Modulating effects of environmental enrichment on stress-induced changes in the gut microbiome

Abstract

Environmental enrichment (EE) involves adding non-standard stimuli, such as running wheels, mazes, and cage mates, to standard animal living conditions to facilitate physical activity, cognitive stimulation, and socialization. Interestingly, exposure to EE can modulate stress and immune responses. However, it is unclear whether housing environments can modulate the effects of stress on the gut microbiome. This study aimed to explore the effects of three different housing conditions—deprived (DH), social (SH), and enriched (EE)—on the central and peripheral immune responses, the HPA axis, and the gut microbiome in 180 male and female mice. Mice were housed in either the DH, SH, or EE condition for 3 weeks starting from post-natal day 21. At 6 weeks of age, during the pubertal stress-sensitive period, mice were treated with either saline or lipopolysaccharide (LPS), a bacterial endotoxin. Eight hours post-treatment, mice were euthanized, and brain, fecal samples, and trunk blood were collected to examine peripheral and central cytokine levels, glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) expressions, along with diversity in the gut microbiome. Contrary to expectations, EE and SH mice showed higher plasma concentrations of TNFα, IL6, and IL12 cytokines than DH mice following LPS treatment, with male mice exhibiting significantly higher levels of these cytokines than their female counterparts. Moreover, EE mice exhibited significantly greater hypothalamic and hippocampal expressions of GR and MR compared to DH mice. The gut microbiome analysis revealed sex-specific beta diversity patterns post-LPS treatment, with male EE and SH mice displaying a more diverse microbiome compared to female counterparts. These findings enhance our understanding of how housing conditions influence the acute immune and stress responses and modulate their effects on the gut microbiome during puberty.