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Host microbiota constantly control maturation and function of microglia in the central nervous system (part 1)

ABSTRACT: As tissue macrophages of the central nervous system (CNS), microglia are critically involved in diseases of the CNS. However, it remains unknown what controls their maturation and activation under homeostatic conditions. Here we reveal significant 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, regulate microglia homeostasis. Accordingly, mice deficient for the SCFA receptor FFAR2 mirrored microglia defects found under GF conditions. These findings reveal that host bacteria vitally regulate microglia maturation and function, whereas microglia impairment can be restored to some extent by complex microbiota.

ORGANISM(S): Mus musculus

PROVIDER: GSE62201 | GEO | 2015/05/25

SECONDARY ACCESSION(S): PRJNA263471

REPOSITORIES: GEO

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Host microbiota constantly control maturation and function of microglia in the central nervous system (part 1)

Project description:As tissue macrophages of the central nervous system (CNS), microglia are critically involved in diseases of the CNS. However, it remains unknown what controls their maturation and activation under homeostatic conditions. Here we reveal significant 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, regulate microglia homeostasis. Accordingly, mice deficient for the SCFA receptor FFAR2 mirrored microglia defects found under GF conditions. These findings reveal that host bacteria vitally regulate microglia maturation and function, whereas microglia impairment can be restored to some extent by complex microbiota. For acute inflammatory challenges, LPS was applied intracranially and 6 hours later, animals were analyzed. Control animals were injected PBS i.c. Transcriptional profiles of FACS-sorted microglia were assessed using Affymetrix® (Santa Clara, USA) GeneChip Arrays (Mouse Gene 2.1 ST Arrays).

2015-05-25 | E-GEOD-62201 | biostudies-arrayexpress

Commensal microbiota constantly control maturation and function of microglia in the central nervous system

2015-05-25 | GSE62710 | GEO

Host microbiota constantly control maturation and function of microglia in the central nervous system (part 2)

Project description:As tissue macrophages of the central nervous system (CNS), microglia are critically involved in diseases of the CNS. However, it remains unknown what controls their maturation and activation under homeostatic conditions. Here we reveal significant 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, regulate microglia homeostasis. Accordingly, mice deficient for the SCFA receptor FFAR2 mirrored microglia defects found under GF conditions. These findings reveal that host bacteria vitally regulate microglia maturation and function, whereas microglia impairment can be restored to some extent by complex microbiota. We used microarrays to determine the gene expression of microglia after LCMV challenge.

2015-05-25 | GSE67857 | GEO

Host microbiota constantly control maturation and function of microglia in the central nervous system (part 2)

Project description:As tissue macrophages of the central nervous system (CNS), microglia are critically involved in diseases of the CNS. However, it remains unknown what controls their maturation and activation under homeostatic conditions. Here we reveal significant 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, regulate microglia homeostasis. Accordingly, mice deficient for the SCFA receptor FFAR2 mirrored microglia defects found under GF conditions. These findings reveal that host bacteria vitally regulate microglia maturation and function, whereas microglia impairment can be restored to some extent by complex microbiota. We used microarrays to determine the gene expression of microglia after LCMV challenge. Lymphocytic Choriomeningitis Virus (LCMV) strain WE was propagated and titrated as plaque forming units (PFU) on L929 cells as described before (Herz,J. et al. Acid sphingomyelinase is a key regulator of cytotoxic granule secretion by primary T lymphocytes. Nat. Immunol. 10, 761-768 (2009)). PFU were multiplied by the factor 10 to be converted into infectious units (IU). Mice were infected by intracerebral inoculation of 103 IU into the right hemisphere.

