Never fear, the gut bacteria are here: Estrogen and gut microbiome-brain axis interactions in fear extinction

Sex differences in the prevalence, symptomatology, severity, and other aspects of various neuropsychiatric diseases have been consistently reported. Stress and fear-related psychopathologies, such as anxiety disorders, depression, and post-traumatic stress disorder, are more prevalent in women. Investigations of the mechanisms underlying this sex disparity have described the influence of gonadal hormones in both humans and animal models. However, gut microbial communities are also likely to play a role, as these communities differ between the sexes, are involved in a bidirectional cycling of sex hormones and their metabolites, and are associated with changes in fear-related psychopathologies when gut microbiota are altered or removed. Here, we focus our review on: (1) the role of gut microbiota-brain connections in stress- and fear-based psychiatric disorders, (2) gut microbiota interactions with sex hormones with a particular focus on estrogen, and (3) investigations of these estrogen-gut microbiome interactions in fear extinction, a laboratory model of exposure therapy, to elucidate potential targets for psychiatric treatment. Finally, we call for more mechanistic research using female rodent models and humans.