The gut-brain axis: microglia in the spotlight
TL;DR: Interactions between the gut microbiota and microglia, and their influence on brain functions in health and disease are contemplated.
Abstract: Summary Microbiome research has grown significantly in the last decade, highlighting manifold implications of the microbiota to the host’s health. The gut microbiota is connected to the brain through several avenues that allow their interaction. Thus, recent studies have attemtpted to characterize these connections and enhance our understanding of the so called ‘gut-brain-axis’. Microglia, the central nervous system resident macrophages, are crucial for the proper development and maintenance of brain functions. As immune cells, they are in the spotlight for relaying signals between the microbiota and cells of the brain. In this review, we contemplate on interactions between the gut microbiota and microglia, and their influence on brain functions in health and disease.
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TL;DR: Recent findings of the interaction between the host microbiota and the CNS in health and disease are summarized, where the resident gut microbiota is highlighted as a crucial environmental factor for microglial function as what is coined “the microbiota‐microglia axis.”
Abstract: The innate immune system in the central nervous system (CNS) is mainly represented by specialized tissue-resident macrophages, called microglia. In the past years, various species-, host- and tissue-specific as well as environmental factors were recognized that essentially affect microglial properties and functions in the healthy and diseased brain. Host microbiota are mostly residing in the gut and contribute to microglial activation states, for example, via short-chain fatty acids (SCFAs) or aryl hydrocarbon receptor (AhR) ligands. Thereby, the gut microorganisms are deemed to influence numerous CNS diseases mediated by microglia. In this review, we summarize recent findings of the interaction between the host microbiota and the CNS in health and disease, where we specifically highlight the resident gut microbiota as a crucial environmental factor for microglial function as what we coin "the microbiota-microglia axis."
38 citations
Cites background from "The gut-brain axis: microglia in th..."
...Given that the gut microbiota has emerged as key regulator of microglial function (13, 34), and microglia being involved in virtually all CNS pathologies, the microbiota–microglia axis became a critical link to CNS disorders (Figure 1), where additional research is essential to better understand the pathogenesis and identify new appropriate therapeutic approaches....
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...Bacteriaderived AHR ligands and SCFAs are known signaling molecules modeling microglial properties and thereby potentially contribute to various CNS diseases in animal models and human patients (13)....
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...Given the regulatory effect of the microbiota on microglial function, including phagocytosis, during homeostasis and disease (13), the perturbations in the gut microbiota post-TBI or stroke can be relevant to the disease prognosis....
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...As such, several CNS diseases have been linked to dysfunctions of the gut microbiota (13, 14)....
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TL;DR: This review summarizes key extrinsic and intrinsic factors, with special focus on the host microbiota, that essentially influence microglia functions and states during development, homeostasis, and disease.
Abstract: Among the myeloid cells in the central nervous system (CNS) microglia are the main representatives of the innate immune system. Microglial fulfil tasks beyond phagocytosing debris and host defense against invading microorganism. During brain development microglia guide for example neurons for proper CNS formation, in adulthood they maintain tissue homeostasis and in aging microglia may become pro-inflammatory and finally exhausted. Recently, several endogenous and exogenous factors were identified that essentially shape the microglial phenotype during both steady-state and pathological conditions. On the one hand, microglia receive inputs from CNS-endogenous sources for example, via crosstalk with other glial cells and neurons but on the other hand microglia are also highly modulated by external signals. Among them, host microbiota-the host's resident bacteria-are vital regulators of the CNS innate immune system. This review summarizes key extrinsic and intrinsic factors, with special focus on the host microbiota, that essentially influence microglia functions and states during development, homeostasis, and disease.
37 citations
TL;DR: In this article, the authors provide an up-to-date overview on the understanding of the gut microbiota effects on innate immunity, with a particular emphasis on aging-associated changes in the Gut microbiota and the implications for the brain innate immune response.
Abstract: The immune system is crucial for defending against various invaders, such as pathogens, cancer cells or misfolded proteins. With increasing age, the diminishing immune response, known as immunosenescence, becomes evident. Concomitantly, some diseases like infections, autoimmune diseases, chronic inflammatory diseases and cancer, accumulate with age. Different cell types are part of the innate immunity response and produce soluble factors, cytokines, chemokines, and type I interferons. Improper maturation of innate immune cells or their dysfunction have been linked to numerous age-related diseases. In parallel to the occurrence of the many functional facets of the immune response, a symbiotic microbiota had been acquired. For the relevant and situation-dependent function of the immune system the microbiome plays an essential role because it fine-tunes the immune system and its responses during life. Nevertheless, how the age-related alterations in the microbiota are reflected in the innate immune system, is still poorly understood. With this review, we provide an up-to-date overview on our present understanding of the gut microbiota effects on innate immunity, with a particular emphasis on aging-associated changes in the gut microbiota and the implications for the brain innate immune response.
