Postpartum depression (PPD) is a common mood disorder after childbirth and is associated with abrupt hormonal withdrawal, systemic inflammation, and neurobiological dysfunction. Increasing evidence implicates dysregulation of the microbiota-gut-brain axis in PPD pathophysiology, but safe and effective treatments remain limited. Here, we investigated the antidepressant-like effects and mechanisms of ineupatorolide B (InB), a bioactive compound isolated from Inula species, using a hormone-simulated withdrawal mouse model of PPD. InB significantly alleviated depressive- and anhedonia-like behaviors, as shown by reduced immobility in the tail suspension and forced swim tests and restored sucrose preference, with efficacy comparable to fluoxetine. InB also reduced serum interleukin-6 and tumor necrosis factor-α levels and restored the expression of postsynaptic density protein 95 and brain-derived neurotrophic factor in the prefrontal cortex. Gut microbiota analysis revealed marked alterations in microbial diversity and composition in hormone-withdrawal mice, accompanied by reduced fecal butyrate levels, which were largely normalized by InB treatment. Correlation analyses suggested associations among specific bacterial phyla, short-chain fatty acid metabolism, and behavioral outcomes. Notably, oral administration of butyric acid also alleviated depressive-like behaviors, suppressed systemic inflammation, and restored PSD-95, BDNF, and occludin expression in the prefrontal cortex of hormone-withdrawal mice. Together, these findings suggest that InB ameliorates PPD-like phenotypes, possibly through modulation of the gut microbiota, butyrate metabolism, systemic inflammation, and synaptic plasticity. However, the causal relationships among these changes remain to be established.
