2026 ECNP Congress

PS02-2072

Microbial metabolites as regulators of neuroimmune response: unravelling mechanisms of host-microbiome interaction using human induced pluripotent stem cells

Cristina Rosell-Cardona — C.M. Yde Ohki, C. Felski, Z. Schickardt, O. Brüstle, R. McNeill, J.F. Cryan, G. Clarke, S. Kittel-Schneider · APC Microbiome Ireland- University College Cork, Department of Psychiatry and Neurobehavioural Science- University College Cork- Cork- Ireland, Cork, Ireland

2026 ECNP Congress

Mental disorders are highly prevalent worldwide, affecting an estimated 15-36% of individuals across countries. Among these, major depressive disorder (MDD) is a leading contributor to global disease burden, with approximately 1 in 6 people experiencing depression at some point in their lifetime and associated with substantial mortality (1). In addition, 30% of patients fail to achieve remission with first-line antidepressants, highlighting an urgent need for innovative, mechanism-based therapies. The gut microbiota is increasingly recognised as a key regulator of mental health via bidirectional communication along the microbiota-gut-brain axis. Emerging evidence implicates microbial metabolites, including short-chain fatty acids (SCFAs), tryptophan-derived metabolites, and bile acids, as key mediators of this signalling. In MDD, metabolites such as butyrate and indole-3-propionic acid (IPA) have been associated with symptom severity and remission (2-3). We previously showed that stress alters microbial production of these metabolites, which modulate neuroplasticity, neuroinflammation, and blood-brain barrier integrity in ex vivo and in vitro models (4-5). However, their effects on human brain cell systems remain unclear. We hypothesize that butyrate and IPA differentially regulate neuronal and microglial structure, synaptic function, and inflammatory signaling using human iPSC-derived neurons and microglia to define metabolite-specific effects on neuronal and microglial function and identify tractable molecular pathways linking gut microbial metabolism to depressive pathology.

Cortical neuron differentiation was performed using a dual SMAD inhibition protocol from hiPSC lines derived from patients recruited at the Departments of Psychiatry and Psychotherapy at the University Hospitals of Würzburg and Frankfurt. Microglia were differentiated from hiPSC lines obtained through collaboration with Life & Brain (scalable production platform). Cells were exposed to sodium butyrate and indole-3-propionic acid (IPA) at physiologically relevant concentrations (0 µM; 0.1 µM; 1 µM; 100 µM), either alone or in combination with lipopolysaccharide (LPS) in microglia to induce inflammatory activation. Immunocytochemistry, proliferation assays, gene expression analyses, and multiplex cytokine assays (MSD platform) were performed to assess cellular identity, viability, neuroplasticity, and inflammatory responses.

Preliminary analyses showed that sodium butyrate and IPA did not affect cell viability in either neurons or microglia. hiPSC-derived NPCs and cortical neurons were successfully generated and characterised by expression of PAX6 and SOX2 in NPCs, and MAP2 and vGlut1 in mature neurons. Microglia were immunostained for Iba1 and NF-κB to evaluate microglial identity and inflammatory activation. In microglia, sodium butyrate attenuated LPS-induced cytokine release, in particular IL-6 and TNF-α, in a dose-dependent manner, whereas IPA showed no acute effects under the conditions tested, although more detailed evaluations are ongoing.

Together, these data support the use of this hiPSC-based platform for systematic investigation of microbial metabolites as modulators of human microglial and neuronal function, and establish a hiPSC-based platform for investigating microbiota-brain interactions, providing mechanistic insight into gut-brain signalling and revealing potential novel therapeutic targets for MDD.

References

  1. Marx, W. et al. Nat Rev Dis Primers. 2023. doi: 10.1038/s41572-023-00454-1.
  2. Liu L, et al. EBioMedicine. 2023 Apr;90:104527. doi: 10.1016/j.ebiom.2023.104527.
  3. Schiweck C, et al. Brain Behav Immun Health. 2025 Jul 19;48:101070. doi: 10.1016/j.bbih.2025.101070.
  4. Rosell-Cardona C, et al. Neuropharmacology. 2025 Aug 1;273:110434. doi: 10.1016/j.neuropharm.2025.110434.
  5. Rosell-Cardona et al., Microbial Tryptophan Metabolites Modulate Blood-Brain And Gut Barriers In Vitro. Volume 5, 2026, 106876 doi:j.nsa.2025.106876