MICROBIOTA–MICROGLIA INTERACTIONS IN HUMAN CORTICAL CIRCUITS FUNCTION AND EPILEPTIC DISORDER

Human brain development requires orchestrated processes, such as neuronal migration, synaptogenesis, and synaptic pruning. Immune brain resident cells, microglia, are essential for shaping cortical circuits. During the early postnatal period, GABAergic interneurons migrate and establish contacts with excitatory neuron synapses, ensuring appropriate excitatory/inhibitory (E/I) balance. In humans, disturbances in these processes can contribute to malformations of cortical development (MCD) and refractory childhood epilepsy. Interestingly, gut microbiota establishment, occurring from birth to three years old, may temporally coincide with interneuron circuit integration and microglia-mediated shaping of the synaptic network. We hypothesise that dysbiosis during this critical period in children may disrupt GABAergic interneuron synaptic formation. Lactobacillus, a beneficial constitutive bacterial family found during this temporal window in the infant microbiota, produce short-chain fatty acids (SCFAs), which can cross the blood–brain barrier and regulate microglia surrounding interneurons.To investigate this microbiota–microglia–interneuron communication, we performed immunohistochemistry, two-photon microscopy, and electrophysiology on fresh biopsies from surgeries of MCD epileptic patients treated with the Lactobacillus metabolite profile. Preliminary results demonstrate that cell-free supernatant from Lactobacillus applied to human MCD slices modulates microglia–interneuron interactions through the microglial P2Y12 receptor. Ex vivo multielectrode array recordings revealed a decrease in neuronal hyperexcitability in MCD slices, highlighting Lactobacillus metabolites as potential targets for reducing epileptic neuronal activity via microglial P2Y12 regulation. Ultimately, these findings suggest that gut microbiota and microglia jointly contribute to E/I balance control in the developing human brain and may represent novel therapeutic targets to reduce surgical resection of epileptic regions.