Trillions of gut microbes to rescue AED: the microbiome associated to clinical response in children epilepsy – TrilliAED

TrilliAED combine meta-omics technologies, mathematic modeling, cell biology and original anaerobic physiology approaches.
The consortium includes a clinicial pediatrician partner (INSERM – APHP) specialized in children epilepsy and several research institutes. INRAE and CEA research teams have varied and complementary expertise in microbial ecology of the gut, microbial-host interactions, global metabolomics and pharmacology. To reach our objectives, we propose an original approach tackling the question of drug-microbiome interaction, without a priori (all members of the microbial communities, involving also syntrophic interactions in the communities, are tested), assessing both drugs and their therapeutic formulations, and providing in vivo comprehension of the underlying mechanisms.

First TrilliAED results indicate that antiepileptic drugs impact gut bacterial growth and can exert toxicity effects on these bacteria. These effects are dose-dependent, appear rapidly (24h) and seem to be specific of the phylogenetic groups. Two major AEDs had a strong impact on bacterial functions. Moreover AED also impacted host epithelial cells mRNA expression by increasing several genes, which was dampened by the presence of gut microbial metabolites.

Expected results of TrilliAED range from prediction tools based on microbial biomarkers to stratify children who will respond to AED, to development of strategy ameliorating response rates to AED (and/or decrease their toxicity).
More specifically, TrilliAED will enable:
• Highlighting specificities in the microbiome of AED-refractory children as compared to responders, and defining early detectable biomarkers of response.
• Unravelling anaerobic microbial metabolic pathways involved in AED response.
• Generating a novel efficient, quantitative, fast, integrated approach for screening patients.
• and finally proposing options to modulate the microbiome in favor of a boosted response to AED.
Being able to offer an efficient treatment option to these patients, as early as possible, or to modulate their microbiome to shift them to good responders is of high interest for both the patients, their families and their clinicians. With 1% of the children affected by epilepsy worldwide and 25% uncontrolled by usual AED, the potential benefits of microbiome-centered manipulations to boost existing anti-epileptic drugs are substantial.

TrilliAED first results were communicated in an international conference (IEC 2021)

Anti-epileptic drugs (AED) are prescribed in 70 Ms of patients worldwide, yet without curing epilepsy. Adverse-drugs events are frequent and diverse, often impairing patients’ quality of life. Children are at higher risk of developing epilepsy and approx. 25% will not respond to available AED. Pharmacoresistance to AED (~30 molecules) is a major burden to patients and society. The brain suffers during the time needed for the physician to empirically find a treatment and refractory epilepsy in young children is associated with severe sequelae. Drug toxicity can also have disastrous consequences
Numerous hypotheses explaining resistance to AEDs have been addressed and involve genetic and epigenetic host factors, disease severity, transporters and targets hypothesis etc. Yet success rate of AEDs has not improved over the last 20 years. TrilliAED will consider the trillions of bacteria from the gut microbiome as potential effectors of AED response in children. The TrilliAED project’s objectives are to i) demonstrate the link between the human microbiome and response to AED in children, ii) define why and how specific microbiomes may sustain or boost AED efficacy, lowering adverse events, both in vitro and in vivo, iii) stratify patients to suggest appropriate therapeutic options early in the disease development by implementing an innovative “microbiomic” approach, and iv) ameliorate effectiveness of these otherwise valuable and affordable molecules. To reach these goals, gut microbiome variations depending on response to AED will be explored in a pediatric cohort. Then, bacteria of interest will be scrutinized for their drug metabolism capacity. Toxicity of drug degradation secundary products will be assessed in vitro. Finally, findings will be recapitulated in animal models of seizures and bacterial add-on therapies will be proposed.
Since uncontrolled seizures occurrences strongly affect social interactions but also education in these developing brains, being able to provide an efficient treatment option to these patients as early as possible, to modulate their microbiome to improve their response to available treatments or to decrease debilitating adverse events is a crucial societal, scientific and medical need.