Host microbiota constantly control maturation and function of microglia in the CNS

By Daniel Erny, Anna Lena Hrabě de Angelis, Diego Jaitin, P. Wieghofer, O. Staszewski, Eyal David, Hadas Keren-Shaul, Tanel Mahlakõiv, Kristin Jakobshagen, T. Buch and 10 more. Nature Neuroscience, 2015

3,034 citations recorded by the source corpus.

As the tissue macrophages of the CNS, microglia are critically involved in diseases of the CNS. However, it remains unknown what controls their maturation and activation under homeostatic conditions. We observed substantial contributions of the host microbiota to microglia homeostasis, as germ-free (GF) mice displayed global defects in microglia with altered cell proportions and an immature phenotype, leading to impaired innate immune responses. Temporal eradication of host microbiota severely changed microglia properties. Limited microbiota complexity also resulted in defective microglia. In contrast, recolonization with a complex microbiota partially restored microglia features. We determined that short-chain fatty acids (SCFA), microbiota-derived bacterial fermentation products, regulated microglia homeostasis. Accordingly, mice deficient for the SCFA receptor FFAR2 mirrored microglia defects found under GF conditions. These findings suggest that host bacteria vitally regulate microglia maturation and function, whereas microglia impairment can be rectified to some extent by complex microbiota.

Subfields: Immunology, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/cdda2c6bc3c7d9a77a93ba2aeeb9e60c52c07c95

How researchers see this paper

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In Immunology

1. O. Butovsky
2. M. Colonna
3. Lan Lin
4. Rob Knight
5. Helen Y Wang
6. Changsheng Xing
7. Rong‐Fu Wang
8. Ted G. Dinan

In Molecular Biology

1. J. Cryan
2. Ted G. Dinan
3. G. Clarke
4. S. Mazmanian
5. C. Stanton
6. P. Kennedy
7. J. Foster
8. T. Sampson

In Neurology

1. M. Colonna
2. Mathias Jucker
3. O. Butovsky
4. R. Yirmiya
5. D. Holtzman
6. J. Long

Citations in the corpus

• The Gut Microbiota and Alzheimer’s Disease (2017, neutral): “Erny et al. treated spe-cific pathogen-free mice orally with broad-spectrum antibiotics for 1 month, resulting in an immature phenotype and unchanged number of microglia [49].”
• The neuropharmacology of butyrate: The bread and butter of the microbiota-gut-brain axis? (2016, background): “For example, a recent study found that GF mice have immature and less active microglia, which could be normalized by adding an SCFA cocktail consisting of acetate, propionate and butyrate to the drinking water (Erny et al., 2015).”
• The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication (2020, background): “The results reported by Erny and collaborators shed light on how the microbiota might influence microglial maturation and function (6).”
• Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019, neutral): “Germ-free mice develop microglia with an immature phenotype, blunted response to inflammatory stimuli and defective immune response to infection (Erny et al., 2015).”
• Kynurenine pathway metabolism and the microbiota‐gut‐brain axis (2017, background): “Similarly, the metabolic fate of kynurenine reaching the CNS is influenced by microglia (See Figure 3 (Schwarcz and Pellicciari, 2002)), whose maturation and function is defective in the absence of a gut microbiota (Erny et al., 2015).”
• iPSC-derived human microglia-like cells to study neurological diseases (2017, neutral): “Interestingly, iMGLs not cultured with neurons differentially expressed early microglia genes including FFAR2 (Erny et al., 2015, Matcovitch-Natan et al., 2016) suggesting that other factors are needed to further educate microglia as tissue-resident macrophages of the brain.”
• Depression as a microglial disease. (2015, background): “Consistently, the gut microbiota has been shown to control the maturation and functioning of microglia under normal steady-state conditions [99].”
• Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models (2017, neutral): “In addition, although we analyzed the effects of bacterial extracts on peripheral immune cells, some bacterial metabolites are able to cross the blood – CNS barrier and directly regulate CNS inflammation via microglia (29, 30) or astrocytes (28).”