What is already known on this topic
Epilepsy is a chronic disease of the central nervous system affecting more than 70 million people globally. About 30-40% of epilepsy patients are resistant to minimum two or more types of antiepileptic medications. This condition is known as drug-resistant epilepsy and it causes a great socio-economic burden to the families and society. Although many new drugs have been discovered, treatments are still limited as the specific mechanisms behind this condition remain unknown.
What this research adds
Researchers analyzed the microbiome composition of patients affected by drug-resistant epilepsy and noted that dysbiosis might be playing a vital role in the pathogenesis of this condition.
Researchers reported the association between dysbiosis and drug-resistant epilepsy. The gut flora in patients with this condition was characterized by a significant richness of rare bacteria and a decrease in the normal commensal bacteria. Bifidobacteria and Lactobacilli could be considered as a protective factor in epilepsy, and they also help to restore the gut microbial community, which may be considered as a novel therapeutic approach for drug-resistant epilepsy.
Dysbiosis may be involved in the mechanism of drug-resistant epilepsy and that the restoration of the gut microbial community may be a novel therapeutic method for drug-resistant epilepsy. It is the conclusion of a study carried out by Anjiao Peng and colleagues at the Sichuan University, Chengdu, in China, and published in the journal Epilepsy Research.
Gut Microbiome and Central Nervous System disorders
Multiple studies have reported that the gut microbiome is closely connected with the central nervous system, and dysbiosis has been reported in many central nervous system (CNS) disorders such as epilepsy, Parkinson’s disease, multiple sclerosis and Alzheimer disease.
The microbiome regulates the CNS through multiple metabolites, neurotransmitters and inflammatory factors. The CNS, in turn, regulates the gut microbiome through the vagus nerve or the hormonal axis. The interaction between the gut microbiome and the CNS is called the Gut-microbial-brain axis.
Whether the gut microbiome plays a role in the pathogenesis of drug-resistant epilepsy is still not clear. In previously conducted studies, researchers found that ABC (ATP-Binding Cassette) transporters were significantly active in patients with drug-resistant epilepsy. ABC transporters (e.g., P glycoprotein and multidrug resistance associated proteins) constantly pump the drug out of the cell relying on the ATP decomposition, thereby resisting the concentration gradient of the drug.
Since the metabolic pathways of ABC transporters are strongly associated with Ruminococcus and other rare bacteria, it was speculated that the altered microbial community may also play a vital role in the pathogenesis of drug-resistant epilepsy by impairing the synthesis and further metabolism of transporters.
Antiepileptic medications and the disruption of gut microflora
Studies have demonstrated that drugs targeting the nervous system, especially antipsychotics and calcium-channel blockers, exhibit significant anti-commensal activity.
When the normal flora is repressed, it results in abnormal overgrowth of Ruminococcus and other rare bacteria with a high level of ABC transporter metabolism. Conversely, the disruption of gut microflora further leads to a decrease in the absorption of drugs, which weakens the antiepileptic effect of the drug. Therefore, in this case, anti-commensal activity should be considered as one of the side effects of antiepileptic medications, the alleviation of which should be helpful for the therapeutic management of the disease.
Bifidobacteria and Lactobacilli were found to be significantly higher in patients with 4 or fewer seizures per year than those who had more than 4 seizures. These floras were found to be responsible in further promoting the synthesis of gamma aminobutyric acid which is a major inhibitory neurotransmitter. These results demonstrated that Bifidobacteria and Lactobacilli might play significantly protective roles in patients with epilepsy.
In this study, a total of 42 patients with drug-resistant epilepsy (DR), 49 patients with drug-sensitive epilepsy (DS) and 65 healthy controls (HC) were enrolled. To further minimize the dietary impact on the gut flora, all healthy controls were selected from the patients’ families. Oxcarbazepine was the most frequently used drug in both groups, followed by levetiracetam and valproate.
Researchers analyzed the microbiome composition by high-throughput sequencing of the bacterial DNA and reported that dysbiosis might be involved in the pathogenesis of drug-resistant epilepsy.
The results showed that the α-diversity of patients with 4 seizures or fewer per year was similar to that of HC while patients with more than 4 seizures reported significantly higher α-diversity.
The β-diversity analyses showed that the microbiome community of the samples in the DR group was different from that of the DS group.
Drug-resistant epilepsy and altered bacterial gut microbiota
The overall gut microbiome composition was found to be similar between the HC and DS groups at the phylum level with Bacteroidetes being the largest phylum and Firmicutes being the second largest.
In the DR group the abundance of Bacteroidetes was comparatively lower. That of Firmicutes was higher and it was reported as the largest phylum. In contrast, many other rare phyla showed an increased tendency in the DR group. For example, Verrucomicrobia was also more abundant in the DR group than in the DS group and HC group.
The differences in bacterial community structure were further confirmed with the help of a linear discriminant effect size (LEfSe) analysis. Bacteroidetes along with its two genera, Bacteroides and Barnesiell, were considerably present in the DS group, while the flora of the DR group seemed to be characterized by an increased abundance of numerous rare bacteria, including Clostridium XVIII, Atopobium, Holdemania, Dorea, Saccharibacteria, Delftia, Coprobacillus, Araprevotella, Ruminococcus, Gemmiger, Akkermansia, Neisseria, Coprococcus, Fusobacterium,Methanobrevibacter, Phascolarctobacterium and Roseburia…etc.
A condition where rare bacteria are dominant
Glucose- and lipid-associated metabolic pathways were all down-regulated. The analysis of the relationship between different species and metabolic pathways showed that these pathways were associated with Ruminococcus and other rare bacteria.
These results suggest that the dysbiosis may be involved in the mechanism of drug-resistant epilepsy and that the restoration of the gut microbial community may be a novel therapeutic method for drug-resistant epilepsy.
This study also demonstrates that patients with drug-resistant epilepsy harbor an altered composition of the gut microbiome characterized by a significantly increased abundance of numerous rare bacteria.
The gut microbiota in patients with drug-sensitive epilepsy was found to be similar to that of healthy controls. The microbial community richness in patients with drug-resistant epilepsy was significantly increased as compared to that of patients with drug-sensitive epilepsy and the healthy controls. This may result from an abnormal increase in numerous rare bacteria mainly belonging to the phylum Firmicutes.
Future studies should assess the microbial metabolites and the resulting host response to further shed light on the composition of the gut microbiome in patients with drug-resistant epilepsy.