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Reyes et al. Neuroimmunol Neuroinflammation 2020;7:215-33 I http://dx.doi.org/10.20517/2347-8659.2020.13 Page 227

Figure 1. A schematic summarizing the pathways of gut–brain bidirectional communication with the emphasis on the immune system,
the vagus nerve, and the endocrine system. The importance of the gut bacterial metabolites in this communication as well as lifestyle
changes that affect microglia functioning in normal physiology and during neurological diseases with neuroinflammatory component are
indicated. LPS: lipopolysaccharide; SCFAs: short-chain fatty acids

tract but also can react to dysbiosis and “leaky” gut, thus relaying this information to the CNS. On the
other hand, there is the involvement of the vagus nerve in the microbiota-gut-brain interactions, which
have several afferent and efferent pathways involving a variety of factors such as gut endocrine cells,
neurotransmitters, and receptors. Importantly, the vagus nerve plays an important function in controlling
inflammation through cholinergic and splenic-sympathetic anti-inflammatory pathways and the HPA
axis. The role of hormones in the microbiota-brain bidirectional communication is also deemed important
through regulation of the HPA and HPG axes. In addition, microbiota-derived metabolites, such as SCFAs
and LCFAs, are integral in maintaining intestinal health and have been shown to also impact neurological
health.

The GMB’s critical influence on host development, immune homeostasis, and metabolism as well as
involvement in the development of the CNS disorders, makes it an ideal candidate for novel preventative
therapies and treatments. These strategies include the use of beneficial “eubiotic” antibiotics or other means
such as lifestyle interventions (diet and exercise) aimed at reversing microbiota “dysbiosis” by targeting
microbiota and their metabolites. Although in its infancy, studies into the efficacy of the microbiome-
targeted manipulation and FMT to treat diseases, including those beyond the GI tract, promise interesting
insights into the importance and impact of the vast and diverse microcosm residing within us every day of
our lives from birth to old age and death.

Certainly, we are still in the beginning of the research trying to reveal the causative links between the GMB
and brain function as it relates to neurological disorders. There is a huge untapped potential in this area of
microbiome in human health and disease, which will be more appreciated with the improvement of new
technologies and methods of GMB research.

DECLARATIONS
Authors’ contributions
Designed the focus and scope of the review and substantially contributed to the bulk of the manuscript:
Reyes REN, Asatryan L