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. 2019 Jan 7;216(1):41-59.
doi: 10.1084/jem.20180794. Epub 2018 Nov 1.

Microbiome-microglia Connections via the Gut-Brain Axis

Free PMC article

Microbiome-microglia Connections via the Gut-Brain Axis

Reem Abdel-Haq et al. J Exp Med. .
Free PMC article


Microglia, the resident immune cells in the brain, are essential for modulating neurogenesis, influencing synaptic remodeling, and regulating neuroinflammation by surveying the brain microenvironment. Microglial dysfunction has been implicated in the onset and progression of several neurodevelopmental and neurodegenerative diseases; however, the multitude of factors and signals influencing microglial activity have not been fully elucidated. Microglia not only respond to local signals within the brain but also receive input from the periphery, including the gastrointestinal (GI) tract. Recent preclinical findings suggest that the gut microbiome plays a pivotal role in regulating microglial maturation and function, and altered microbial community composition has been reported in neurological disorders with known microglial involvement in humans. Collectively, these findings suggest that bidirectional crosstalk between the gut and the brain may influence disease pathogenesis. Herein, we discuss recent studies showing a role for the gut microbiome in modulating microglial development and function in homeostatic and disease conditions and highlight possible future research to develop novel microbial treatments for disorders of the brain.


Figure 1.
Figure 1.
Gut microbiota influences microglial development and maturation. (A) Microglial maturation states can be described in three primary phases: early, pre-, and adult microglia. Each phase of development can be defined by expression of a subset of genes that correspond to a core set of microglial functions. Early and premicroglia have two main functions during early brain development: synaptic remodeling and subsequent shaping of neural circuitry and regulating the number of neurons through mechanisms of programmed cell death (PCD). A few weeks after birth, microglia transition to the “adult microglia” stage, in which they constantly survey their immediate surroundings and actively maintain homeostatic conditions. In the presence of tissue damage or an immune stimulus, microglia activate pro- and anti-inflammatory signaling cascades to clear pathogens and repair tissue damage to restore brain health. Recent evidence suggests that prenatal and postnatal inputs from the gut microbiota are critical for microglial maturation and function. (B) In SPF mice, a diverse gut microbiota promotes microglial development and maturation. Microglial development appears arrested in GF mice, as supported by high expression of genes characteristic of early and premicroglia in microglia from adult GF mice. This arrest in microglial maturation impedes their ability to initiate a sufficient immune response during infection. EMP, erythromyeloid progenitor.
Figure 2.
Figure 2.
Gut–brain communication pathways. Communication between the gut microbiota and the CNS encompasses several conduits along neural, enteric, and immune pathways. (A) Proper microglial maturation and behavior is dependent on crosstalk along the gut–brain axis. Information about the state of peripheral inflammation and GI health is received in the CNS via vagal afferents that innervate the GI tract and can influence microglial activation and neuroinflammation. Fine-tuning of the intestinal barrier by gut microbiota and their interactions with gut immune cells modulates peripheral inflammation and can trigger downstream inflammatory responses in the CNS. BBB-permeable bacterial metabolites, including SCFAs, modulate microglial maturation through mechanisms that are yet to be determined. (B) The absence of gut microbes in GF mice confers a variety of physiological abnormalities in neural and microglial behavior in the CNS, resulting in heightened anxiety, stress, hyperactivity, and other behavioral symptoms. BDNF, brain-derived neurotrophic factor; HDAC, histone deacetylase.

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