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Review
, 20 (2), 145-155

Interactions Between the Microbiota, Immune and Nervous Systems in Health and Disease

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Review

Interactions Between the Microbiota, Immune and Nervous Systems in Health and Disease

Thomas C Fung et al. Nat Neurosci.

Abstract

The diverse collection of microorganisms that inhabit the gastrointestinal tract, collectively called the gut microbiota, profoundly influences many aspects of host physiology, including nutrient metabolism, resistance to infection and immune system development. Studies investigating the gut-brain axis demonstrate a critical role for the gut microbiota in orchestrating brain development and behavior, and the immune system is emerging as an important regulator of these interactions. Intestinal microbes modulate the maturation and function of tissue-resident immune cells in the CNS. Microbes also influence the activation of peripheral immune cells, which regulate responses to neuroinflammation, brain injury, autoimmunity and neurogenesis. Accordingly, both the gut microbiota and immune system are implicated in the etiopathogenesis or manifestation of neurodevelopmental, psychiatric and neurodegenerative diseases, such as autism spectrum disorder, depression and Alzheimer's disease. In this review, we discuss the role of CNS-resident and peripheral immune pathways in microbiota-gut-brain communication during health and neurological disease.

Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1
Effects of the microbiota on microglia and astrocyte biology. (a) Microglial maturation and function are affected by the presence or absence of a complex microbiota. Compared to conventionally colonized (specific pathogen–free, SPF) controls, mice reared in the absence of microbial colonization (germ free, GF) have microglia with abnormal morphology, altered gene expression and impaired functional response to stimulation. Similar microglial abnormalities are seen in microbiota-depleted mice, produced by antibiotic treatment of SPF mice (ABX) or colonization of GF mice with three bacterial taxa from a limited altered Schaedler flora (ASF) consortium (B. distasonis, L. salivarius, and Clostridium cluster XIV). Microglial abnormalities in GF mice are corrected by supplementation with short-chain fatty acids (SCFAs), products of bacterial fermentation. (b) Microbial metabolites bind to the aryl hydrocarbon receptor (AHR) in astrocytes, reducing symptoms of EAE. Type I interferon signaling in astrocytes diminishes inflammation and decreases EAE clinical scores, and this effect is reversed by antibiotic treatment. Particular tryptophan metabolites produced by the microbiota stimulate AHR and reduce EAE clinical scores. This suggests that the microbiota have a direct effect on AHR signaling and inflammation in astrocytes, which may have relevance to multiple sclerosis, where patients show decreased tryptophan-derived metabolites in sera. TNase, tryptophanase; IPA, indole-3-propionic acid; IAld, indole-3-aldehyde; I3S, indoxyl-3-sulfate.
Figure 2
Figure 2
Effects of the microbiota on peripheral immune cells and CNS function. Intestinal microbes in the gastrointestinal tract regulate peripheral immune responses, CNS function and behavior. Intestinal colonization by specific members of the microbiota is associated with activation of pro- or anti-inflammatory CD4+ T cell responses that regulate susceptibility to EAE. The material immune activation (MIA) model of ASD leads to microbial dysbiosis that is associated with elevated TH17 cell responses, which are sufficient to trigger social and behavioral defects. Mouse models of CNS injury (stroke, spinal cord injury) also appear to be regulated by microbiota–immune interactions. Oral administration of probiotics can elicit a population of Ly6C+ monocytes that increase hippocampal neurogenesis and enhance memory responses. Probiotics such as Bifidobacterium and Lactobacillus have potent anti-inflammatory properties that reduce behaviors associated with anxiety and depression. Furthermore, microbial infections can trigger antibody-dependent CNS autoimmunity and promote neurodegeneration. Collectively, regulation of peripheral immune responses is a critical pathway by which the intestinal microbiota and exogenous microbial challenges influence CNS function and behavior. ABX, antibiotic treatment of SPF mice; IELs, intraepithelial lymphocytes; LAG-3, lymphocyte activation gene-3.
Figure 3
Figure 3
Crosstalk between the microbiota, immune system and CNS. Interactions between the intestinal microbiota, peripheral immune system and CNS are essential for the maintenance of host health. Recognition of microbial derived products such as microbe-associated molecular patterns (MAMPs) and metabolic by-products of microbes (short chain fatty acids, SCFAs) activates distinct immune pathways throughout the host. The microbiota and immune system can independently or cooperatively regulate neurophysiology. Therefore, a prevailing theme in studies aimed at understanding the microbiota–gut–brain axis involves the role of intestinal microbes in modulating CNS function through CNS-resident and peripheral immune pathways. Biochemical changes in the CNS can also lead to altered microbial composition and immune cell responses through the HPA axis. Altogether, these findings suggest that the microbiota, immune system and CNS communicate bidirectionally. Future studies investigating the functional outcomes of these bidirectional interactions will inform the development of new therapeutic strategies for the treatment of neurological disorders. IFNγ, interferon gamma; LPS, lipopolysaccharide; NLR, Nod-like receptor; PGN, peptidoglycan; TLR, Toll-like receptor.

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