Page 38 - Read Online

Page 216 Reyes et al. Neuroimmunol Neuroinflammation 2020;7:215-33 I http://dx.doi.org/10.20517/2347-8659.2020.13

INTRODUCTION
Microglia are the central nervous system (CNS) resident macrophages responsible for initiating innate
[1]
immune responses to a variety of different stress and damage signals in the brain . For example, when
less mobile “resting” microglia recognize these signals with actively surveying processes, they become
highly motile and assume an activated phenotype, facilitating the release of pro-inflammatory and cell-
[2]
recruiting cytokines (e.g., IL-6, IL-12, IL-1β, and TNF-α) at the damage site . After isolating and resolving
the problem, it becomes critical for microglia to reestablish homeostatic conditions through the release of
[3]
anti-inflammatory cytokines (e.g., IL-4, IL-10, and TGF-β) and return to the sentinel deactivated state .
On the other hand, prolonged microglial activation has been linked to harmful inflammatory states leading
to dysfunctional brain activity and irreversible tissue damage, such as within Alzheimer’s and Parkinson’s
[4,5]
diseases . Beyond their immune functions, microglia are also important regulators of synaptic pruning
[6]
and neural patterning during development and throughout adulthood . Despite its evident importance in
health and disease, it remains unclear whether signals to modulate microglia activity originate within the
CNS only or may also occur externally from other organ/tissue systems. Identification of these additional
factors related to microglial function will warrant a better understanding of causes of neuroinflammation
and its relationship to CNS disorders.

Recently, one such factor has made a surprisingly strong debut within the scientific community: the vast
microflora inhabiting the gastrointestinal (GI) tract has emerged as a critical player connected to multiple
host systems, including those outside the GI tract. The gut microbiome (GMB) is able to modulate mucosal
immunity and systemic immune activity as well as immune responses within the CNS. For example, the
[7]
GMB has been demonstrated to affect the development and ongoing activity of microglia . Aberrant
changes to the microbiota (“dysbiosis”) and dysregulated microglial activity have both been linked to some
of the same neurodevelopmental, neurobehavioral and neurodegenerative disorders, including autism
spectrum disorder, anxiety, depression, and Alzheimer’s and Parkinson’s diseases [8-12] . Of note, the GMB
and its relationship to immune system maturation and developmental disorders have been extensively
described in multiple reviews and are not discussed in detail within this article [13-15] . This review instead
focuses on the multidirectional pathways and microbial metabolites within the microbiota-gut-brain axis
as they specifically relate to neuroinflammation-induced neuropathologies. Finally, we discuss recent and
novel microbiome-targeted strategies as potential treatment options for neurological disorders.

MICROBIOME, MICROGLIA AND NEUROLOGICAL DISORDERS
A mother’s womb is aseptic, and, as such, we begin to develop our microbiome environments within the
first few days after being born, and several factors, including method of birth, institution of breastfeeding or
formula diet, and exposure to different environmental elements, determine initial microbiota compositions
and continual adaptations . The presence of early microbial colonization is essential for the maturation
[16]
and healthy function of numerous CNS systems. The innate immune system require microbiota-induced
[7]
[17]
epithelial signaling in order to correctly respond to pathogenic exposure . For example, Erny et al.
demonstrated that adult germ-free (GF) mice were found to have major deficits in neuroimmune response
compared to conventional controls, such as expressing reduced repertoire of cytokine and chemokine
related genetic changes and inactivated microglial morphology (e.g., “failed to display rounded perikarya
and small processes”) in response to lipopolysaccharide (LPS) exposure. Furthermore, they were able
to demonstrate that reestablishing microbiota diversity and supplementation with microbial-derived
short-chain fatty acids (SCFAs), rather than total bacterial abundance load was important for partial
[7]
[18]
recovery of microglial function . In another example, Sudo et al. showed that sterile-bred GF mice,
devoid of microbiota, express hyperresponsive irregular hypothalamic-pituitary-adrenal (HPA) activity
in response to stress compared to conventionally bred laboratory mice. The HPA axis is considered one
of the main relay stations between the GMB and host CNS immune responses, which has been linked to