Pathogenesis and potential therapies for perimenopausal depression: Insights from the estrogen-gut microbiota axis

Jan 21, 2026Frontiers in neuroendocrinology

How Changes in Estrogen and Gut Bacteria May Influence Depression Around Menopause and Possible Treatments

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Abstract

Fluctuations in estrogen levels during perimenopause may disrupt gut microbiota, impacting mental health.

Estrogen fluctuations can influence neurogenesis and neuroinflammation, potentially contributing to depression.
Changes in estrogen levels are associated with reduced microbial diversity and stability in the gut.
Disruptions in gut microbiota may affect the balance of metabolites and neurotransmitters, linked to depressive symptoms.
The gut microbiota plays a role in metabolizing estrogen, which is crucial for maintaining estrogen levels.
Estrogen deficiency and imbalances in gut microbiota could create a cycle that heightens the risk of perimenopausal depression.
Bioactive compounds from diet or plants may help manage perimenopausal depression by affecting the estrogen-gut microbiota axis.

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Perimenopause represents a critical phase during which women are particularly susceptible to depression. Although fluctuations in estrogen levels resulting from ovarian aging and imbalances in the gut microbiota have been identified as contributing factors to the onset of depression, the interplay among these elements is frequently overlooked. Fluctuations in estrogen levels can further influence neurogenesis or apoptosis through effects on neurotransmitter balance, neuroinflammation, neuroendocrine regulation, and mitochondrial function. Meanwhile, dramatic shifts in estrogen levels can diminish microbial diversity and stability, thereby disrupting the homeostasis of metabolites and neurotransmitters via the gut-brain axis (GBA). Such disturbances may induce neuroinflammation, potentially leading to or exacerbating depressive symptoms. Additionally, the estrobolome (gut bacterial genes encoding estrogen-metabolizing enzymes) plays a regulatory role in the reabsorption, excretion, and systemic levels of estrogen through the modulation of β-glucuronidase activity, thereby affecting estrogen homeostasis. This review first examines the influence of fluctuations in estrogen levels on the composition and function of the gut microbiota, as well as the role of the gut microbiota in estrogen metabolism. It then discusses how estrogen deficiency and dysbiosis of the gut microbiota contribute to the pathogenesis of perimenopausal depression, discussing the potential for a vicious cycle mediated by the estrogen-gut microbiota axis that increases susceptibility to this condition. Finally, this review presents bioactive compounds derived from dietary sources or medicinal plants that exhibit estrogenic and prebiotic properties, which may offer diverse strategies for the prevention and management of perimenopausal depression through modulation of the estrogen-gut microbiota axis.

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Pathogenesis and potential therapies for perimenopausal depression: Insights from the estrogen-gut microbiota axis

Abstract

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