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Komagataella pastoris KM71H Mitigates Depressive-Like Phenotype, Preserving Intestinal Barrier Integrity and Modulating the Gut Microbiota in Mice

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Abstract

The role of intestinal microbiota in the genesis of mental health has received considerable attention in recent years, given that probiotics are considered promising therapeutic agents against major depressive disorder. Komagataella pastoris KM71H is a yeast with probiotic properties and antidepressant-like effects in animal models of depression. Hence, we evaluated the antidepressant-like effects of K. pastoris KM71H in a model of antibiotic-induced intestinal dysbiosis in male Swiss mice. The mice received clindamycin (200 μg, intraperitoneal) and, after 24 h, were treated with K. pastoris KM71H at a dose of 8 log CFU/animal by intragastric administration (ig) or PBS (vehicle, ig) for 14 consecutive days. Afterward, the animals were subjected to behavioral tests and biochemical analyses. Our results showed that K. pastoris KM71H administration decreased the immobility time in the tail suspension test and increased grooming activity duration in the splash test in antibiotic-treated mice, thereby characterizing its antidepressant-like effect. We observed that these effects of K. pastoris KM71H were accompanied by the modulation of the intestinal microbiota, preservation of intestinal barrier integrity, and restoration of the mRNA levels of occludin, zonula occludens-1, zonula occludens-2, and toll-like receptor-4 in the small intestine, and interleukin-1β in the hippocampi of mice. Our findings provide solid evidence to support the development of K. pastoris KM71H as a new probiotic with antidepressant-like effects.

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Data Availability

The datasets generated during and/or analyzed in the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We would also like to thank Atlas Assessoria Linguística for language editing.

Funding

The authors received support from UFPel, especially Biotechnology Graduate Program (UFPel) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) (PRONEM 16/2551-0000240-1, PqG 17/2551-00011046-9). L. S., T. C., F. K. S., and F. R. C. are recipients of CNPq fellowships. This study was partly financed by the CAPES - Finance Code 001.

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Authors and Affiliations

  1. Neurobiotechnology Research Group, Graduate Program in Biotechnology, Technologic Development Center, Federal University of Pelotas, (UFPel), Pelotas, RS, CEP 96010-900, Brazil

    Paloma T. Birmann, Angela M. Casaril, Ana Paula Pesarico & Lucielli Savegnago

  2. Applied Immunology Laboratory, Graduate Program in Biotechnology, Technological Development Center, Federal University of Pelotas, Pelotas, RS, Brazil

    Rafael R. Rodrigues & Fabricio R. Conceição

  3. Molecular and Cellular Oncology Research Group and Functional Genomics Laboratory, Graduate Program in Biotechnology, Technological Development Center, Federal University of Pelotas, Pelotas, RS, Brazil

    Fernanda Severo Sabedra Sousa, Tiago Collares & Fabiana K. Seixas

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  3. Ana Paula Pesarico
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  4. Rafael R. Rodrigues
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  5. Fabricio R. Conceição
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  9. Lucielli Savegnago
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Contributions

P.T. Birmann performed the experimental design, behavioral tests, biochemical assessments, and data analysis and wrote the manuscript. L. Savegnago performed the experimental design, data analysis, writing, reviewing, and editing of the manuscript, supervised the experiments, acquired funding, and is the corresponding author*. A.M. Casaril and A. Pesarico performed the behavioral tests and the biochemical assessments and wrote the manuscript. F.S.S. Sousa, F.K. Seixas, and T. Collares performed the qRT-PCR analyses. Rochedo and R.R. Rodrigues performed the cultivation and preparation of K. pastoris. L. Savegnago and F.C. Rochedo were responsible for funding acquisition and reviewing and editing the manuscript.

Corresponding author

Correspondence to Lucielli Savegnago.

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Ethics Approval

The experiments with animals were carried out in accordance with the Institutional Animal Care and Use Committee of the Federal University of Pelotas (approval number of the ethics committee: 11133-20), affiliated with the National Council for Animal Experimentation Control (CONCEA).

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The authors declare no competing interests.

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Birmann, P.T., Casaril, A.M., Pesarico, A.P. et al. Komagataella pastoris KM71H Mitigates Depressive-Like Phenotype, Preserving Intestinal Barrier Integrity and Modulating the Gut Microbiota in Mice. Mol Neurobiol 60, 4017–4029 (2023). https://doi.org/10.1007/s12035-023-03326-7

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