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

Molecular Psychiatry (2025)Cite this article

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Abstract

This study investigated the impact of different bacterial populations on the biomolecular structures of cerebral organoids (COs) at various levels. COs were co-cultured with non-pathogenic (NM) and pathogenic (PM) bacterial populations. PM reduced the number of TUJ1+ neurons and disrupted the intact structure of COs. In addition, PM was found to induce changes in the transcript profile of COs, including a decrease in the activity of the glycolysis pathway and an increase in the pentose phosphate pathway, leading to deterioration in cellular energy metabolism, which is linked to neurodegenerative diseases. Proteomic analysis revealed a unique cluster of proteins in COs. PM exposure upregulated proteins related to neurological diseases, consistent with RNA-seq data. Communication between bacteria and neural cells was demonstrated using 18O-stable isotope labeling (SIL)-based metabolic flux analysis. COs showed higher 18O-enrichment of TCA cycle intermediates when co-cultured with NM and PM, indicating increased oxidative phosphorylation activity upon exposure to bacteria. This study provides a useful platform to monitor metabolic signals and communication between microbiotas and human brain cells. The findings suggest that pathogenic bacteria release metabolites that alter biomolecular structures in brain organoids, potentially contributing to neurodegenerative diseases.

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Fig. 1: Microscopical and functional assessments of COs before and after co-culture.
Fig. 2: Post-microbial interaction transcript profiles in COs.
Fig. 3: Post-microbial interaction protein profiles in COs (biological replicate=3).
Fig. 4: Metabolomic alterations in COs co-cultured with NM or PM (biological replicate=3).
Fig. 5: Altering metabolic flux rates in COs in response to NM and PM.
Fig. 6: Testing the hypothesis and rescuing PM-mediated neural degeneration with external G6P.

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Data availability

The data that support the findings of this study are available from the authors on reasonable request, see author contributions for specific data sets.

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Acknowledgements

This work was financially funded by the Scientific and Technological Research Council of Turkey (TUBITAK, grant number: 219S661) and Ankara University - Scientific Research Projects Coordination Unit (grant number: TSA-2024-3217). B.D. also thanks the Turkish Academy of Science (TUBA) and the Science Academy (Istanbul) for their support. The authors thank the NEUROM Cell Culture Unit for their kind help in MEA study.

Author information

Authors and Affiliations

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

    Melis Isik, Emel Emregul & Burak Derkus

  2. Analytical Chemistry Division, Faculty of Pharmacy, Hacettepe University, Ankara, Türkiye

    Cemil Can Eylem & Emirhan Nemutlu

  3. Department of Biotechnology and Biosafety, Graduate School of Natural and Applied Science, Eskisehir Osmangazi University, Eskisehir, Türkiye

    Kubra Erdogan-Gover, Pinar Aytar-Celik & Ahmet Cabuk

  4. Great Lakes Bioenergy Research Center, University of Wisconsin–Madison, Madison, WI, USA

    Blaise Manga Enuh

  5. Wisconsin Energy Institute, University of Wisconsin–Madison, Madison, WI, USA

    Blaise Manga Enuh

  6. Department of Cardiovascular Surgery, University Heart & Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Yalin Yildirim

  7. Omics and Bioanalytic Laboratory, Faculty of Pharmacy, Hacettepe University, Ankara, Türkiye

    Emirhan Nemutlu

  8. Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, USA

    Alysson Renato Muotri

  9. Department of Cellular and Molecular Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA

    Alysson Renato Muotri

  10. Integrated Space Stem Cell Orbital Research (ISSCOR) Center, Center for Academic Research and Training in Anthropogeny (CARTA), Kavli Institute for Brain and Mind, Archealization Center (ArchC), La Jolla, CA, USA

    Alysson Renato Muotri

  11. Neuroscience and Neurotechnology Excellence Joint Application and Research Center (NEUROM), Ankara, Türkiye

    Burak Derkus

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Contributions

BD developed the concept, received the grant, and supervised this study. BD, MI, and EN designed the experiments. MI, CCE, KE-G performed the experiments. BD, EN, PA-C, and EBM cured and analyzed the data. YY provided cell lines and commented on the manuscript. BD wrote the manuscript. AC, EE, and ARM edited and commented on the manuscript. All authors approved the final version of the manuscript.

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Correspondence to Burak Derkus.

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Isik, M., Eylem, C.C., Erdogan-Gover, K. et al. Pathogenic microbiota disrupts the intact structure of cerebral organoids by altering energy metabolism. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03152-4

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