Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Sep 7;8(1):187.
doi: 10.1038/s41398-018-0240-5.

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

Yuanyuan Luo  1   2   3 , Benhua Zeng  4 , Li Zeng  1   5 , Xiangyu Du  1   2 , Bo Li  1   2   6 , Ran Huo  1   2   6 , Lanxiang Liu  1   2   7 , Haiyang Wang  1   2 , Meixue Dong  1   2   7 , Junxi Pan  1   2   6 , Peng Zheng  1   2   7 , Chanjuan Zhou  1   2 , Hong Wei  8 , Peng Xie  9   10   11   12   13
Affiliations

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

Yuanyuan Luo et al. Transl Psychiatry. .

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.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1. Absence of microbiota leads to antianxiety- and antidepressant-like phenotypes, and E. coli lipopolysaccharide (LPS) treatment leads to an antidepressant-like phenotype.
a–d The total distance a and the percentage of center distance b in the open field test (OFT), the immobility time c in the forced swim test (FST), and the latency to feed d in the novelty suppressed feeding test (NSFT) of germ-free (GF) (n = 19) and specific pathogen-free (SPF) (n = 20) mice. e–g The total distance e and the percentage of center distance f in the OFT, and the immobility time g in the FST of E. coli LPS-treated mice (n = 13) and control mice (n = 13). Data represent the mean ± SEM. * p < 0.05, ** p < 0.01, *** p < 0.001
Fig. 2
Fig. 2. Real-time PCR validation of the expression of glucocorticoid receptor pathway genes in three mouse models.
a Real-time PCR validation of the 23 differentially expressed glucocorticoid receptor pathway genes detected by the microarray analysis between germ-free (GF) mice (n = 8) and specific pathogen-free (SPF) mice (n = 8). b, c The six significantly expressed genes detected by PCR validation in GF mice were verified in the hippocampus of E. coli LPS-treated mice (LPS, n = 8; control, n = 8) b and of “depression microbiota” recipient mice (depression, n = 8; Healthy, n = 8) c. Data represent the mean ± SEM. * (p < 0.05, FDR < 0.1), ** (p < 0.01, FDR < 0.1)
Fig. 3
Fig. 3. Brief summary of the entire research.
The left panel shows the behavioral phenotypes for the three mouse models. The right panel illustrates the expression and biological functions of the six glucocorticoid receptor pathway genes. Abbreviations: AMP, adenosine monophosphate; IMP, inosine monophosphate; Nr3c1, glucocorticoid receptor
Fig. 4
Fig. 4. The basal serum cortisol levels in three mouse models.
a The basal serum cortisol levels were quantified between germ-free (GF) mice (n = 6) and specific pathogen-free (SPF) mice (n = 6), b between E. coli lipopolysaccharide (LPS)-treated mice (n = 6) and control mice (n = 6) and c between “depression microbiota” recipient mice and “healthy microbiota” recipient mice (Depression, n = 6; Healthy, n = 6). Data represent the mean ± SEM. * p < 0.05
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Qin J, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464:59–65. doi: 10.1038/nature08821. - DOI - PMC - PubMed
    1. Eckburg PB, et al. Diversity of the human intestinal microbial flora. Science. 2005;308:1635–1638. doi: 10.1126/science.1110591. - DOI - PMC - PubMed
    1. Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R. Diversity, stability and resilience of the human gut microbiota. Nature. 2012;489:220–230. doi: 10.1038/nature11550. - DOI - PMC - PubMed
    1. Clemente JC, Ursell LK, Parfrey LW, Knight R. The impact of the gut microbiota on human health: an integrative view. Cell. 2012;148:1258–1270. doi: 10.1016/j.cell.2012.01.035. - DOI - PMC - PubMed
    1. Bauer KC, Huus KE, Finlay BB. Microbes and the mind: emerging hallmarks of the gut microbiota-brain axis. Cell Microbiol. 2016;18:632–644. doi: 10.1111/cmi.12585. - DOI - PubMed

Publication types