Gut microbiota regulates mouse behaviors through glucocorticoid receptor pathway genes in the hippocampus

Abstract

Gut microbiota has an important role in the immune system, metabolism, and digestion, and has a significant effect on the nervous system. Recent studies have revealed that abnormal gut microbiota induces abnormal behaviors, which may be associated with the hypothalamic–pituitary–adrenal (HPA) axis. Therefore, we investigated the behavioral changes in germ-free (GF) mice by behavioral tests, quantified the basal serum cortisol levels, and examined glucocorticoid receptor pathway genes in hippocampus using microarray analysis followed by real-time PCR validation, to explore the molecular mechanisms by which the gut microbiota influences the host’s behaviors and brain function. Moreover, we quantified the basal serum cortisol levels and validated the differential genes in an Escherichia coli-derived lipopolysaccharide (LPS) treatment mouse model and fecal “depression microbiota” transplantation mouse model by real-time PCR. We found that GF mice showed antianxiety- and antidepressant-like behaviors, whereas E. coli LPS-treated mice showed antidepressant-like behavior, but did not show antianxiety-like behavior. However, “depression microbiota” recipient mice exhibited anxiety- and depressive-like behaviors. In addition, six glucocorticoid receptor pathway genes (Slc22a5, Aqp1, Stat5a, Ampd3, Plekhf1, and Cyb561) were upregulated in GF mice, and of these only two (Stat5a and Ampd3) were upregulated in LPS-treated mice, whereas the shared gene, Stat5a, was downregulated in “depression microbiota” recipient mice. Furthermore, basal serum cortisol levels were decreased in E. coli LPS-treated mice but not in GF mice and “depression microbiota” recipient mice. These results indicated that the gut microbiota may lead to behavioral abnormalities in mice through the downstream pathway of the glucocorticoid receptor. Herein, we proposed a new insight into the molecular mechanisms by which gut microbiota influence depressive-like behavior.

The role of inflammation and the gut microbiome in depression and anxiety

“…For instance, a seminal study reported that GF male mice have an overreactive HPA axis leading to increased concentrations of corticosterone and adrenocorticotropic hormone (ACTH) following a stressful stimulus (Sudo et al, ). These findings have been replicated several times (Clarke et al, ; Luo et al, ; K. A. Neufeld, Kang, Bienenstock, & Foster, ; K. M. Neufeld, Kang, Bienenstock, & Foster, ); and have been expanded to GF male rats (Crumeyrolle‐Arias et al, ). Furthermore, an in‐depth epigenetic study reported that gene expression in the brain of GF male mice was significantly different from controls, the most notable differences were observed in the hippocampus, cortex, striatum, and cerebellum (Heijtz et al, ).…”

“…The most notable differences are seen in the brain and the immune system, both particularly relevant in addressing anxiety and depression‐like behaviors. Moreover, both depression and anxiety disorders are heavily influenced by stress pathways such as the hypothalamus–pituitary–adrenal (HPA) axis, which can be strongly modified by the gut microbiome composition (Luo et al, ; Sudo et al, ).…”

The changes of gut microbiota in drug-naïve first-episode MDD patients under treatment by SSRIs

“…In several paralleled researches, MDD patients showed speci c features of gut microbes differing from normal controls [5][6][7][8]. Several studies have reported that transplantation of stool from MDD patients into rodents could lead to depression-like behaviors, which had be used to establish animal models of MDD [5,9,10]. The similar phenomenon was observed in fecal bacteria transplantation between animal models.…”

Development of a Bioinformatics Framework for Identification and Validation of Genomic Biomarkers and Key Immunopathology Processes and Controllers in Infectious and Non-infectious Severe Inflammatory Response Syndrome

“…Its function therefore may be linked to that of DENND3. AMPD3 (adenosine monophosphate deaminase 3) is also involved in energy metabolism and may also play a role in microbial interactions with the host (206).…”