Estrogen Receptor β Deficiency Impairs Gut Microbiota: A Possible Mechanism for IBD-Related Anxiety-Like Behavior

Abstract Background: Although lack of ERβ is an acknowledged risk factor for the development of inflammatory bowel disease (IBD) and psychiatric disorders, the underlying cellular and molecular mechanisms are not fully understood. Here, we revealed the role of gut microbiota in the development of IBD and related anxiety-like behavior in ERβ deficiency mice. Results: In this study, we showed that ERβ knockout mice upon dextran sodium sulfate (DSS) insult displayed significant shifts in fecal microbiota composition with increasing enrichment of genus Prevotellaceae_UCG_001, aggravated colitis severity and anxiety-like behaviors. In addition, DSS induced colitis also enhanced hypothalamic-pituitary-adrenal (HPA) axis hyperactivity in ERβ-deficiency mice, which linked colitis and anxiety-like behaviors. In line with these observations, RNA sequencing data further identified ErbB4 might be the target of ERβ involved in regulating HPA axis hyperactivity caused by DSS insult. Gut microbiota remodeling by co-housing showed both colitis severity and anxiety-like behaviors were aggravated in co-housed WT mice compared with single-housed WT mice, suggesting that gut microbiota plays a critical role in mediating colitis disease activity and related anxiety-like behaviors via aberrant neural processing within the gut-brain axis. Conclusions: Our findings demonstrate ERβ has the potential to inhibit colitis development and anxiety-like behaviors via remodeling of gut microbiota, which reveals ERβ as a promising therapeutic target for treating IBD and related anxiety-like behaviors.