerative diseases [6]
.
First, the researchers compared the bulk RNA-seq (Figure 1A) and ChIP-seq data (Figure 1 D, E) of microglia under sterile (GF) and specific pathogen-free (SPF) conditions, and Ingenuity pathway analysis (ingenuity pathway analysis, IPA) was done on differential genes
.
The results of IPA analysis showed that in the GF group, pathways such as immune cell proliferation and cell survival were activated, and pathways such as macrophage development, cytokine quantity, neuroinflammatory signal transduction pathway, and STAT3 pathway were inhibited (Figure 1 B) , C), these results are consistent with the view that the function of microglia in the GF group is immature
.
In addition, the results of IPA also enriched pathways related to metabolism such as lipid concentration, number of mitochondria, and macrophage reactive oxygen species (ROS) production (Figure 1 B, C)
.
These results suggest that there may be changes in the proliferation, activation, and metabolism of microglia in the GF group (Figure 1)
.
Figure 1 RNA-seq, ChIP-seq difference and IPA results between GF group and SPF group
.
(Source: Erny D et al.
, Cell Metab, 2021) Next, the researchers focused on the metabolism of microglia.
They conducted a comprehensive metabolomics analysis of microglia in the SPF and GF groups.
107 significantly different metabolites were found.
Among them, the tricarboxylic acid cycle, purine metabolism, and nicotinate and nicotinamide metabolism of microglia were changed due to the lack of microorganisms (Figure 2)
.
The author further applied flow cytometry to detect the number of mitochondria, lipid droplets, lysosomes and ROS production in microglia under two conditions.
Among them, the number of mitochondria in microglia in the GF group was significantly increased.
Production has also increased significantly (Figure 3)
.
Figure 2 Targeted metabolomics analysis results of microglia in GF and SPF groups (Source: Erny D et al.
, Cell Metab, 2021) Figure 3 Flow cytometry observation of microglia in GF and SPF groups The content of the various components
.
(Source: Erny D et al.
, Cell Metab, 2021) So what exactly changed the function of microglia in the GF group? Previous studies have shown that SCFAs, acetate, propionate, and butyrate are essential for the maturation and function of microglia under steady-state and pathological environments [2], However, it is unclear whether these different SCFAs work together or individually on microglia
.
Therefore, the researchers added the SCFAs mixture and acetate, propionate, and butyrate to the drinking water of the GF group mice.
The results showed that the SCFAs mixture group and the acetate group mouse brain microglia The density (Figure 4 A, B), morphology (Figure 4 D) and DDit4 (DNA damage-inducing transcript 4) gene expression (Figure 4 C) are similar to those in the SPF group, but the propionate and butyrate groups are smaller The condition of murine microglia has not improved (Figure 4 AC)
.
In addition, the number of mitochondria in the microglia of the SCFAs and acetate treatment groups also returned to the level of the GF group (Figure 5)
.
This shows that acetate plays a vital role in regulating the maturation and metabolism of microglia
.
Figure 4 Changes in the number and morphology of microglia after treatment with SCFAs (Source: Erny D et al.
, Cell Metab, 2021) Figure 5 Changes in mitochondria in microglia after treatment with SCFAs (Source: Erny D et al.
, Cell Metab, 2021) Since acetate plays such an important role in regulating the function of microglia under normal physiological conditions, does it have the same mechanism in disease conditions? Previous studies in Marco Prinz's laboratory found that Aβ deposition was reduced in the GF group AD mouse model (5xFAD), but it is not clear whether SCFAs are involved in regulating the changes in Aβ deposition [4]
.
So they experimented with the 5xFAD mouse model
.
The 5xFAD mice in the GF group were fed drinking water containing acetate, and the Aβ deposition in their brains was observed
.
The results showed that the Aβ deposition and the number of microglia in the brain of the GF+acetate group were close to those in the SPF group (Figure 6 AD), but the Aβ deposition in the brain of the 5xFAD mice in the GF group was significantly less than that of the other two groups.
