EPIGUT: EPILEPSY AND GASTROINTESTINAL MICROBIOTA: UNDERSTANDING THERAPY RESPONSE

NCT ID: NCT07253701

Last Updated: 2025-11-28

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 1500 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2024-02-27
• Study Completion Date: 2028-03-31

Brief Summary

The goal of this observational study is to learn how the bacteria in the gut and mouth (called the microbiota) are linked to different types of epilepsy and how they may affect how well seizure medicines work.

Researchers want to answer two main questions:

Are certain types of epilepsy linked to changes in the gut or mouth microbiota? Do the bacteria in the gut change how seizure medicines work for each person?

Epilepsy is a brain condition that causes seizures. Even though there are many medicines for epilepsy, some people still have seizures or side effects. Studies in animals show that gut bacteria can raise or lower the chance of seizures. Smaller studies in people suggest the same thing, but they have been limited in size and scope.

In this study, researchers will collect biological samples from people who have newly diagnosed epilepsy and from people without epilepsy (called healthy controls). The samples will be tested to learn which bacteria are present. The researchers will then look for patterns that may explain which types of epilepsy are linked to changes in the microbiota.

The study will also look at whether the bacteria in the gut and mouth affect how well anti-seizure medicines (ASMs) work. For example, the researchers will explore if certain bacteria make medicines work better or worse.

Patients will provide blood, stool and saliva samples. If collected for medical reasons, cerebrospinal fluid (CSF) - the clear liquid that surrounds the brain and spinal cord -will also be used.

Healthy controls will provide stool and saliva samples only

All participants will be asked to fill an online questionnaire to share health and lifestyle information.

Patients also allow researchers to confidentially access data from medical records related to diagnosis and treatment.

By comparing data from many participants across Sweden, researchers hope to understand how gut and mouth bacteria influence epilepsy and seizure control.

This research may help doctors in the future to use a person's microbiota profile to choose the best seizure medicine. The long-term goal is to improve seizure control, reduce side effects, and raise the quality of life for people living with epilepsy.

Detailed Description

Background:

Clinical studies in humans on the role of the microbiota in promoting seizures and epilepsy are sparse and limited to small, heterogenous cohorts of epileptic patients already treated with ASMs. Larger, treatment-naïve cohorts followed longitudinally are needed to investigate the role of the microbiota in seizures and anti-seizure drug therapy. EpiGUT is building such a cohort in order to study both the oral and gut microbiota by analysis of saliva and fecal samples (primary outcomes). Blood and CSF samples for metabolic and inflammation profiling are collected to analyze how the microbiota may influence systemic and central inflammation and metabolism (secondary outcomes).

In vitro, non-antibiotic drugs can inhibit growth of gut microbes and microbes can metabolize drugs to produce active or toxic metabolites. In vivo, almost nothing is known about the interactions of the microbes and ASMs. Yet these interactions can profoundly influence treatment outcome, as demonstrated for anti-PD1 therapy of patients with cancer as well as for many other treatments of various diseases. It is thus plausible that individual differences in the gut microbiota may be part of the reason why some individuals respond to certain ASMs, and others do not. By confirming this hypothesis and further in vitro validation of specific drug-microbe interactions we can create valuable clinical guidelines for personalizing anti-seizure treatments based on the composition of the gut microbiota, thus increasing the probability of a positive treatment response of the individual patient.

Study design:

EpiGUT studies individuals with newly diagnosed epilepsy and their microbiota in response to different ASMs both on an individual level and in comparison to healthy controls. We will analyze the gut and oral microbial composition and function at baseline, i.e., time of diagnosis and study associations with specific subtypes of epilepsies. Building a unique sample collection of blood and CSF enables mechanistic studies on how specific microbes may modulate seizures through metabolites or inflammatory signaling. We will also study correlations between components of the microbiota and ASM treatment efficacy, as well as drug therapy-associated alterations in the gut microbiota.

In the initial part, we have two sampling time points, at baseline, i.e., time of diagnosis and at follow-up at the time of evaluation of monotherapeutic outcome at three months (or before start of additional ASM, if earlier). About 30% of patients will present with drug-resistent epilepsy. Those will be asked to provide additional samples and quetionnaire answers before and after alternative treatment which may include the ketogenic diet, vagus nerve stimulation or surgery.

Methods:

Our primary outcome variable is the composition of the oral and intestinal microbiota, both on a taxonomic as well as functional level. This will be measured by high throughput whole-metagenomic sequencing of saliva and fecal samples with a minimum of 10 million reads per sample which provides a detailed microbial profile. The role of the microbiota for both research questions will be analyzed using advanced metagenomics-specific bioinformatics tools as well as state-of-the-art machine learning algorithms to identify microbial predictors of seizures and/or ASM therapy outcome. Blood levels of ASMs are measured routinely during follow-up and will be correlated to prescribed dose and components of the gut microbiota to identify potential candidates of ASM metabolizing intestinal microbes. Clinical data such as patient history, epilepsy classification, etiology, seizure burden and current medications will be entered in an anonymized Redcap database. In addition, patients/caregivers will be asked to answer a questionnaire with standard questions relevant to microbiota studies including other diagnoses, dietary habits, oral health, birth mode, physical activity etc. PERMANOVA analysis will identify significant factors contributing to our main outcome, the microbial composition. Regression analysis will take these significant factors into account when analyzing the contribution of microbes to the diagnosis or ASM therapeutic outcome.

