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Page 218 Reyes et al. Neuroimmunol Neuroinflammation 2020;7:215-33 I http://dx.doi.org/10.20517/2347-8659.2020.13

Microbiota-derived LPS and neural-immune interactions
The brain and connected CNS have previously been regarded as “privileged” and immunologically isolated
[41]
from the rest of the body . Consequently, we assumed the peripheral immune system was in place to
assure healthy functioning and security for the rest of the body. Despite this separation, we have begun to
identify factors outside the CNS which directly impact neurology and behaviors.

The commensal gut microbiota confers colonization protection from pathogens through nutrient and
spatial niche competition, in addition to their ability to interact with the mucosal immune system and
influence release of soluble IgA antibodies, antimicrobial peptides, and defensins against invaders [42,43] .
However, damage to the mucosal wall, for example due to antibiotic-induced microbiota dysbiosis,
overgrowth of opportunistic pathogens, and chronic inflammation, can lead to increased susceptibility to
infection and permeability of the intestinal epithelial layer, known as “leaky gut”, allowing luminal contents
to escape into circulation and induce systemic inflammation [44,45] .

The Gram-negative bacterial membrane component LPS is an endotoxin commonly utilized to study the
effects of inflammation on behavior in rodent models, including voluntary ethanol intake, anxiety-like
behaviors, and blood-brain barrier integrity [46-49] . Studies have demonstrated the direct effects of LPS on
microglial activation and subsequent neurological pathologies and behaviors. For example, systemically
introduced LPS has been shown to induce depressive-like behaviors in animals, similar to “sickness behavior”
[50]
[50]
commonly comorbid with human infection diseases . Biesmans et al. showed that intraperitoneal injection
of LPS increased serum levels of cytokines, including IL-1β, IL-6, TNF-α, IL-10, and MCP-1, peaking at 2 h
after administration. This correlated with upregulation of CNS astrocytic immune activity biomarker glial
fibrillary acidic protein, decreased locomotion, and reduced sucrose preference which indicates anhedonia
[51]
[50]
associated with sickness behavior . In another example, Hoogland et al. demonstrated increased
microglial activation after 48 h of LPS administration and 72 h after live E.coli injection. Furthermore, they
found increased inflammatory cytokines within brain homogenates (TNF-α, IL-1β, MCP-1, and M-CSF) at
3 h after LPS stimulation compared to 20 h after E. coli infection. This indicates that E. coli-associated LPS
endotoxins induced neuroinflammation before circulatory introduction of LPS-producing bacteria, suggesting
the importance of bacterial substrates in triggering immune responses. Furthermore, blocking TLR4-LPS
recognition in a rat model prevented sickness behavior following LPS challenge . While unclear of its origin,
[52]
whether having migrated from the gut microbiome or being derived from a brain microbiome, bacterial LPS
has also been identified within the neuronal parenchyma of Alzheimer’s patients . Zhao et al. observed that
[53]
[54]
LPS tended to self-associate and congregate around neurons, indicated by neuronal marker NeuN- and DAPI
(nuclear)-staining, within brain tissues from patients with Alzheimer’s Disease compared to age-matched
controls that instead expressed more punctate and dispersed LPS. Furthermore, they were able to show that
primary co-cultures of human neuronal-glial cells significantly reduced DNA transcription factors when
[54]
incubated with LPS . Collectively, these observations suggest the critical role of the GMB and microbial
endotoxins in influencing systemic and CNS inflammation related to neurological disorders.

THE GUT AND VAGUS NERVE SYSTEM INTERACTIONS
Vagal afferents and chemosensing through G-protein coupled receptors
The vagus nerve allows for bidirectional communication between the gut and brain, where afferent
signaling conveys sensory information from the gut to a mesh-like system of neurons in the brain.
Microglia are sensitive to intestinal microbiome changes and are effective at receiving signals from the
vagus nerve to regulate neuroimmune activity and function. Gut endocrine cells (EECs) play important
roles in mediating intestinal information to the CNS. They serve as chemosensors that integrate extrinsic
and intrinsic signals within the gut. EECs interact with the vagus nerve by responding to different stimuli,
such as nutrients, harmful toxins, and bacterial products. Through this cell-mediated sensing mechanism,
EECs interact with vagus afferents by releasing serotonin, gut hormones (CCK, PYY, ghrelin, leptin,