Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Cell. 2018 Jun 14;173(7):1728-1741.e13. doi: 10.1016/j.cell.2018.04.027. Epub 2018 May 24.
The ketogenic diet (KD) is used to treat refractory epilepsy, but the mechanisms underlying its neuroprotective effects remain unclear. Here, we show that the gut microbiota is altered by the KD and required for protection against acute electrically induced seizures and spontaneous tonic-clonic seizures in two mouse models. Mice treated with antibiotics or reared germ free are resistant to KD-mediated seizure protection. Enrichment of, and gnotobiotic co-colonization with, KD-associated Akkermansia and Parabacteroides restores seizure protection. Moreover, transplantation of the KD gut microbiota and treatment with Akkermansia and Parabacteroides each confer seizure protection to mice fed a control diet. Alterations in colonic lumenal, serum, and hippocampal metabolomic profiles correlate with seizure protection, including reductions in systemic gamma-glutamylated amino acids and elevated hippocampal GABA/glutamate levels. Bacterial cross-feeding decreases gamma-glutamyltranspeptidase activity, and inhibiting gamma-glutamylation promotes seizure protection in vivo. Overall, this study reveals that the gut microbiota modulates host metabolism and seizure susceptibility in mice.
生酮饮食（KD）用于治疗难治性癫痫，但其神经保护作用的机制仍不清楚。在这里，我们表明肠道微生物群受 KD 改变，并需要保护免受两种小鼠模型中急性电诱导癫痫发作和自发性强直 - 阵挛性发作的影响。用抗生素治疗或无菌饲养的小鼠对 KD 介导的癫痫发作保护具有抗性。与 KD 相关的 Akkermansia 和 Parabacteroides 的富集和定植共生恢复了对癫痫发作的保护。此外，将 KD 肠道微生物群移植和用 Akkermansia 和 Parabacteroides 治疗各自赋予喂食对照饮食的小鼠癫痫发作保护。结肠腔、血清和海马代谢组学谱的改变与癫痫发作保护相关，包括全身性γ-谷氨酰化氨基酸减少和海马 GABA/谷氨酸水平升高。细菌交叉喂养降低了γ-谷氨酰转肽酶活性，抑制γ-谷氨酰化在体内促进癫痫发作保护。总的来说，这项研究表明肠道微生物群调节了小鼠的宿主代谢和癫痫易感性。
