Host microbiota constantly control maturation and function of microglia in the CNS
TL;DR: It is determined that short-chain fatty acids (SCFA), microbiota-derived bacterial fermentation products, regulated microglia homeostasis and mice deficient for the SCFA receptor FFAR2 mirroredmicroglia defects found under GF conditions, suggesting that host bacteria vitally regulate microglian maturation and function.
Abstract: 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.
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TL;DR: Data is reviewed supporting the diverse functional roles carried out by a major class of bacterial metabolites, the short-chain fatty acids (SCFAs), which affect various physiological processes and may contribute to health and disease.
3,363 citations
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...However, when GF mice were administered SCFAs in the water for 4 weeks, the number of microglia was restored, as was their function and morphology (Erny et al., 2015)....
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TL;DR: It is reported herein that gut microbiota are required for motor deficits, microglia activation, and αSyn pathology, and suggested that alterations in the human microbiome represent a risk factor for PD.
2,142 citations
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...…167, 1469–1480, December 1, 2016 SCFAs Are Sufficient to Promote aSyn-Mediated Neuroinflammation Recently, it was revealed that gut bacteria modulate microglia activation during viral infection through production of microbial metabolites, namely short-chain fatty acids (SCFAs) (Erny et al., 2015)....
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...Despite a requirement for the SCFA receptor FFAR2 for microglia maturation, these cells are not known to express FFAR2, but do express other SCFA-responsive genes such as the histone deactylases that modulate gene expression (Erny et al., 2015)....
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...…of insoluble protein aggregates. aSyn-Dependent Microglia Activation by the Microbiota The microbiota modulates immune development in the CNS (Erny et al., 2015; Matcovitch-Natan et al., 2016), and aSyn aggregates activate immune cells, including brain-resident microglia (Kim et al., 2013;…...
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...Neuroprotective Bdnf and the cell cycle marker Ddit4 levels are upregulated in GF animals (Figure S2I), as observed in previous studies (Erny et al., 2015; Matcovitch-Natan et al., 2016)....
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...Based on the common occurrence of GI symptoms in PD, dysbiosis among PD patients, and evidence that the microbiota impacts CNS function, we tested the hypothesis that gut bacteria regulate the hallmark motor deficits and pathophysiology of synucleinopathies....
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TL;DR: Technological and computational approaches for investigating the microbiome, as well as recent advances in the understanding of host immunity and microbial mutualism are discussed with a focus on specific microbial metabolites, bacterial components and the immune system.
Abstract: The microbiota - the collection of microorganisms that live within and on all mammals - provides crucial signals for the development and function of the immune system. Increased availability of technologies that profile microbial communities is facilitating the entry of many immunologists into the evolving field of host-microbiota studies. The microbial communities, their metabolites and components are not only necessary for immune homeostasis, they also influence the susceptibility of the host to many immune-mediated diseases and disorders. In this Review, we discuss technological and computational approaches for investigating the microbiome, as well as recent advances in our understanding of host immunity and microbial mutualism with a focus on specific microbial metabolites, bacterial components and the immune system.
1,926 citations
TL;DR: Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders.
Abstract: The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within ...
1,775 citations
Journal Article•
TL;DR: Schulz et al. as discussed by the authors investigated whether adult macrophages all share a common developmental origin and found that a population of yolk-sac-derived, tissue-resident macophages was able to develop and persist in adult mice in the absence of hematopoietic stem cells.
Abstract: Macrophage Development Rewritten Macrophages provide protection against a wide variety of infections and critically shape the inflammatory environment in many tissues. These cells come in many flavors, as determined by differences in gene expression, cell surface phenotype and specific function. Schulz et al. (p. 86, published online 22 March) investigated whether adult macrophages all share a common developmental origin. Immune cells, including most macrophages, are widely thought to arise from hematopoietic stem cells (HSCs), which require the transcription factor Myb for their development. Analysis of Myb-deficient mice revealed that a population of yolk-sac–derived, tissue-resident macrophages was able to develop and persist in adult mice in the absence of HSCs. Importantly, yolk sac–derived macrophages also contributed substantially to the tissue macrophage pool even when HSCs were present. In mice, a population of tissue-resident macrophages arises independently of bone marrow–derived stem cells. Macrophages and dendritic cells (DCs) are key components of cellular immunity and are thought to originate and renew from hematopoietic stem cells (HSCs). However, some macrophages develop in the embryo before the appearance of definitive HSCs. We thus reinvestigated macrophage development. We found that the transcription factor Myb was required for development of HSCs and all CD11bhigh monocytes and macrophages, but was dispensable for yolk sac (YS) macrophages and for the development of YS-derived F4/80bright macrophages in several tissues, such as liver Kupffer cells, epidermal Langerhans cells, and microglia—cell populations that all can persist in adult mice independently of HSCs. These results define a lineage of tissue macrophages that derive from the YS and are genetically distinct from HSC progeny.
1,673 citations
References
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TL;DR: By following this protocol, investigators are able to gain an in-depth understanding of the biological themes in lists of genes that are enriched in genome-scale studies.
