Aging Cell Review︱ Zhang Hong/Chen Yingzhi/Tian Mei collaborated to review the mechanism of gut microbiota regulating microglia function in cognitive aging

Written by ︱ Zhou Rui editor ︱ Wang Sizhen Aging is an inevitable life process that almost all living things have to go through
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In recent years, with the improvement of living standards and the advancement of medical technology, human life expectancy has been significantly prolonged
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The World Health Organization predicts that by 2050, the proportion of the aging population over the age of 60 will exceed 20% [1]
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Cognitive aging (cognitive aging) is a common phenomenon in aging population, which is defined as age-related cognitive function decline; its function is mainly manifested as the decline of working memory, episodic memory and decision-making ability, while language ability and counting ability decline.
There is no significant change [2]
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Neuroinflammation caused by aging can cause the release of cytokines, leading to the death of neurons in the brain and the decline of cognitive function [3]
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The continuous progress of cognitive aging can lead to cognitive dysfunction, which seriously affects the quality of life of the aging population and increases the risk of Alzheimer's disease [4]
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In recent years, the role of gut microbiota in tumor immunity, diabetes and obesity has been increasingly revealed
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The discovery of the gut-brain axis indicates that the gut microbiota plays an important role in the regulation of brain function, and its role in the regulation of cognitive function is gradually recognized, becoming an important potential method to delay cognitive aging [5]
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However, the mechanism by which the gut microbiota regulates brain function remains unclear
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 On March 13, 2022, Zhang Hong/Tian Mei's research group from the Second Affiliated Hospital of Zhejiang University School of Medicine and Chen Yingzhi's research group from Hong Kong Polytechnic University published a paper entitled "Microbiota-microglia connections in age-related "cognition decline", reviewed the main components of the gut microbiota in aging populations, outlined the relationship between changes in gut microbiota and cognitive decline from the perspective of neuroinflammation, and discussed the regulation of microglia in the brain by gut microbiota The possible pathway of function provides research ideas for the related research on the intervention of gut microbiota in the aging process
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1.
Disturbing factors affecting the composition of intestinal flora in adulthood and the composition of intestinal flora in the aging state So far, there are about 2172 kinds of microorganisms in the adult intestine, which are divided into 12 phyla
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Among them, about 93.
5% are Proteobacteria, Firmicutes, Actinobacteria and Bacteroidetes [6]
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Although the gut microbiota in adults is relatively stable, its composition can be influenced by factors such as mental state, dietary structure, drugs, geographic location, and life stage
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The authors focus on the role of mental state and diet: anxiety or depressive states can lead to increased abundance of gut microbiota involved in pathways that degrade butyrate or gamma-aminobutyric acid, whereas antidepressant treatment restores butyrate-producing gut microbiota Abundance of intestinal flora [7, 8]; high-fat diet can increase the proportion of Firmicutes/Bacteroidetes in the gut [9]
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In old age, the diversity and stability of the intestinal flora in the human body decreases, and the content of Bacteroidetes is relatively abundant, while the content of Firmicutes is relatively small
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Its composition is largely influenced by residential environment, exercise, nutrition, and age-related changes
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As a long-lived population, centenarians have their own unique composition of intestinal flora, dominated by Bacteroidetes and Proteobacteria [10] (Table 1)
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Table 1 Special composition of the gut microbiota of centenarians (Source: Rui Zhou et al.
, Aging Cell, 2022) 2.
Changes of microglia during cognitive aging Remaining immune cells play an important role in regulating neurogenesis, synapse shaping, and regulating neuroinflammation
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In adulthood, microglia are regulated by the microenvironment of the central nervous system and maintain a relatively dynamic equilibrium state [11]
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During aging, the morphology and function of microglia undergo dramatic changes
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Several common variations include dystrophic microglia and hypertrophic microglia/primed microglia
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Dystrophic microglia are characterized by increased cell body size, shortened lengths of dendritic branches, and interruptions in continuity, changes that support the false hypothesis that microglia lose their ability to respond to chronic inflammatory stimuli in the senescent state [12]
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Hypertrophic microglia/primed microglia are commonly used to describe activated microglia in aging brains or Alzheimer's disease brains, with morphological changes manifested by enlarged cell bodies and elongated dendritic branches [13]
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Functionally, the phagocytic function of senescent microglia changed significantly, and the expression of phagocytic receptors such as CD36, TREM2b and CD14 increased [14]
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However, senescent microglia cannot effectively clear Aβ plaques in the brain [15]
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At the same time, the impaired Ca2+ signaling of senescent microglia induces the release of pro-inflammatory factors, aggravates neuroinflammation, and then damages the nerves in the brain [16] (Fig.
1)
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Figure 1 Inflammatory factors from atherosclerosis and microglia aggravate neuroinflammation (Source: Rui Zhou et al.
, Aging Cell, 2022) 3.
