Gut microbiota-bile acid metabolic disorder involved in the cognitive impairments in epilepsy through HO-1 dependent ferroptosis

Abnormal bile acid (BA) metabolism has been implicated in the pathogenesis of central nervous system (CNS) diseases, but its role in epilepsy remains unclear. In this study, we investigated the relationship between gut microbiota-driven dysregulation of BA metabolism and seizure-induced ferroptotic neuronal death in epilepsy. Our targeted metabolomic analysis revealed elevated levels of deoxycholic acid (DCA) in the serum and cerebrospinal fluid (CSF) of epileptic patients, which correlated with cognitive impairment. In a pentylenetetrazol (PTZ)-induced mouse model of epilepsy, 16S ribosomal RNA (16S rRNA) sequencing showed significant alterations in gut microbiota composition. Importantly, fecal microbiota transplantation (FMT) from healthy mice into epileptic mice significantly reduced seizure activity and improved cognitive function, primarily by normalizing serum and brain levels of secondary bile acids (SBAs), including DCA. Both <i>in vitro</i> and <i>in vivo</i> experiments demonstrated that DCA promotes ferroptosis in hippocampal neurons by activating the farnesoid X receptor (FXR). This activation triggered the nuclear factor erythroid 2-related factor 2 (Nrf2)-heme oxygenase-1 (HO-1) signaling pathway, known to be involved in oxidative stress and cell death regulation. Our findings suggest that the upregulation of DCA, through its effects on FXR and HO-1, plays a critical role in the progression of epilepsy by inducing ferroptosis in hippocampal neurons. Targeting the DCA-FXR-HO-1 axis may provide a novel therapeutic strategy for treating seizures and associated cognitive deficits in epilepsy.