2015-05-25 | E-GEOD-67857 | biostudies-arrayexpress

MICROBIOTA-DERIVED ACETATE ENABLES THE METABOLIC FITNESS OF THE CNS INNATE IMMUNE SYSTEM DURING HEALTH AND DISEASE

Project description:As tissue macrophages of the central nervous system (CNS) microglia constitute the pivotal immune cells of this organ. Microglial features are strongly dependent on environmental cues such as commensal microbiota. Gut bacteria are known to continuously modulate microglia maturation and function by the production of short-chain fatty acids (SCFA). However, the precise mechanism of this crosstalk is unknown. Here we determined that the immature phenotype of microglia from germ-free (GF) mice is epigenetically imprinted by H3K4me3 and H3K9ac on metabolic genes associated with substantial functional alterations including increased mitochondrial mass and specific respiratory chain dysfunctions. We identified acetate as the essential microbiome-derived SCFA driving microglia maturation and regulating the homeostatic metabolic state, and further showed that it is able to modulate microglial phagocytosis and disease progression during neurodegeneration. These findings indicate that acetate is an essential bacteria-derived molecule driving metabolic pathways and functions of microglia during health and perturbation.

2021-11-01 | GSE184881 | GEO

Ffar2 modulates dendritic cell-derived IL-27 and CD8+ T cell exhaustion in colorectal cancer

Project description:Background and aims: Gut microbial metabolites and their host signaling pathways hold therapeutic potential for colorectal cancer (CRC). One example is short-chain fatty acids (SCFA), which are microbial metabolites generated from dietary fiber. This study aims to determine the pathogenesis of CRC from the host-microbiota perspective and the contributions of Ffar2, a SCFA receptor, to CRC. Methods: We have employed Apc-based models of CRC in conjunction with Ffar2 knock-out (ko) mice, Ffar2 conditional ko mice, and Ffar2 chemical agonism to reveal how a microbial metabolite receptor influences tumorigenesis in the colon. Utilizing human CRC datasets from The Cancer Genome Atlas aided our discovery of the links between Ffar2 function in dendritic cells and tumoral T cell dysfunction. Herein, we also used preclinical CRC models to test IL-27p28 neutralization or Ffar2 agonism as proof of concept for CRC prevention and treatment. Results: We have identified a mechanism by which Ffar2 deficiency potentiates tumorigenesis by affecting gut barrier integrity that increases tumor bacterial load and then altering IL-27+ dendritic cell populations and tumor CD8+ T cell phenotype and function. These events create a tumor immune milieu notable for dying and over-activated DCs and exhausted CD8+ T cells, which enables tumor growth. Proof-of-concept experiments in mice employing IL-27p28 neutralization or Ffar2 agonism reduced tumor burden. Conclusions: Our data support that loss of Ffar2 signaling potentiates tumorigenesis via a “two-hit” model, first by gut barrier breach and then by immune cell dysfunction. Our work supports that altering Ffar2 signaling or neutralizing IL-27 represent potential immunotherapy CRC treatment strategies.

2020-01-16 | GSE142691 | GEO

Microbiota-derived acetate enables the metabolic fitness of the brain innate immune system during health and disease

Project description:As tissue macrophages of the central nervous system (CNS) microglia constitute the pivotal immune cells of this organ. Microglial maturation and function are strongly dependent on environmental cues such as commensal microbiota. Gut bacteria are known to continuously modulate microglia features by the production of short-chain fatty acids (SCFA). However, the precise mechanism of this crosstalk is unknown. Here we determined that the immature phenotype of microglia from germ-free (GF) mice is epigenetically imprinted by H3K4me3 and H3K9ac on metabolic genes associated with substantial functional alterations including increased mitochondrial mass and specific respiratory chain dysfunctions. We identified acetate as the essential microbiome-derived SCFA driving microglia maturation and regulating the homeostatic metabolic state, and further showed that it is able to modulate microglial phagocytosis and disease progression during neurodegeneration. These findings indicate that acetate is an essential bacteria-derived molecule driving metabolic pathways and functions of microglia during health and perturbation.

