Editors' ChoiceNeuroscience

Microglia get a gut feeling

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Science Signaling  14 Jul 2015:
Vol. 8, Issue 385, pp. ec194
DOI: 10.1126/scisignal.aac9922

Microglia are macrophage-like cells found in the brain that scavenge dead cells, kill pathogens, and are involved in brain development. Noting that microglial development and function are affected by factors from outside the brain, Erny et al. investigated whether the gut microbiota played a role. Comparative gene expression analysis of microglia from mice housed under specific pathogen-free (SPF) conditions (which have gut microbiota) and from mice housed under germ-free (GF) conditions (which have no gut microbiota) showed the increased expression of genes, such as Ddit4, Sfpi1, and Csf1r, in microglia from the GF mice. The products of these genes mediate process such as transcriptional inhibition and DNA damage induction, suggesting that microglia from GF mice are not fully mature. The cell surface proteins CSF1R, F4/80, and CD31 are normally expressed during microglial development and then decrease in abundance after microglial maturation; however, these receptors remained abundant on microglia from GF mice. Gene expression analysis of microglia from SPF and GF mice injected intracerebrally or intraperitoneally with the Toll-like receptor 4 (TLR4) agonist lipopolysaccharide revealed that the expression of genes encoding cytokines and chemokines was decreased in microglia from the GF mice, which suggested that they had a compromised immune response. In addition, semiautomatic, morphometric three-dimensional measurements revealed that microglia from GF mice had longer processes and increased branching and terminal points than did microglia from SPF mice, which had a normal morphology. SPF mice treated with broad-spectrum antibiotics, which depleted the gut microbiota, showed immature and malformed microglia, which resembled those of GF mice. When short-chain fatty acids (which are bacterial fermentation products) were provided in drinking water to GF mice for four weeks, normal microglial growth was restored, and the microglia had less morphological defects. In addition, the extent of expression of Ddit4, Sfpi1, and Csf1r in microglia from these GF mice was restored to that of SPF mice. However, mRNA profiling indicated that FFAR2, the receptor for short-chain fatty acids, was not expressed in microglia, but rather in myeloid cells in the spleen. This suggested that the short-chain fatty acids might act on cells in the spleen, which in turn might regulate the microglia. As Mosher and Wyss-Coray discuss in commentary, these findings highlight the importance of gut-brain communication for the development and maturation of microglia.

D. Erny, A. L. H. de Angelis, D. Jaitin, P. Wieghofer, O. Staszewski, E. David, H. Keren-Shaul, T. Mahlakoiv, K. Jakobshagen, T. Buch, V. Schwierzeck, O. Utermöhlen, E. Chun, W. S. Garrett, K. D. McCoy, A. Diefenbach, P. Staeheli, B. Stecher, I. Amit, M. Prinz, Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18, 965–977 (2015). [PubMed]

K. I. Mosher, T. Wyss-Coray, Go with your gut: Microbiota meet microglia. Nat. Neurosci. 18, 930–931 (2015). [PubMed]

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