Abstract: DAVID bioinformatics resources consists of an integrated biological knowledgebase and analytic tools aimed at systematically extracting biological meaning from large gene/protein lists. This protocol explains how to use DAVID, a high-throughput and integrated data-mining environment, to analyze gene lists derived from high-throughput genomic experiments. The procedure first requires uploading a gene list containing any number of common gene identifiers followed by analysis using one or more text and pathway-mining tools such as gene functional classification, functional annotation chart or clustering and functional annotation table. By following this protocol, investigators are able to gain an in-depth understanding of the biological themes in lists of genes that are enriched in genome-scale studies.
31,015 citations
TL;DR: Findings indicating that developmental aspects of the adaptive immune system are influenced by bacterial colonization of the gut are discussed, and the possibility that the mammalian immune system, which seems to be designed to control microorganisms, is in fact controlled by microorganisms is raised.
Abstract: Immunological dysregulation is the cause of many non-infectious human diseases such as autoimmunity, allergy and cancer. The gastrointestinal tract is the primary site of interaction between the host immune system and microorganisms, both symbiotic and pathogenic. In this Review we discuss findings indicating that developmental aspects of the adaptive immune system are influenced by bacterial colonization of the gut. We also highlight the molecular pathways that mediate host–symbiont interactions that regulate proper immune function. Finally, we present recent evidence to support that disturbances in the bacterial microbiota result in dysregulation of adaptive immune cells, and this may underlie disorders such as inflammatory bowel disease. This raises the possibility that the mammalian immune system, which seems to be designed to control microorganisms, is in fact controlled by microorganisms.
4,079 citations
TL;DR: Results identify microglia as an ontogenically distinct population in the mononuclear phagocyte system and have implications for the use of embryonically derived microglial progenitors for the treatment of various brain disorders.
Abstract: Microglia are the resident macrophages of the central nervous system and are associated with the pathogenesis of many neurodegenerative and brain inflammatory diseases; however, the origin of adult microglia remains controversial. We show that postnatal hematopoietic progenitors do not significantly contribute to microglia homeostasis in the adult brain. In contrast to many macrophage populations, we show that microglia develop in mice that lack colony stimulating factor-1 (CSF-1) but are absent in CSF-1 receptor-deficient mice. In vivo lineage tracing studies established that adult microglia derive from primitive myeloid progenitors that arise before embryonic day 8. These results identify microglia as an ontogenically distinct population in the mononuclear phagocyte system and have implications for the use of embryonically derived microglial progenitors for the treatment of various brain disorders.
3,894 citations
TL;DR: This study determined that short-chain fatty acids, gut microbiota–derived bacterial fermentation products, regulate the size and function of the colonic Treg pool and protect against colitis in a Ffar2-dependent manner in mice, revealing that a class of abundant microbial metabolites underlies adaptive immune microbiota coadaptation and promotes colonic homeostasis and health.
Abstract: Regulatory T cells (T regs ) that express the transcription factor Foxp3 are critical for regulating intestinal inflammation. Candidate microbe approaches have identified bacterial species and strain-specific molecules that can affect intestinal immune responses, including species that modulate T reg responses. Because neither all humans nor mice harbor the same bacterial strains, we posited that more prevalent factors exist that regulate the number and function of colonic T regs . We determined that short-chain fatty acids, gut microbiota–derived bacterial fermentation products, regulate the size and function of the colonic T reg pool and protect against colitis in a Ffar2 -dependent manner in mice. Our study reveals that a class of abundant microbial metabolites underlies adaptive immune microbiota coadaptation and promotes colonic homeostasis and health.
3,733 citations
TL;DR: GOrilla is a web-based application that identifies enriched GO terms in ranked lists of genes, without requiring the user to provide explicit target and background sets, and its unique features and advantages over other threshold free enrichment tools include rigorous statistics, fast running time and an effective graphical representation.
Abstract: Since the inception of the GO annotation project, a variety of tools have been developed that support exploring and searching the GO database In particular, a variety of tools that perform GO enrichment analysis are currently available Most of these tools require as input a target set of genes and a background set and seek enrichment in the target set compared to the background set A few tools also exist that support analyzing ranked lists The latter typically rely on simulations or on union-bound correction for assigning statistical significance to the results GOrilla is a web-based application that identifies enriched GO terms in ranked lists of genes, without requiring the user to provide explicit target and background sets This is particularly useful in many typical cases where genomic data may be naturally represented as a ranked list of genes (eg by level of expression or of differential expression) GOrilla employs a flexible threshold statistical approach to discover GO terms that are significantly enriched at the top of a ranked gene list Building on a complete theoretical characterization of the underlying distribution, called mHG, GOrilla computes an exact p-value for the observed enrichment, taking threshold multiple testing into account without the need for simulations This enables rigorous statistical analysis of thousand of genes and thousands of GO terms in order of seconds The output of the enrichment analysis is visualized as a hierarchical structure, providing a clear view of the relations between enriched GO terms GOrilla is an efficient GO analysis tool with unique features that make a useful addition to the existing repertoire of GO enrichment tools GOrilla's unique features and advantages over other threshold free enrichment tools include rigorous statistics, fast running time and an effective graphical representation GOrilla is publicly available at: http://cbl-gorillacstechnionacil
3,157 citations