Abstract
Intestinal microbes are an important system in the human body, with significant effects on behavior. An increasing body of research indicates that intestinal microbes affect brain function and neurogenesis, including sensitivity to stress. To investigate the effects of microbial colonization on behavior, we examined behavioral changes associated with hormones and hormone receptors in the hypothalamic-pituitary-adrenal (HPA) axis under stress. We tested germ-free (GF) mice and specific pathogen-free (SPF) mice, divided into four groups. A chronic restraint stress (CRS) protocol was utilized to induce external pressure in two stress groups by restraining mice in a conical centrifuge tube for 4 h per day for 21 days. After CRS, Initially, GF restraint-stressed mice explored more time than SPF restraint-stressed mice in the center and total distance of the OFT. Moreover, the CRH, ACTH, CORT, and ALD levels in HPA axis of GF restraint-stressed mice exhibited a significantly greater increase than those of SPF restraint-stressed mice. Finally, the Crhr1 mRNA levels of GF CRS mice were increased compared with SPF CRS mice. However, the Nr3c2 mRNA levels of GF CRS mice were decreased compared with SPF CRS mice. All results revealed that SPF mice exhibited more anxiety-like behavior than GF mice under the same external stress. Moreover, we also found that GF mice exhibited significant differences in, hormones, and hormone receptors compared with SPF mice. In conclusion, Imbalances of the HPA axis caused by intestinal microbes could affect the neuroendocrine system in the brain, resulting in an anxiety-like behavioral phenotype. This study suggested that intervention into intestinal microflora may provide a new approach for treating stress-related diseases.
Highlights
The intestine is the largest system in the mammalian body, containing 100 trillion organisms
Two-way analysis of variance (ANOVA) revealed that the specific pathogen-free (SPF) stressed control group moved a shorter total distance in the Open Field Test (OFT) compared with the GF stressed group (p < 0.01)
The current results revealed that GF chronic restraint stress (CRS) mice exhibited anti-anxiety behavior accompanied by HPA axis over-activity compared with SPF CRS mice
Summary
The intestine is the largest system in the mammalian body, containing 100 trillion organisms. Intestinal microbial flora are established in early life in mammals, and affect the host’s physiological function (Grenham et al, 2011; Lozupone et al, 2012; Heitlinger et al, 2017). Recent studies have reported that intestinal microbial steady-state imbalances can cause a range of metabolic diseases (Wen et al, 2008; Henaomejia et al, 2012; Koren et al, 2012). A number of studies have explored the mechanisms of intestinal microorganisms, and a range of microbe-related diseases have been discovered and explored in neuropsychiatric subjects. The precise mechanisms of action of intestinal microbial flora remain unclear. Among the known pathogenetic mechanisms, several mental illnesses have been linked to the hypothalamic-pituitary-adrenal (HPA) axis (Schatzberg et al, 2014; Fries et al, 2015)
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