DEVELOPING A HIPSC-BASED MODEL TO STUDY MICROBIAL METABOLITES IN DEPRESSION

Major depressive disorder (MDD) affects ~5% of adults, with non-responder rates to antidepressant medication of 20-30%, highlighting the need for novel and personalized therapies (1). The gut microbiota has emerged as a key regulator of mood and cognition via the microbiota-gut-brain axis, but mechanisms remain unclear. Microbial metabolites such as butyrate and indole-3-propionic acid (IPA) are altered in MDD (2,3) and can modulate neuroplasticity, and blood-brain barrier integrity ex vivo and in vitro(4,5). Human-based studies are needed to understand translational relevance. Human induced pluripotent stem cells (hiPSCs) offer a promising platform to study patient-specific cellular mechanisms. To establish a hiPSC-based model to determine how microbial metabolites, sodium butyrate and IPA, modulate cortical neuron function in MDD. hiPSCs derived from patients recruited at University Hospitals Würzburg and Frankfurt were differentiated into neural progenitor cells (NPCs) and subsequently into cortical neurons. Cells were exposed to sodium butyrate or IPA (0-100 µM). Viability, immunocytochemistry, proliferation, and gene expression analyses were performed. hiPSC-derived NPCs and cortical neurons were successfully generated and expressed essential markers: PAX6 and SOX2 in NPCs; MAP2 and vGlut1 in neurons. Metabolites receptors were also expressed in both NPC and cortical neurons. Tested concentrations of sodium butyrate or IPA did not impact cell viability. In conclusion, we establish a robust hiPSC-based platform to study microbiota-brain interactions in depression. Sodium butyrate and IPA are non-toxic at tested concentrations, enabling further analysis of effects on synaptic plasticity and inflammatory pathways. This model supports evaluation of microbial metabolites on neuronal function in MDD.