In addition, we biobank blood samples collected at both time points and CSF at baseline (only if taken as part of the clinical workup) to analyze inflammatory and metabolomic profiles of the patients using the Olink® inflammation panel and untargeted metabolomics. These profiles will be analyzed both independently and in relation to the microbial profiles to identify host and microbiota-mediated disease- and therapy-relevant factors as secondary outcomes.

Selection of participants:

1,000 patients will be recruited, 300 children and 700 adults from university and regional hospitals across Sweden A healthy control group will be recruited in a 1:2 ratio and matched by age.

Data analysis and statistics:

Data analysis will be performed using advanced metagenomics-specific bioinformatics tools. The diversity of the resulting baseline taxonomic and functional profiles will be analyzed for confounding and other influencing clinical and lifestyle factors and ranked by effect size (R2) and statistical significance (p) in relation to our variables of interest (e.g. epilepsy type, seizure burden and refractoriness, etiology) using Permutational Multivariate Analysis of Variance (PERMANOVA). We will apply state-of-the-art machine learning algorithms to identify microbial predictors of seizures and/or AMS therapy outcome. The most important microbial features of the best model will be extracted and tested in silico as potential biomarkers for diagnosis and/or therapeutic outcome.

Conditions

Epilepsy; Microbiota; Proteomics; Metabolomics; Biomarker Discovery

Study Design

• Observational Model Type: CASE_CONTROL
• Study Time Perspective: OTHER

Study Groups

Patients

Age 2-79 years, newly diagnosed with epilepsy, treatment-naive at time of enrollment. Exclusion criteria: already started ASM treatment (more then one dose), has used antibiotics or probiotics in the last three months, has a gastrointestinal diagnosis, has surgically removed parts of the GIT, obesity (BMI\>30), T2D, follows a strict exclusion diet, is pregnant or breastfeeding, has a gastrostomy, PEG or jejunostomy

No interventions assigned to this group

Controls

Age 2-79 years, exclusion criteria: previous epilepsy diagnosis or ASM treatment, has used antibiotics or probiotics in the last three months, has a gastrointestinal diagnosis, has surgically removed parts of the GIT, obesity (BMI\>30), T2D, follows a strict exclusion diet, is pregnant or breastfeeding, has a gastrostomy, PEG or jejunostomy

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

• Patients: Age 2-79 years, newly diagnosed with epilepsy, treatment-naive at time of enrollment
• Controls: Age 2-79 years

Exclusion Criteria

• Patients: already started ASM treatment (more then one dose), has used antibiotics or probiotics in the last three months, has a gastrointestinal diagnosis, has surgically removed parts of the GIT, obesity (BMI>30), T2D, follows a strict exclusion diet, is pregnant or breastfeeding, has a gastrostomy, PEG or jejunostomy
• Controls: previous epilepsy diagnosis or ASM treatment, has used antibiotics or probiotics in the last three months, has a gastrointestinal diagnosis, has surgically removed parts of the GIT, obesity (BMI>30), T2D, follows a strict exclusion diet, is pregnant or breastfeeding, has a gastrostomy, PEG or jejunostomy

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 79 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Karolinska Institutet

OTHER

Sponsor Role: lead

Responsible Party

Stefanie P rast-Nielsen

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Stefanie Prast-Nielsen, PhD

Role: STUDY_DIRECTOR

Karolinska Institutet

Locations

Drottning Silvias Barnsjukhus

Gothenburg, , Sweden

Site Status: RECRUITING

Universitetssjukhuset i Linköping

Linköping, , Sweden

Site Status: RECRUITING

Skånes universitetssjukhus

Lund, , Sweden

Site Status: RECRUITING

Karolinska Universitetssjukhus

Stockholm, , Sweden

Site Status: RECRUITING

Norrlands universitetssjukhus

Umeå, , Sweden

Site Status: RECRUITING

Akademiska Sjukhuset

Uppsala, , Sweden

Site Status: RECRUITING

Countries

Sweden

Central Contacts

Ronny Wickström, MD, PhD

Role: CONTACT

ronny.wickstrom@ki.se

+46 70 68 38 182

Stefanie Prast-Nielsen, PhD

Role: CONTACT

stefanie.prast-nielsen@ki.se

+46 76 21 67 781

Facility Contacts

Ann-Louise Esserlind, MD

Role: primary

ann-louise.esserlind@vgregion.se

+46 31 343 63 00

Helena Gauffin, MD

Role: primary

Helena.Gauffin@regionostergotland.se

+46 10 103 00 00

Erik Eklund, MD

Role: primary

Erik.Eklund@skane.se

+46 46 17 85 00

Sigrid Bjuresäter, Registered nurse

Role: primary

sigrid.bjuresater@ki.se

+46 8 123 774 61

Ronny Wickström, MD

Role: backup

ronny.wickstrom@ki.se

+46 8 123 706 27

Måns Berglund, MD

Role: primary

mans.berglund@regionvasterbotten.se

+46 90 785 91 40

Christian Wentzel, MD

Role: primary

christian.wentzel@uu.se

+46 18 611 58 48

Related Links

https://ki.se/mtc/epigut

Karolinska Institutets official site for EpiGUT which includes a link for registration of participation

Other Identifiers

2023-04648-01

Identifier Type: -

Identifier Source: org_study_id