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.

Overview of Brain-to-Gut Axis Exposed to Chronic CNS Bacterial Infection(s) and a Predictive Urinary Metabolic Profile of a Brain Infected by Mycobacterium tuberculosis

“…Short-chain fatty acids derived from the gut-microbiome play a pivotal role in the function and maturation of microglia. Hence, microglia are crucial mediators in the interaction between the CNS and the gut microbiota (Wang et al, 2018;Abdel-Haq et al, 2019).…”

Chemogenetic analysis of how receptors for short chain fatty acids regulate the gut-brain axis

“…Given the rapidly emerging evidence that the microbiota and their dysbiosis can be key contributors to a variety of long-term central nervous system deficits and malfunctions (47)(48)(49)(50) the current studies provide insights into direct chemical links via the gut brain axis produced by SCFAs that are the most abundant products of fermentation of fibre, and more generally of metabolism, by the microbiota. Whilst circulating SCFAs can cross the blood-brain barrier directly and may influence the activity of microglia involved in neuroinflammation via such a systemic route (48) it is unclear if concentrations of SCFAs in the circulation would routinely be sufficiently high to achieve substantial activation of receptors such as FFA2 and FFA3 at that level. By contrast, as well as providing entirely new insights into the roles of FFA2 and 20 FFA3, these studies provide fascinating hints as to how the high concentrations of SCFAs generated in the gut may transmit such signals to the brain via a neuronal gut-brain relay.…”

The Microbiome and the Gut‐Liver‐Brain Axis for Central Nervous System Clinical Pharmacology: Challenges in Specifying and Integrating In Vitro and In Silico Models

“…The gut microbiota postbiotics have multiple means for influencing the CNS through the enteric and vagus nerves, the hypothalamic-pituitary-adrenal (HPA) axis, and microglia. 17,[38][39][40] The vagus and enteric nervous systems. The enteric nervous system (ENS) provides local control of digestive functions and an intimate connection between the stromal cells of the GI tract and the autonomic nervous system.…”

“…2 Gut microbiota are able to affect behavior, mood, and decision making. 15 There is growing evidence of strong connections between the microbiome and serious diseases of the central nervous system (CNS), most notably Alzheimer's and Parkinson's diseases, among many 16,17 (see the Supplementary Information for a more extensive list); hence, the pressing need to understand the microbiome-gut-liver-immune-brain axis (M-GLIBA).…”

“…The gut microbiota has no established mechanistic links to CNS diseases, because the primary evidence is only in the form of correlations of various bacteria populations with individuals with the CNS diseases, as compared with normal, healthy individuals. 17 Recent studies have been aimed at understanding how diet, drugs, surgery, and environmental toxins affect gut microbiota. Such knowledge has implications for establishing the missing mechanistic connection for diseases caused by dysbiosis (i.e., a change in microbial composition or function that has an adverse impact on the host-microbiome relationship), as can be induced by antibiotics during a Clostridium difficile infection, 33 or as can occur following an ileocecal resection and antibiotics.…”