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Transplant of fecal microbiota from healthy young mice relieves cognitive defects in late-stage diabetic mice by reducing metabolic disorders and neuroinflammation

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Fecal microbiota transplant (FMT) is becoming as a promising area of interest for treating refractory diseases. In this study, we investigated the effects of FMT on diabetes-associated cognitive defects in mice as well as the underlying mechanisms. Fecal microbiota was prepared from 8-week-aged healthy mice. Late-stage type 1 diabetics (T1D) mice with a 30-week history of streptozotocin-induced diabetics were treated with antibiotics for 7 days, and then were transplanted with bacterial suspension (100 μL, i.g.) once a day for 14 days. We found that FMT from healthy young mice significantly alleviated cognitive defects of late-stage T1D mice assessed in Morris water maze test. We revealed that FMT significantly reduced the relative abundance of Gram-negative bacteria in the gut microbiota and enhanced intestinal barrier integrity, mitigating LPS translocation into the bloodstream and NLRP3 inflammasome activation in the hippocampus, thereby reducing T1D-induced neuronal loss and astrocytic proliferation. FMT also reshaped the metabolic phenotypes in the hippocampus of T1D mice especially for alanine, aspartate and glutamate metabolism. Moreover, we showed that application of aspartate (0.1 mM) significantly inhibited NLRP3 inflammasome activation and IL-1β production in BV2 cells under a HG/LPS condition. We conclude that FMT can effectively relieve T1D-associated cognitive decline via reducing the gut–brain metabolic disorders and neuroinflammation, providing a potential therapeutic approach for diabetes-related brain disorders in clinic.

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Fig. 1: FMT reshapes the gut microbiota in T1D mice.
Fig. 2: FMT alleviates cognitive impairment in T1D mice.
Fig. 3: FMT enhances colonic barrier integrity in T1D mice.
Fig. 4: FMT suppresses neuroinflammation in hippocampus of T1D mice.
Fig. 5: FMT reduces neuronal loss and astrocytic proliferation in hippocampus of T1D mice.
Fig. 6: FMT remodels the metabolic phenotype in hippocampus of T1D mice.
Fig. 7: FMT restores alanine, aspartate, and glutamate metabolism in hippocampus of T1D mice.
Fig. 8: Aspartate reduces IL-1β production through inhibiting NLRP3 inflammasome activation in BV2 cells.
Fig. 9: Schematic diagram on the protective effect of FMT on cognitive function in T1D mice.

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Data availability

All data used in this study are present in the main text and supplementary materials. Metabolomics and microbiomics data have been made publicly available in Figshare (https://doi.org/10.6084/m9.figshare.16344801.v1).

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (22074106) and Zhejiang Provincial Natural Science Foundation of China (LY23H090008). We are grateful for the help from the Scientific Research Center and the Laboratory Animal Center of Wenzhou Medical University.

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  1. These authors contributed equally: Xian-xi Ye, Qiao-ying Jiang

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  1. State Key Laboratory of Macromolecular Drugs and Large-scale Manufacturing, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China

    Xian-xi Ye, Qiao-ying Jiang, Meng-jun Wu, Qing-huai Ye & Hong Zheng

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Contributions

HZ contributed to the experimental design. XXY and QYJ contributed to animal experiment and operation. XXY, QYJ, MJW, and QHY contributed to sample collection and omics analysis. XXY, QYJ, MJW and QHY contributed to RT-PCR and histological analyses. HZ, XXY and QYJ contributed to result discussion and interpretation. HZ, XXY, and QYJ contributed to the data analysis and draft writing. All authors have read, revised, and approved the final manuscript.

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Correspondence to Hong Zheng.

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Ye, Xx., Jiang, Qy., Wu, Mj. et al. Transplant of fecal microbiota from healthy young mice relieves cognitive defects in late-stage diabetic mice by reducing metabolic disorders and neuroinflammation. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01340-6

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