Project 6

The impact on gut microbiome of anti-seizure medicines

 

Supervisors  

Dr Rhys Thomas (rhys.thomas@ncl.ac.uk)

Dr Chris Stewart (chris.stewart@ncl.ac.uk)

 

Overview

Background

There are an estimated 10^8 to 10^11 bacterial cells from 1000 different species living symbiotically within us. Termed the gut microbiome, this area of research has emerged as an important bi-directional modifier that works alongside neural, endocrine, metabolic and immune pathways. Gut microbiota have a crucial role in modulating intestinal permeability, altering immune responses, and producing essential metabolites and neurotransmitters. Several neurological disorders demonstrate a gut-brain relationship, but such research is lacking in epilepsy. What makes the microbiome so attractive to understand is our ability to manipulate the gut flora to either make people less susceptible to disease or help treatments become more effective or tolerable.

We have the expertise and capability to conduct a prospective pilot study. Dr Stewart is eager to transfer his impactful work on the microbiome in early childhood type 1 diabetes and rotavirus infection to look at the effect anti-seizure medication could be having on the gut microbiome of people with epilepsy.

Hypothesis

What are the changes in gut microbiome profile when starting an anti-seizure medicine, and does this depend on the type of drug?

Methods

We propose an observational study of adults with epilepsy starting antiepileptic medication.  Choice of anti-seizure medications and titration schedule will be decided by the treating clinician, but most participants are likely to start one of three first-line anti-seizure medications: carbamazepine, lamotrigine or levetiracetam.

Recruitment will be through the First Seizure service at the Royal Victoria Infirmary. We aim to recruit 100 people with epilepsy, each with a paired control (cohabitant of similar diet, without confounders, to provide paired faecal samples). We aim to analyse at least 25 case-control pairs for each of the three common first-line AEDs. We expect that there will be at least 8 good and 8 poor responders. This allows for exclusion of 25% from analyses due to patient drop-out, sequencing failure or confounders.

16S rRNA gene Sequencing and Bioinformatics will be performed as per previous work by the applicants. Briefly, DNA will be extracted from the samples using the QIAGEN powerlyzer powersoil DNA extraction kit.  Sequencing will be performed 16S rRNA gene amplicon-based sequencing of the V4 region on the Illumina MiSeq using the 2x 300 protocol.  This amplicon-based approach will maximise the detection of low abundant and potentially important bacteria to the genus level. Raw sequence data will be processed using in-house pipelines.

 Outcomes measured at one year will be seizure-freedom, discontinuation of anti-seizure medications, and change in patient-reported Quality Of Life In Epilepsy score. We will collect details of side-effects, seizure frequency, and potential confounders such as diet, medications (particularly antibiotics, chemotherapy and additional anti-seizure medications), lifestyle and health at anti-seizure medication initiation and 2-monthly.

Patient Impact

The pilot study will enable us to adequately power a clinical trial to look at the impact of anti-seizure drugs on the microbiome for people with chronic epilepsy, and whether certain profiles may be associated with seizure rates. The ambition is to find microbiome biomarkers of seizure outcome, that can be manipulated.

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