<i>Lachnospira eligens</i> attenuates epileptogenesis via gut-brain axis regulation of blood-brain barrier integrity and neuroinflammation

<b>Rationale:</b> Emerging evidence implicates the gut microbiota in epilepsy pathogenesis through the microbiota-gut-brain axis, yet the functional contribution of specific microbial taxa to epileptogenesis remains unclear. This study aimed to investigate whether <i>Lachnospira eligens</i> (<i>L. eligens</i>) can alleviate epileptic activity by modulating the gut-brain axis, with a focus on intestinal barrier integrity, blood-brain barrier (BBB) integrity, and neuroimmune responses. <b>Methods:</b> Using a cobalt wire-induced rat epilepsy model, we performed fecal 16S rDNA sequencing to assess gut microbiota alterations. Rats received daily oral gavage of <i>L. eligens</i> or PBS for 15 days, with colonization confirmed by qPCR. Seizure activity was monitored using long-term video electroencephalogram (EEG) and Racine scores. Barrier function, systemic inflammation, and microglial activation were assessed using FITC-dextran (FD<b>-</b>4, 4 kDa) assay, Western blotting (WB), immunohistochemistry (IHC), immunofluorescence (IF), ELISA, and qPCR. Serum short-chain fatty acids (SCFAs) were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). <b>Results:</b> Epileptic rats exhibited early gut microbiota dysbiosis, with a significant decline in <i>Lachnospira</i> abundance both preceding and succeeding seizure onset (<i>P</i> = 0.041, <i>P</i> = 0.026). <i>L. eligens</i> stably colonized the gut (Day 6 and Day 15, both <i>P <</i> 0.001). Supplementation significantly reduced grade 4-5 seizure frequency (<i>P</i> = 0.002) and prolonged seizure latency (<i>P</i> = 0.005). Barrier integrity improved, as indicated by lower plasma FD<b>-</b>4 (<i>P</i> < 0.001), increased colonic (WB: <i>P</i> = 0.013; IHC: <i>P</i> = 0.003) and cortical occludin expression (WB: <i>P</i> = 0.002; IHC: <i>P</i> = 0.01), and decreased serum lipopolysaccharide-binding protein (LBP) (<i>P</i> = 0.011). Neuroinflammation was attenuated, including reduced microglial activation (<i>P</i> = 0.048), lower pro-inflammatory cytokines (IL-1β, <i>P</i> = 0.047; IL-6, <i>P =</i> 0.001; TNF-α, <i>P =</i> 0.002), and decreased M1 polarization (<i>P</i> = 0.004). Serum butyrate increased (<i>P</i> = 0.014), and SCFAs, especially butyrate, suppressed lipopolysaccharide (LPS)-induced iNOS (<i>P</i> = 0.031) in BV2 cells. <b>Conclusions:</b> These findings demonstrate that <i>L. eligens</i> mitigates epileptic activity by restoring intestinal barrier and BBB integrity and suppressing neuroinflammation. Our study highlights <i>L. eligens</i> as a promising microbiota-based intervention for epilepsy through modulation of the gut-brain axis.