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Transmission of Alzheimer’s disease-associated microbiota dysbiosis and its impact on cognitive function: evidence from mice and patients

Molecular Psychiatry volume 28, pages 4421–4437 (2023)Cite this article

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Abstract

Spouses of Alzheimer’s disease (AD) patients are at a higher risk of developing incidental dementia. However, the causes and underlying mechanism of this clinical observation remain largely unknown. One possible explanation is linked to microbiota dysbiosis, a condition that has been associated with AD. However, it remains unclear whether gut microbiota dysbiosis can be transmitted from AD individuals to non-AD individuals and contribute to the development of AD pathogenesis and cognitive impairment. We, therefore, set out to perform both animal studies and clinical investigation by co-housing wild-type mice and AD transgenic mice, analyzing microbiota via 16S rRNA gene sequencing, measuring short-chain fatty acid amounts, and employing behavioral test, mass spectrometry, site-mutations and other methods. The present study revealed that co-housing between wild-type mice and AD transgenic mice or administrating feces of AD transgenic mice to wild-type mice resulted in AD-associated gut microbiota dysbiosis, Tau phosphorylation, and cognitive impairment in the wild-type mice. Gavage with Lactobacillus and Bifidobacterium restored these changes in the wild-type mice. The oral and gut microbiota of AD patient partners resembled that of AD patients but differed from healthy controls, indicating the transmission of microbiota. The underlying mechanism of these findings includes that the butyric acid-mediated acetylation of GSK3β at lysine 15 regulated its phosphorylation at serine 9, consequently impacting Tau phosphorylation. Pending confirmative studies, these results provide insight into a potential link between the transmission of AD-associated microbiota dysbiosis and development of cognitive impairment, which underscore the need for further research in this area.

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Fig. 1: WT mice developed cognitive impairment after co-housing with AD Tg mice.
Fig. 2: WT mice developed cognitive impairment after fecal microbiota transplantation from AD Tg mice.
Fig. 3: ADWT mice acquired AD-associated gut microbiota dysbiosis after co-housing with AD Tg mice.
Fig. 4: Differences in brain levels of SCFAs, PSD-95, phosphorylated Tau, IL-6 and Aβ among AD Tg, ADWT and WT mice.
Fig. 5: Butyric acid increased p-GSK3β-S9 levels through lysine acetylation at position 15 of GSK3β.
Fig. 6: Treatment with bacteria (Lactobacillus and Bifidobacterium) mitigated the behavioral and cellular changes in ADWT mice.
Fig. 7: Microbiota in oral and fecal samples of Alzheimer’s disease (AD) patients, partners of AD patients (PAD), and control (CON) individuals.

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Data availability

All data are available in the main text or the supplementary materials. The source data can be available from the corresponding authors on reasonable request.

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Acknowledgements

We gratefully acknowledge the funding support for this study provided by the National Institutes of Health through R01AG041274, R01AG062509, and RF1070761, and Henry L. Beecher Professorship from Harvard University (awarded to Zhongcong Xie), and R21AG065606 (awarded to Yiying Zhang). The GMB analyses presented in this paper were partially conducted at the Harvard Chan Microbiome Analysis Core, located at the Harvard Public Health School, Boston, MA. We also acknowledge Dr. Jackie Washington and Dr. Zhiyi Zuo from University of Virginia for conducting the Brain SCFAs analysis. We would like to thank Dr. Yang Shi of Ludwig Cancer Research at the University of Oxford for his valuable comments and insightful discussions.

Author information

Author notes

  1. These authors contributed equally: Yiying Zhang, Yuan Shen.

Authors and Affiliations

  1. Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129, USA

    Yiying Zhang, Yuan Shen, Ning Liufu, Ling Liu, Wei Li, Zhongyong Shi, Xinchun Mei, Yuanlin Dong, Feng Liang & Zhongcong Xie

  2. Anesthesia and Brain Research Institute, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, 200072, PR China

    Yuan Shen, Zhongyong Shi, Hailin Zheng & Xinchun Mei

  3. Mental Health Center affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, PR China

    Yuan Shen, Zhongyong Shi & Xinchun Mei

  4. Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province, 510120, PR China

    Ning Liufu & Ling Liu

  5. Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129, USA

    Chih-Yu Chen, Zengliang Jiang & Jing X. Kang

  6. Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, PR China

    Zengliang Jiang

  7. Biostatistics Department and Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, 02115, USA

    Shabnamsadat Abtahi & Jeremy E. Wilkinson

  8. Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China

    Yujiang Shi

  9. Departments of Radiology and Pathology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, 02129, USA

    Leo L. Cheng

  10. Department of Anesthesiology, Columbia University Medical Center, New York, NY, 10032, USA

    Guang Yang

Authors
  1. Yiying Zhang
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  2. Yuan Shen
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  3. Ning Liufu
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  4. Ling Liu
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  5. Wei Li
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  6. Zhongyong Shi
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  7. Hailin Zheng
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  8. Xinchun Mei
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  9. Chih-Yu Chen
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  10. Zengliang Jiang
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  11. Shabnamsadat Abtahi
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  12. Yuanlin Dong
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  13. Feng Liang
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  14. Yujiang Shi
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  15. Leo L. Cheng
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  16. Guang Yang
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  17. Jing X. Kang
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  18. Jeremy E. Wilkinson
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  19. Zhongcong Xie
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Contributions

Study concept and design: YZ and ZX. Acquisition of data: YZ, YS, NL, LL, WL, ZS, HZ, XM, CYC, SA, and ZJ. Analysis and interpretation of data: YZ, YS, NL, LL, WL, ZS, HZ, XM, CYC, ZJ, SA, and ZJ. Drafting of the manuscript: YZ and ZX. Critical revision of the manuscript for important intellectual content: YZ, YJS, LC, JXK, GY, JK, JW and ZX. Obtained funding: YZ and ZX. Administrative, technical, and material support: YZ, YS, YD, FL and ZX. Study supervision: YZ, YS and ZX.

Corresponding authors

Correspondence to Yiying Zhang or Zhongcong Xie.

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Competing interests

The authors declare that they have no competing interests. ZX provided consulting services to Shanghai’s 9th and 10th hospitals, Baxter (invited speaker), NanoMosaic, and Journal of Anesthesiology and Perioperative Science in the last 36 months.

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Zhang, Y., Shen, Y., Liufu, N. et al. Transmission of Alzheimer’s disease-associated microbiota dysbiosis and its impact on cognitive function: evidence from mice and patients. Mol Psychiatry 28, 4421–4437 (2023). https://doi.org/10.1038/s41380-023-02216-7

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  • DOI: https://doi.org/10.1038/s41380-023-02216-7

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