The effect of gut microbiota on microglia in cognitive aging Regulatory pathways The gut microbiota plays an important role in the development, maturation and function of microglia [17]
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So far, the gut microbiota mainly regulates the function of microglia through three pathways, and then participates in the regulation of cognitive function in the aging brain
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(1) Intestinal flora-vagal nerve-microglia: Short-chain fatty acids (SCFAs) or extracellular vesicles secreted by intestinal flora can be taken up by vagal afferent junctions in the gut, regulating vagal nerve activity, thereby affecting microglial activity.
The function of glial cells is involved in the regulation of cognitive function in the brain [18]
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(2) Intestinal flora-blood circulation-microglia: Metabolites secreted by intestinal flora, such as SCFAs, can be transported in the intestinal lumen by monocarboxylate transporters (monocarboxylate transporters) on the surface of intestinal epithelial cells.
MCTs) are transported through the intestinal barrier into the blood circulation and cross the blood-brain barrier to regulate the function of microglia, thereby affecting cognitive function [19, 20]
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(3) Intestinal flora-immune cells-microglia: In the aging state, microbiota-originated molecular patterns derived from the intestinal flora can also be compared with B cells or T cells in the peripheral immune system.
The interaction induces the release of pro-inflammatory factors, aggravates neuroinflammation and increases the infiltration of T cells in the brain, thereby directly or indirectly regulating the function of microglia in the brain [21, 22] (Figure 2)
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Figure 2 The relationship between gut microbiota and microglia (Source: Rui Zhou et al.
, Aging Cell, 2022) 4.
Summary and outlook In conclusion, the relationship between gut microbiota and microglia It plays an important role in the regulation of neuroinflammation and cognitive function
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However, existing research has only shown the tip of the iceberg of the intricate interactions between gut microbiota and microglia
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Currently, the overarching question that needs to be answered is what is the exact mechanism by which the gut microbiota modulates microglial phenotype and function
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The advent of new technologies such as single-cell sequencing, spatial transcriptomics, and in situ high-throughput bacterial tracing will bring new approaches to related research, while in vivo tracing techniques such as two-photon microscopy and positron emission tomography will Provide strong support for the in vivo display of the interaction between gut microbiota and microglia
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With the deepening of relevant research, the mechanism of cognitive decline or cognitive dysfunction caused by aging will be further elucidated, and the defense methods of cognitive aging will be expected to be found
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Link to the original text: https://onlinelibrary.
wiley.
com/doi/10.
1111/acel.
13599 The first author of the article is Dr.
Zhou Rui of the Second Affiliated Hospital of Zhejiang University School of Medicine, and the corresponding author is Zhang Hong of the Second Affiliated Hospital of Zhejiang University School of Medicine Professor, Professor Tian Mei from the Second Affiliated Hospital of Zhejiang University School of Medicine (now the Institute of Human Phenotyping, Fudan University) and Associate Professor Chen Yingzhi, Department of Health Technology and Informatics, Hong Kong Polytechnic University
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Professor Zhang Hong (left), Professor Tian Mei (middle), and Associate Professor Chen Yingzhi (right)
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(Photo provided by: Zhang Hong/Tian Mei/Chen Yingzhi's team) Talent recruitment[1] "Logical Neuroscience" is looking for an associate editor/editor/operation position (online office) Selected articles from previous issues[1] Trends Neurosci Review︱Biological Clock Research progress on circadian rhythm of blood glucose [2] Front Aging Neurosci︱ Sun Tao's group proposed a new protocol for 11C-PiB-PET imaging for early diagnosis of Alzheimer's disease [3] Front Aging Neurosci Review︱Astrocytes in the brain Double-edged sword effect in neurovascular unit after ischemia [4] HBM︱Region-based method for spatial standardization of brain MRI images to achieve accurate registration of brain regions [5]J Neuroinflammation︱Peng Ying's research group reveals microglia The regulatory role of mitophagy in morphine-induced central nervous system inflammatory inhibition [6] Curr Biol︱ Novelty detection and the relationship between surprise and recency in the primate brain [7] Revealed by Neurosci Bull︱ Qian Lingjia's group Homocysteine ​​affects cognitive function by regulating DNA methylation in the process of chronic stress【8】Front Aging Neurosci︱Ma Tao's team reveals the role of traditional Chinese medicine compound in improving energy metabolism in Alzheimer's disease through multiple pathways and multiple targets Mechanism【9】Aging Cell︱Gao Xu’s group found that good sleep quality can delay the accelerated aging caused by air pollution【10】Autophagy︱Shen Hanming’s group revealed a new mechanism of autophagy-related protein WIPI2 regulating mitochondrial outer membrane protein degradation and mitophagy Recommended high-quality scientific research training courses [1] Symposium on Patch Clamp and Optogenetics and Calcium Imaging Technology Tencent Conference on May 14-15 [2] Scientific Research Skills ︱ The 4th NIR Brain Function Data Analysis Class (Online: 2022.
4.
18~4.
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