8 citations
TL;DR: In this paper , the authors discuss the role of the gut microbiota and the effects of its depletion in modulating the morphology and function of glial cells (microglia and astrocytes).
Abstract: Studies on host microbiota and their interactions with the central nervous system (CNS) have grown considerably in the last decade. Indeed, it has been widely demonstrated that dysregulations of the bidirectional gut–brain crosstalk are involved in the development of several pathological conditions, including chronic pain. In addition, the activation of central and peripheral glial cells is also implicated in the pathogenesis and progression of pain and other neurodegenerative disorders. Recent preclinical findings suggest that the gut microbiota plays a pivotal role in regulating glial maturation, morphology and function, possibly through the action of different microbial metabolites, including the most studied short-chain fatty acids (SCFAs). Moreover, altered microbiota composition has been reported in CNS disorders characterized by glial cell activation. In this review, we discuss recent studies showing the role of the gut microbiota and the effects of its depletion in modulating the morphology and function of glial cells (microglia and astrocytes), and we hypothesize a possible role for glia–microbiota interactions in the development and maintenance of chronic pain.
References
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TL;DR: MGWAS analysis showed that patients with type 2 diabetes were characterized by a moderate degree of gut microbial dysbiosis, a decrease in the abundance of some universal butyrate-producing bacteria and an increase in various opportunistic pathogens, as well as an enrichment of other microbial functions conferring sulphate reduction and oxidative stress resistance.
Abstract: Assessment and characterization of gut microbiota has become a major research area in human disease, including type 2 diabetes, the most prevalent endocrine disease worldwide. To carry out analysis on gut microbial content in patients with type 2 diabetes, we developed a protocol for a metagenome-wide association study (MGWAS) and undertook a two-stage MGWAS based on deep shotgun sequencing of the gut microbial DNA from 345 Chinese individuals. We identified and validated approximately 60,000 type-2-diabetes-associated markers and established the concept of a metagenomic linkage group, enabling taxonomic species-level analyses. MGWAS analysis showed that patients with type 2 diabetes were characterized by a moderate degree of gut microbial dysbiosis, a decrease in the abundance of some universal butyrate-producing bacteria and an increase in various opportunistic pathogens, as well as an enrichment of other microbial functions conferring sulphate reduction and oxidative stress resistance. An analysis of 23 additional individuals demonstrated that these gut microbial markers might be useful for classifying type 2 diabetes.
4,981 citations
TL;DR: A strategy to understand the microbial components of the human genetic and metabolic landscape and how they contribute to normal physiology and predisposition to disease.
Abstract: A strategy to understand the microbial components of the human genetic and metabolic landscape and how they contribute to normal physiology and predisposition to disease.
4,730 citations
TL;DR: New studies are revealing how the gut microbiota has coevolved with us and how it manipulates and complements the authors' biology in ways that are mutually beneficial.
Abstract: The distal human intestine represents an anaerobic bioreactor programmed with an enormous population of bacteria, dominated by relatively few divisions that are highly diverse at the strain/subspecies level. This microbiota and its collective genomes (microbiome) provide us with genetic and metabolic attributes we have not been required to evolve on our own, including the ability to harvest otherwise inaccessible nutrients. New studies are revealing how the gut microbiota has coevolved with us and how it manipulates and complements our biology in ways that are mutually beneficial. We are also starting to understand how certain keystone members of the microbiota operate to maintain the stability and functional adaptability of this microbial organ.
4,526 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: In a recent study, this article showed that low cerebrospinal fluid (CSF) Aβ42 and amyloid-PET positivity precede other AD manifestations by many years.
Abstract: Despite continuing debate about the amyloid β‐protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer9s disease (AD). Confirmation that presenilin is the catalytic site of γ‐secretase has provided a linchpin: all dominant mutations causing early‐onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild‐type APP gene in Down9s syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD. Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated from AD patients9 brains can decrease synapse number, inhibit long‐term potentiation, and enhance long‐term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD‐relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau‐positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) Aβ42 and amyloid‐PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target.
3,824 citations