There were more plasma cells than the other two groups (Figure 6 BD), and more microglia gathered around Aβ plaques in the brains of 5xFAD mice in the GF group (Figure 6 C, E)
.
The researchers further observed the phagocytic ability of Aβ plaques and the metabolism of microglia in 5xFAD mice that were given acetate drinking water, and found that the phagocytic ability of microglia in the acetate group and the metabolism of microglia ROS are all increased (Figure 7 F, H), which indicates that acetate is also involved in regulating the phagocytosis and metabolism of microglia under neurodegenerative diseases
.
Figure 6 The number of microglia and Aβ in the brain of 5xFAD mice treated with acetate were the same as those in the SPF group (Source: Erny D et al.
, Cell Metab, 2021) Figure 7 Microglia of 5xFAD mice in the acetate group Both phagocytic capacity and ROS are increased (Source: Erny D et al.
, Cell Metab, 2021) Conclusion and discussion of the article, inspiration and prospects In short, this work combines transcriptomics technology, epigenetics technology, and metabolomics Technology and other means clarified the regulation of the intestinal flora on the metabolic state of microglia, and found the most critical component that regulates the metabolic function of microglia under physiological and pathological conditions-microbial source acetate, Reveal the mechanism of intestinal microbes regulating the brain immune system
.
However, this study also has some problems to be solved
.
For example, the Aβ deposition in the brain of 5xFAD mice in the GF group was significantly less than that in the SPF group.
In this case, how does the behavior of the 5xFAD mice in learning, cognition, and memory compare to the SPF group? Is it worse or better? Or is there no change? In addition, the infiltration of peripheral immune cells often occurs in AD mice.
Is the intestinal flora also involved in the function of peripheral immune cells that infiltrate the brain? These issues are worth exploring in the future
.
Original link: https:// Selection of previous articles [1] Sci Adv︱ Is it beneficial to eat more? 7 kinds of amino acid nutrients can improve neurodegenerative dementia dysfunction [2] Nat Metab︱ Tang Qiqun/Qian Shuwen team found that M2 macrophages promote thermogenesis of adipose tissue through sympathetic nerves [3] Nature︱ Behind the practice and performance of bird singing Neural dynamics-stereotyped singing but with heartbeat signals [4] PNAS︱ Chen Sijie’s research group developed a new type of aggregation-inducing luminescence probe for three-dimensional myelin fluorescence imaging of sciatic nerve and brain tissue [5] Sci Adv | Adolescent High Glucose Ingestion is a potential risk factor for the development of mental illness [6] Nat Biotechnol | Li Yulong's laboratory develops a new fluorescent probe to detect the spatiotemporal dynamic changes of endocannabinoids [7] Discovered by Nat Aging︱ Wang Guohao/Lu Wei/Hou Xianyu and others Neurons accumulate lipid peroxides to activate the microglia NLRP3 inflammasome to promote demyelination and neuronal degeneration [8] Cell Rep︱ for the first time! A new mechanism by which the axon guide molecule Robo2 affects the function of the hippocampal circuit [9] A new discovery from the Neuron︱ Nobel Prize Laboratory! The olfactory landmarks and paths are integrated to form a cognitive spatial map [10] Nat Neurosci︱ breakthrough! Corticospinal neurons transmit complex motor signals to the spinal cord and striatum loops.
Recommended high-quality scientific research training courses [1] Discount countdown ︱ EEG data analysis introductory class (online: 2021.
12.
4~12.
16) [2] Online Brain Electrical Data Analysis Full Course (2021.
12.
19~2022.
1.
9) Lectures/Conferences/Seminars/Forums [1] Review of the second phase of the Brain Talk Academician Forum: Axon Regeneration and Neural Stem Cell References (Slide up and down to view) [ 1]Baaklini CS, Rawji KS, Duncan GJ, et al.
Central Nervous System Remyelination: Roles of Glia and Innate Immune Cells [J].
Frontiers in molecular neuroscience, 2019, 12(225.
[2]Erny D,
