Özcan Ezgi, Yu Kristie B, Dinh Lyna, Lum Gregory R, Lau Katie, Hsu Jessie, Arino Mariana, Paramo Jorge, Lopez-Romero Arlene, Hsiao Elaine Y
Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095.
UCLA Goodman-Luskin Microbiome Center, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, Los Angeles, CA 90095, USA.
bioRxiv. 2024 Jul 31:2024.07.31.606041. doi: 10.1101/2024.07.31.606041.
The gut microbiome is emerging as an important modulator of the anti-seizure effects of the classic ketogenic diet. However, many variations of the ketogenic diet are used clinically to treat refractory epilepsy, and how different dietary formulations differentially modify the gut microbiome in ways that impact seizure outcome is poorly understood. We find that clinically prescribed ketogenic infant formulas vary in macronutrient ratio, fat source, and fiber content and also in their ability to promote resistance to 6-Hz psychomotor seizures in mice. By screening specific dietary variables for their effects on a model human infant microbial community, we observe that dietary fiber, rather than fat ratio or source, drives substantial metagenomic shifts. Addition of dietary fiber to a fiber-deficient ketogenic formula restores seizure resistance, and supplementing protective ketogenic formulas with excess dietary fiber further potentiates seizure resistance. By screening 13 fiber sources and types, we identify distinct subsets of metagenomic responses in the model human infant microbial community that correspond with increased seizure resistance in mice. In particular, supplementation with seizure-protective fibers enriches microbial representation of genes related to queuosine biosynthesis and preQ biosynthesis and decreases representation of microbial genes related to sucrose degradation, which is also seen in seizure-protected mice that are fed fiber-containing ketogenic infant formulas. Overall, this study reveals that different formulations of clinical ketogenic diets, and dietary fiber content in particular, differentially impact seizure outcome in mice, likely through modification of the gut microbiome. Understanding interactions between dietary components of the ketogenic diet, the gut microbiome, and host susceptibility to seizures could inform novel microbiome-guided approaches to treat refractory epilepsy.
肠道微生物群正逐渐成为经典生酮饮食抗癫痫作用的重要调节因子。然而，临床上使用多种生酮饮食变体来治疗难治性癫痫，而不同的饮食配方如何以影响癫痫发作结果的方式差异性地改变肠道微生物群，目前尚不清楚。我们发现，临床处方的生酮婴儿配方奶粉在宏量营养素比例、脂肪来源和纤维含量方面存在差异，在促进小鼠对6赫兹精神运动性癫痫发作的抵抗力方面也存在差异。通过筛选特定饮食变量对模型人类婴儿微生物群落的影响，我们观察到膳食纤维而非脂肪比例或来源驱动了显著的宏基因组变化。向缺乏纤维的生酮配方奶粉中添加膳食纤维可恢复癫痫抵抗力，而在保护性生酮配方奶粉中添加过量膳食纤维可进一步增强癫痫抵抗力。通过筛选13种纤维来源和类型，我们在模型人类婴儿微生物群落中确定了与小鼠癫痫抵抗力增加相对应的宏基因组反应的不同子集。特别是，补充具有癫痫保护作用的纤维可丰富与queuosine生物合成和preQ生物合成相关的微生物基因表达，并减少与蔗糖降解相关的微生物基因表达，这在喂食含纤维生酮婴儿配方奶粉的癫痫保护小鼠中也可见到。总体而言，这项研究表明，临床生酮饮食配方不同，尤其是膳食纤维含量不同，可能通过改变肠道微生物群对小鼠癫痫发作结果产生不同影响。了解生酮饮食的饮食成分、肠道微生物群和宿主癫痫易感性之间的相互作用可为治疗难治性癫痫的新型微生物群导向方法提供依据。
