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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 219

and GLP-1) and SCFAs that target receptors located on vagus fibers. Long chain fatty acids (LCFAs) also
interact with vagus receptors through cholecystokinin-dependent mechanisms.

Direct measurements of EEC activities have been challenging due to their location in the gut wall. Recently,
[55]
the lab of Reimann et al. has developed a method to directly investigate EEC activity by genetically tagging
EECs with a fluorescent protein which expresses under the control of the promoter for a peptide hormone
precursor proglucagon, GLP-1. Using this approach, they established the important role of G-protein
coupled receptors (GPCRs) in chemosensing and their ability to activate EECs leading to the secretion of
peptide hormones. GPCRs are critical for a variety of physiological functions, such as regulation of immune
system, autonomic nervous system regulation, sensory (taste and smell) functions, and maintaining energy
homeostasis. Recently, some GPCR chemoreceptors were found to be activated by bile acids, SCFAs, and
[56]
LCFAs, which are also linked to EECs . It was shown that the LCFA receptors GPR40 and GPR120 and the
[55]
[57]
bile acid receptor GPR131 (TGR5) are all expressed on the surface of EECs . In addition, Samuel et al. found
that isolated EECs express GPR41, a receptor for SCFAs. It has been shown that these chemosensors are
[58]
located on the basolateral membrane of of EECs, which interact with the circulatory system . In addition,
it is likely that GPCRs co-store and co-release with gut-derived hormones, which indicate that GPCRs may
be regulated by associated intestinal hormones. SCFAs and LCFAs, released from gut microbiota or derived
nutritionally, can activate release of CKK hormone, which can bind to CCK-A and CCK-B receptors
[59]
(CCK-r) on vagal afferents that signal the brain . In response, the brain develops immune responses
and triggers vagal efferent fibers to release acetylcholine (ACh), which is the principal parasympathetic
[60]
neurotransmitter . These observations suggest that gut dysbiosis can result in pathological changes in the
levels of gut hormones and metabolites, thus influencing GPCR function and dysregulating the vagus nerve
and subsequent CNS activities.

The interactions between gamma-aminobutyric acid and vagus nerve
Gut microbiota also produce a number of neurotransmitters similar to mammalian physiological systems,
including dopamine, norepinephrine, serotonin, and gamma-aminobutyric acid (GABA). GABA is the
major inhibitory neurotransmitter in the CNS; however, GABA receptors are expressed throughout
[61]
the body, including on the vagus nerve . In human intestines, GABA is produced by the microbiota
populations Lactobacillus brevis and Bifidobacterium dentium. GF animals were shown to have reduced
levels of GABA, suggesting that the gut microbiota is able to influence GABA levels. Furthermore, altered
GABA levels have also been associated with neurological conditions, such as depression, anxiety, autism,
and schizophrenia [62,63] . For example, studies into rodents were found to have reduced depressive and
anxiety-like behaviors after receiving chronic administration of the probiotic Lactobacillus rhamnosus,
which was accompanied by decreases in GABA receptor subunit mRNA expression and corticosterone
[64]
levels . The GABA-related reductions in behavioral effects did not occur in vagotomized rats and
[65]
mice . Considering this effect existed only when the vagus nerve was intact, it suggests that intestinal
microorganisms regulate GABA signaling through the vagus nerve. In support of this conclusion, animal
[66]
studies by Takanaga et al. demonstrated that GABA produced by intestinal bacteria are able to cross the
blood-brain barrier and influence CNS activities. In addition, the impairment of GABA-mediated neuronal
inhibition associated with epilepsy might contribute to the therapeutic efficacy of vagus nerve stimulation,
as was demonstrated in patients with drug-resistant partial epilepsy .
[67]
Vagus nerve pathways in controlling inflammation
The microbiota-gut-brain interaction through the vagus nerve plays a major role in regulating
inflammation. The anti-inflammatory properties of vagus nerve function is mediated through several
debated pathways, such as the cholinergic anti-inflammatory pathway, the HPA axis and the splenic-
sympathetic nerve anti-inflammatory pathway.

Previous studies demonstrated that the cholinergic anti-inflammatory pathway (CAP) plays a pivotal role
in controlling neuroinflammation. The CAP modulates inflammation through vagal efferent fibers that