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Pathogenic microbiota disrupts the intact structure of cerebral organoids by altering energy metabolism

Melis Isik1, Cemil Can Eylem2, Kubra Erdogan-Gover3

  • 1Stem Cell Research Lab, Department of Chemistry, Faculty of Science, Ankara University, Ankara, Türkiye.

Molecular Psychiatry
|August 18, 2025
PubMed

Insights

Pathogenic bacteria harm brain organoids by disrupting neural structures and altering cellular metabolism, potentially contributing to neurodegenerative diseases. This research highlights bacterial impact on brain organoid biomolecular structures.

Area of Science:

  • Neuroscience
  • Microbiology
  • Biochemistry

Background:

  • Cerebral organoids (COs) offer a model for studying human brain development and disease.
  • The gut-brain axis and microbial influence on neurological health are areas of intense research.
  • Understanding microbial interactions with neural tissue is crucial for neurodegenerative disease research.

Purpose of the Study:

  • To investigate the impact of pathogenic (PM) and non-pathogenic (NM) bacteria on cerebral organoid (CO) biomolecular structures.
  • To analyze metabolic and transcriptomic changes in COs upon bacterial co-culture.
  • To explore bacterial communication with neural cells using metabolic flux analysis.

Main Methods:

  • Co-culture of COs with non-pathogenic (NM) and pathogenic (PM) bacterial populations.
  • Immunohistochemistry to assess neuronal markers (TUJ1+).
  • RNA-sequencing (RNA-seq) for transcriptomic profiling.
  • Proteomic analysis to identify protein expression changes.
  • 18O-stable isotope labeling (SIL)-based metabolic flux analysis.

Main Results:

  • PM exposure reduced TUJ1+ neurons and disrupted CO structure.
  • PM altered CO transcript profiles, decreasing glycolysis and increasing pentose phosphate pathway activity.
  • Proteomic analysis revealed PM upregulated proteins associated with neurological diseases.
  • Bacterial co-culture increased oxidative phosphorylation activity in COs, indicated by TCA cycle intermediate enrichment.

Conclusions:

  • Pathogenic bacteria can induce detrimental changes in brain organoid biomolecular structures and cellular metabolism.
  • Metabolic alterations observed in COs upon PM exposure are linked to neurodegenerative disease pathways.
  • This study establishes a platform for monitoring microbiota-brain cell communication and its metabolic consequences.

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