Gut Microbiota to Microglia: Microbiome Influences Neurodevelopment in the CNS

Abstract

The brain is traditionally viewed as an immunologically privileged site; however, there are known to be multiple resident immune cells that influence the CNS environment and are reactive to extra-CNS signaling. Microglia are an important component of this system, which influences early neurodevelopment in addition to modulating inflammation and regenerative responses to injury and infection. Microglia are influenced by gut microbiome-derived metabolites, both as part of their normal function and potentially in pathological patterns that may induce neurodevelopmental disabilities or behavioral changes. This review aims to summarize the mounting evidence indicating that, not only is the Gut-Brain axis mediated by metabolites and microglia throughout an organism's lifetime, but it is also influenced prenatally by maternal microbiome and diet, which holds implications for both early neuropathology and neurodevelopment.

Keywords: Gut–Brain axis; gut microbiome; metabolite; microglia; neurodevelopment.

Figure 1

Both in vivo and in vitro, microglia appear to be dependent on Interleukin-34 (IL-34) for stimulation to proliferate. IL-34 is a cytokine that serves as one ligand to the receptor CSF-1R, which is central to signaling for proliferation and development of mononuclear phagocyte cells [11]. This cytokine is strongly expressed in mouse brains during embryogenesis, and strongly correlates with the proliferation of mononuclear phagocytic cells [12,13]. Additionally, IL-34 induces microglia to produce insulin degrading enzyme (IDE) and heme oxygenase-1 (HO-1), which are associated with clearing oligomeric amyloid Beta and defend against reactive oxygen species, respectively [14].

Figure 2

Microbiota influence on microglia. Microbe-associated molecular proteins (MAMPs) are produced by bacteria in the colon. MAMPs travel through tight junctions within the intestinal wall and activate macrophages to stimulate TNF-a and IL-6 release. Metabolites from microbiota, such as short chain fatty acids (SCFAs), are absorbed in the small intestine and begin to interact with T-cells, B-cells, and macrophages, which starts the release of pro-inflammatory cytokines such as TGF-β, IL-6, and TNF-α. Pro-inflammatory cytokines produced in the GI tract will then enter the bloodstream and activate the vagus nerve tract, which carries direct activity to the CNS, directly, or via T-cells that have the capacity to interact with microglia in the brain. CD4 T cells in the brain can interact with microglia and stimulate expression of surface factors, such as MHC-II, IL-10, and IL-2, on microglial cells. TGF-β binds to receptors on microglial cells and downregulates the Smad3 signaling pathway. T-cells can release TNF-α, an inflammatory cytokine after being activated by microglial cells and lead to decreased proliferation of neuronal stem cells, resulting in direct influence on microglial proliferation. “Reproduced with permission from Blackwell Publishing” [47].