The Gut-Microglia Connection: Implications for Central Nervous System Diseases

Abstract

The importance of the gut microbiome in central nervous system (CNS) diseases has long been recognized; however, research into this connection is limited, in part, owing to a lack of convincing mechanisms because the brain is a distant target of the gut. Previous studies on the brain revealed that most of the CNS diseases affected by the gut microbiome are closely associated with microglial dysfunction. Microglia, the major CNS-resident macrophages, are crucial for the immune response of the CNS against infection and injury, as well as for brain development and function. However, the current understanding of the mechanisms controlling the maturation and function of microglia is obscure, especially regarding the extrinsic factors affecting microglial function during the developmental process. The gut microflora has been shown to significantly influence microglia from before birth until adulthood, and the metabolites generated by the microbiota regulate the inflammation response mediated by microglia in the CNS; this inspired our hypothesis that microglia act as a critical mediator between the gut microbiome and CNS diseases. Herein, we highlight and discuss current findings that show the influence of host microbiome, as a crucial extrinsic factor, on microglia within the CNS. In addition, we summarize the CNS diseases associated with both the host microbiome and microglia and explore the potential pathways by which the gut bacteria influence the pathogenesis of CNS diseases. Our work is thus a comprehensive theoretical foundation for studies on the gut-microglia connection in the development of CNS diseases; and provides great potential for researchers to target pathways associated with the gut-microglia connection and overcome CNS diseases.

Keywords: brain; central nervous system diseases; gut microbiome; gut-microglia connection; microglia.

Figure 1

Potential mechanisms by which intestinal microbiota regulate the maturation and function of microglia. (a) Short-chain fatty acids (SCFAs) generated by the gut microbiota cross the blood-brain barrier (BBB) via the circulatory system of the host, and target microglia to regulate their function or maturation. (b) Immune cells expressing receptors that recognize SCFAs can migrate to the brain via the BBB after signaling by SCFAs that originate from the gut flora. (c) The gut microbiota may communicate directly with brain-resident microglia via the vagus nerve. (d) Before receptors recognizing SCFAs are expressed, other bacterial metabolites or microbe-associated molecular patterns (MAMPs) generated by the gut microbiota can cross the BBB and target microglia to regulate their function or maturation. (e) Peripheral macrophages that can recognize the relevant metabolites or MAMPs can migrate to the brain via the BBB after receiving signals from bacterial metabolites or MAMPs released by the gut flora. Black lines indicated that the corresponding pathways were recognized in a prior study, and red lines represented uncertain pathway. Black lines represent known pathways and red lines indicated uncertain pathways.

Figure 2

NO and APP generated by microglia and several gut-specific microbes accelerate the development of AD pathogenesis. Chronically activated microglia contribute to the progression of neurodegenerative diseases such as AD. Several gut-specific microbes are able to generate NO and APP, which activate microglia and further exacerbate the development of AD. Specifically, NO generated by gut flora, can be carried to the brain by RBC. APP secreted by gut flora can cross the BBB via the RAGE receptor. After reaching the CNS, both NO and APP activate the microglia, which exhibit an ameboid form. Activated microglia can then secrete several risk factors for AD, including iNOS, chemokines, cytokines, APP, and NO, which further accelerate the pathogenesis of AD. iNOS, inducible nitric oxide synthase; NO, nitric oxide; RBC, red blood cell; RAGE, receptor for advanced glycosylation products.

Figure 3

The microbial metabolism of dietary Trp regulates the inflammatory response of astrocytes by microglia in EAE mouse model of MS through the AHR generated within microglia. Metabolism of dietary Trp by microbiota generates AHR agonists, which cross the BBB into the brain to activate microglia through an AHR-mediated mechanism within the microglia. In detail, these AHR agonists function as ligands for the AHR expressed in the microglia to bind the genes encoding VEGF-B and TGF-α, as indicated, to facilitate TGF-α transcription and to inhibit VEGF-B expression. Notably, VEGF-B increases the inflammatory activation of astrocytes to control the development of EAE. In contrast, TGF-α weakens the inflammatory activation of astrocytes to worsen EAE. Of note, both of Akkermansia and Parabacteroides distasonis, MS associated microbiota, may be the producer of AHR agonist, which required to be further researched. AHR, aryl hydrocarbon receptor; Trp, tryptophan; MS, multiple sclerosis; EAE, experimental autoimmune encephalomyelitis.