| MSV000088093 | MassIVE

HOST MICROBIOTA REGULATE SELECTIVE MYELOID SUBSETS IN THE CENTRAL NERVOUS SYSTEM DURING HOMEOSTASIS AND DISEASE

Project description:The immune cells of the central nervous system (CNS) comprise parenchymal microglia and at the CNS border regions meningeal, perivascular and choroid plexus macrophages (summarized as CNS-associated macrophages, CAMs). Previous work has uncovered that microglial properties are strongly dependent on environmental signals from the commensal microbiota while its effect on CAMs remained unknown. By combining several microbiota manipulation approaches, genetic mouse models and single-cell RNA-sequencing, we comprehensively characterized CNS myeloid cell composition and function. Under steady-state, the transcriptional profile and numbers of choroid plexus macrophages were found to be tightly steered by complex microbiota. Divergently, perivascular and meningeal macrophages were affected to a lesser extent. An acute perturbation through viral infection evoked an attenuated immune response of all CAMs in germ-free mice. Additionally, we assessed CAMs in a more chronic pathological state in 5xFAD mice as a model for Alzheimer’s disease whereby exclusively perivascular macrophages displayed enhanced amyloid beta uptake in GF 5xFAD mice. Our results provide novel insights for understanding distinct microbiota-CNS macrophage interactions during health and perturbation that could potentially be targeted therapeutically.

2021-10-01 | GSE178956 | GEO

Different effects of constitutive and induced microbiota modulation on microglia in a mouse model of Alzheimer’s disease

Project description:It was recently revealed that gut microbiota promote amyloid-beta (Aβ) burden in mouse models of Alzheimer’s disease (AD). However, the underlying mechanisms when using either germ-free (GF) housing conditions or treatments with antibiotics (ABX) remained unknown. In this study, we show that GF and ABX-treated 5x familial AD (5xFAD) mice developed attenuated hippocampal Aβ pathology and associated neuronal loss, and thereby delayed disease-related memory deficits. While Ab production remained unaffected in both GF and ABX-treated 5xFAD mice, we noticed in GF 5xFAD mice enhanced microglial Aβ uptake at early stages of the disease compared to ABX-treated 5xFAD mice. Furthermore, RNA-sequencing of hippocampal microglia from SPF, GF and ABX-treated 5xFAD mice revealed distinct microbiota-dependent gene expression profiles associated with phagocytosis and altered microglial activation states. Taken together, we observed that constitutive or induced microbiota modulation in 5xFAD mice differentially controls microglial Aβ clearance mechanisms preventing neurodegeneration and cognitive deficits.

2020-07-15 | GSE154428 | GEO

Germfree C57BL/6J mice are resistant to high fat diet-induced insulin resistance and have altered cholesterol metabolism

Project description:Germfree (GF) mice have been used as a model to study the contribution of the intestinal microbiota to metabolic energy balance of the host. Despite a wealth of knowledge accumulated since the 1940’s, the response of GF mice to a high fat diet is largely unknown. In the present study, we compared the metabolic consequences of a high fat (HF) diet on GF and conventional (Conv) C57BL/6J mice. As expected, Conv mice developed obesity and glucose intolerance with a HF diet. In contrast, GF mice remained lean and resisted the HF diet-induced insulin resistance. The anti-obesity phenotype of GF/HF mice was accompanied by reduced caloric intake, diminished food efficiency, and excessive fecal lipid excretion contributed to the reduced food efficiency. In addition, HF diet-induced hypercholesterolemia was ameliorated, which was partially due to an increase in fecal cholesterol excretion. However, hepatic cholesterols were increased in GF/HF mice. Elevated nuclear SREBP2 proteins and the up-regulation of cholesterol biosynthesis genes support the increased liver cholesterol biosynthesis in GF/HF mice. The resistance to HF diet-induced metabolic abnormalities in GF mice was also associated with a reduced immune response, indicated by low plasma pro-inflammatory and anti-inflammatory markers. These data suggest that the gut microbiota of Conv mice contributes to HF diet-induced obesity, insulin resistance, dyslipidemia and hepatic steatosis in mice. Thus, results of the present study describe the metabolic responses of GF mice to a HF diet and further our understandings of the relationship between the gut microbiota and the host. Germfree and conventional C57BL/6J mice were fed with a high fat diet for 11 weeks. Then, all mice were sacrified under 10-h food deprevation, and liver samples of germfree (n=14) and conventional (n=16) were examined.

2010-08-20 | E-GEOD-19038 | biostudies-arrayexpress

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