Association between seizure reduction during ketogenic diet treatment of epilepsy and changes in circulatory metabolites and gut microbiota composition.

IF 9.7 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL EBioMedicine Pub Date : 2024-11-04 DOI:10.1016/j.ebiom.2024.105400

Maria Dahlin, Craig Edward Wheelock, Stefanie Prast-Nielsen

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Abstract

Background: The ketogenic diet (KD) is a high fat, sufficient protein, and low carbohydrate dietary therapy for drug-resistant epilepsy. The underlying mechanisms of action of the KD remain unclear. In mice, the microbiota is necessary for the anti-seizure effect and specific microbes influence circulatory levels of metabolites that are linked to seizure reduction. However, it remains unclear which changes are linked to seizure reduction in patients with epilepsy.

Methods: We analysed the serum metabolome of children with drug-resistant epilepsy (n = 14) before and after three months on KD. Metabolomic changes were correlated to the gut microbiome and treatment outcome, i.e., seizure reduction.

Findings: In this prospective observational study, we uncovered associations between microbial species and serum metabolites that correlated with seizure reduction. Plasmalogens were most strongly linked to seizure reduction and had significant positive correlations with several gut microbes (e.g., Faecalibacterium prausnitzii, Alistipes communis, Alistipes shahii, and Christensenella minuta) while significant negative correlations were found for five strains of Escherichia coli. Infant-type Bifidobacteria correlated negatively with other metabolites associated with seizure reduction.

Interpretation: The microbes and metabolites identified here may contribute to the therapeutic effect of the KD in children with drug-resistant epilepsy. Several of these metabolites (e.g., plasmalogens) play important roles in neurobiology and may influence seizures. Based on our findings, anti-seizure therapeutic strategies could be developed involving the targeted manipulation of the gut microbiota and/or its metabolites.

Funding: This study was supported by the Swedish Brain Foundation, Margarethahemmet Society, Sunnerdahls Handikappfond, Stockholm County Council Research Funds, and Linnea & Josef Carlssons Foundation.

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生酮饮食治疗癫痫期间癫痫发作减少与循环代谢物和肠道微生物群组成变化之间的关系。

背景：生酮饮食（KD）是一种治疗耐药性癫痫的高脂肪、足量蛋白质和低碳水化合物饮食疗法。生酮饮食的基本作用机制仍不清楚。在小鼠中，微生物群是抗癫痫作用的必要条件，特定微生物会影响与减少癫痫发作有关的代谢物的循环水平。然而，目前仍不清楚哪些变化与癫痫患者癫痫发作的减少有关：我们分析了耐药性癫痫患儿（14 人）在服用 KD 三个月前后的血清代谢组。代谢组变化与肠道微生物组和治疗结果（即癫痫发作减少）相关：在这项前瞻性观察研究中，我们发现了微生物种类与血清代谢物之间的关联，这些代谢物与癫痫发作减少有关。质粒菌与癫痫发作减少的关系最为密切，与几种肠道微生物（如普氏粪杆菌、Alistipes communis、Alistipes shahii和Christensenella minuta）呈显著正相关，而与五种大肠埃希氏菌株呈显著负相关。婴儿型双歧杆菌与其他与减少癫痫发作相关的代谢物呈负相关：解读：这里发现的微生物和代谢物可能有助于KD对耐药性癫痫患儿的治疗效果。其中一些代谢物（如质氨酸）在神经生物学中发挥着重要作用，并可能影响癫痫发作。根据我们的研究结果，可以开发出抗癫痫治疗策略，其中包括有针对性地控制肠道微生物群和/或其代谢物：本研究得到了瑞典脑基金会（Swedish Brain Foundation）、玛格丽塔海默特协会（Margarethahemmet Society）、Sunnerdahls Handikappfond、斯德哥尔摩郡议会研究基金（Stockholm County Council Research Funds）以及林奈和约瑟夫卡尔森斯基金会（Linnea & Josef Carlssons Foundation）的支持。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.