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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 221

Glucocorticoids through HPA axis
The HPA axis is a complex set of direct pathways and feedback interactions which include the
hypothalamus, the pituitary gland, and the adrenal glands. The hypothalamus produces and releases
corticotropin-releasing hormone (CRH), which can induce the pituitary to release adrenocorticotropic
hormone (ACTH). ACTH then stimulates the adrenal cortex, producing glucocorticoid hormones.
Each of these hormones can in turn act back on the hypothalamus and pituitary in a negative feedback
cycle. Glucocorticoids are corticosteroids which bind to glucocorticoid receptors present in almost
every vertebrate animal cell. They can reduce certain aspects of immune activities through a feedback
mechanism. Cortisol is the most important human glucocorticoid which has a variety of cardiovascular,
metabolic, immunologic, and homeostatic functions. The influence of microbiota on the HPA axis depends
on many factors including bacterial strain, host age and sex, and different mouse strains [83-89] . Individual
strains of bacteria can regulate the HPA axis and the microbiota as a whole participate in developmentally
[90]
programming stress responses . Conversely, microglial activity can also affect hormone release through
HPA axis. In response to cerebral insults, microglia secrete a variety of inflammatory molecules, such as
cytokines, stimulating neuronal activity within the paraventricular nucleus of the hypothalamus to activate
the HPA axis anti-inflammatory feedback loop to reduce prolonged neuroinflammation.

Glucocorticoids released by the HPA axis bind to glucocorticoid receptors, which are highly expressed
in neurons and microglia to affect cellular responses [85,90] . Glucocorticoids work to suppress both stress
and immune responses by binding to specific glucocorticoid receptors and mineralocorticoid receptors
[91]
in CNS and immune cells . Studies have demonstrated that acute stress induced higher levels of ACTH
and corticosterone in the serum of GF mice compared to conventionally-raised control mice [85-87] .
Recent targeted microarray analysis found 23 upregulated glucocorticoid receptor pathway genes in the
hippocampus of GF mice compared to controls, of which six genes (Slc22a5, Aqp1, Stat5a, Ampd3, Plekhf1,
[87]
and Cyb561) were confirmed by PCR validation . Among these six genes, two (Stat5a and Ampd3)
were upregulated in E. coli-derived LPS-treated mice. The GF mice demonstrated reduced anxiety-like
behaviors in response to acute stress, whereas LPS-treated control mice demonstrated anti-depressive
but not anti-anxiety behavior and a decrease in the basal serum cortisol levels. LPS-induced abnormal
behavior was consistent with previous findings that E. coli colonization in GF mice enhanced the HPA
[86]
axis response to stress . In another study, plasma ACTH and corticosterone hormones were decreased
in mice monocolonized with Bifidobacterium infantis, but were increased in E. coli-monocolonized mice.
In addition, after receiving fecal samples from patients diagnosed with severe depression (“depression
microbiota”), control mice exhibited anxiety- and depressive-like behaviors with parallel downregulation
of Stat5a gene in their hippocampus compared with “healthy microbiota” recipient mice . Stat5a is
[92]
a member of STAT family encoded transcription factors, mediating signals for a broad spectrum of
cytokines. The JAK2-STAT5 signaling pathway plays a critical role in mediating IL-3-induced activation
[93]
of microglia . Furthermore, STAT5 may play a protective role in damaged nerve cells and has been
implicated in cellular functions of proliferation, differentiation, and apoptosis with relevance to processes
[92]
including hematopoiesis and immunoregulation . Collectively, these observations suggest that microbiota
related STAT5 levels may influence neuroinflammation and related disorders.

CRH and glucocorticoids from the HPA axis have been shown to directly affect microglia activity by
[94]
binding to functional CRH-R1 receptors on microglia and initiate apoptosis of microglia . In that study,
Ock et al. demonstrated that CRH-induced apoptosis did not induce nitric oxide production or increase
[94]
expression of pro-inflammatory genes, which indicates that CRH does not affect inflammatory activation of
microglia. This mechanism has been linked to the mitochondrial pathway and induction of reactive oxygen
[95]
species (ROS) production, which can damage microglia cells and promote apoptosis . In support, the
antioxidant N-acetyl cysteine inhibited CRH-induced microglial cell death suggesting that ROS was a main
cause of apoptosis.