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

What was reviewed?

This review article explores the complex interactions between estrogen, the gut microbiome, and the brain, particularly focusing on how these interactions influence fear extinction, a process critical to anxiety and stress-related psychiatric disorders. It synthesizes current knowledge on the bidirectional communication within the gut microbiota-brain axis, emphasizing sex differences, estrogen’s role, and how microbial metabolites and signaling pathways may modulate fear extinction behaviors and related neural circuits.

Who was reviewed?

The review draws on a broad range of preclinical and clinical studies involving human subjects and animal models, primarily rodents. It incorporates findings from microbiome analyses, behavioral neuroscience, endocrinology, and psychiatry literature. Studies examining sex differences in gut microbial composition, estrogen receptor activity, microbial enzymatic metabolism of estrogens (the estrobolome), and gut-brain signaling pathways are integrated to provide a comprehensive picture of estrogen-microbiome-brain interactions relevant to fear and anxiety regulation.

Most important findings

The review highlights that gut microbiota composition and diversity are influenced by sex and fluctuating estrogen levels, with certain bacterial taxa, including Bifidobacterium, Clostridium, and Lactobacillus, capable of metabolizing estrogens via β-glucuronidase activity. This estrobolome function modulates circulating estrogen levels and thus potentially impacts brain regions involved in fear extinction, such as the amygdala, hippocampus, and medial prefrontal cortex. Preclinical models demonstrate that microbiome depletion impairs fear extinction learning, whereas probiotics may enhance it, implicating microbial metabolites and neural pathways, particularly via the vagus nerve, in mediating these effects. Estradiol, acting predominantly through estrogen receptor β (ERβ), facilitates fear extinction memory recall and modifies GABAergic signaling in fear circuits. However, most mechanistic studies focus on males, with a critical lack of female-specific data, especially across hormonal cycles. Human studies are limited but suggest associations between gut microbial taxa and fear-related neural activity. Progesterone’s role remains less clear but may also interact with the gut microbiome to influence anxiety behaviors.

Key implications

This review underscores the need for more sex-specific research into the gut microbiome’s role in neuropsychiatric disorders, particularly anxiety and PTSD, given the higher prevalence in women and estrogen’s modulatory effects on fear extinction. Understanding the estrogen-gut microbiome-brain axis could reveal novel therapeutic targets, including microbiota-based interventions like probiotics or fecal microbiota transplantation, tailored by sex and hormonal status. It also highlights that estrogen’s influence on brain circuits critical for fear learning is potentially mediated or modulated by microbial activity and metabolites, suggesting a new dimension for personalized psychiatry. Future studies must include females, consider hormonal cycles, and employ integrated microbiome and neurobiological approaches to improve mental health outcomes and address sex disparities in psychiatric disease.