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Intermittent fasting protects against Alzheimer’s disease in mice by altering metabolism through remodeling of the gut microbiota

Nature Aging volume 2, pages 1024–1039 (2022)Cite this article

Subjects

Abstract

Alzheimer’s disease (AD) is the most common form of dementia without effective clinical treatment. Here, we show that intermittent fasting (IF) improves cognitive functions and AD-like pathology in a transgenic AD mouse model (5XFAD). IF alters gut microbial composition with a significant enrichment in probiotics such as Lactobacillus. The changes in the composition of the gut microbiota affect metabolic activities and metabolite production. Metabolomic profiling analysis of cecal contents revealed IF leads to a decreased carbohydrate metabolism (for example, glucose) and an increased abundance in amino acids (for example, sarcosine and dimethylglycine). Interestingly, we found that the administration of IF-elevated sarcosine or dimethylglycine mimics the protective effects of IF in 5XFAD mice, including the amelioration of cognitive decline, amyloid-β (Aβ) burden and glial overactivation. Our findings thus demonstrate an IF regimen is a potential approach to prevent AD progression, at least through the gut-microbiota-metabolites-brain axis, and constitutes an innovative AD therapeutic avenue.

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Fig. 1: IF improves cognitive declines in 5XFAD mice.
Fig. 2: IF reduces Aβ burden and the extent of glial activation in 5XFAD mice.
Fig. 3: IF alters the composition of gut microbiota in 5XFAD mice.
Fig. 4: Gut microbiota is required for the beneficial effects of IF against AD.
Fig. 5: Metabolomic profiles of cecal contents in IF-treated 5XFAD mice.
Fig. 6: Sar or DMG treatment ameliorates cognitive declines and LTP impairment in 5XFAD mice.
Fig. 7: Sar or DMG treatment reduces Aβ burden and the extent of glial activation in 5XFAD mice.

Data availability

16S rRNA sequence data have been deposited at NCBI Sequence Read Archive and are available under accession number: PRJNA872262. Metabolomics data are provided in Supplementary Table 1. Source data are provided within this paper. Any additional data generated and analyzed in this study are available from the corresponding authors upon reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grants 82230042, 81930029 and 81630026 to Z.Y.), the National Major Project of Support Program (grant 2019-JCJQ-ZD-195 to Z.Y.) and the China Postdoctoral Science Foundation (grant 2020M683748 to R.-Y.P.).

Author information

Author notes

  1. These authors contributed equally: Rui-Yuan Pan, Jing Zhang.

Authors and Affiliations

  1. The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, China

    Rui-Yuan Pan, Jing Zhang, Jinlei Wang, Yingyi Wang, Yang Liao, Zhiqiang Liu & Zengqiang Yuan

  2. Cognitive and Mental Health Research Center, Beijing Institute of Radiation Medicine, Beijing, China

    Zhihui Li & Chenggang Zhang

  3. Department of neurology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China

    Yajin Liao

  4. Shanxi University of Chinese Medicine, Jinzhong, China

    Jing Zhang, Lijuan Song & Jiezhong Yu

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Contributions

Z.Y. conceived and directed the project. R.-Y.P. and J.Z. designed and performed the experiments, analyzed the data and wrote the manuscript. J.W. and Yang Liao provided assistance with animal behavioral tests. Y.W. performed electrophysiological recording. Z.L. provided assistance with the bioinformatic analysis of the gut microbiome. Yajin Liao, C.Z., Z.L., L.S. and J.Y. contributed to data analysis. All authors discussed and commented on the manuscript.

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Correspondence to Rui-Yuan Pan or Zengqiang Yuan.

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Extended data

Extended Data Fig. 1 IF reduces the expression levels of Aβ in 5XFAD mice.

Western blotting analysis of Aβ in hippocampal lysates from 5XFAD-AL and 5XFAD-IF mice (left panel), with quantification of Aβ levels (right panel, n = 4 mice per group). Data are represented as the mean ± SEM. **p < 0.01. Two-tailed unpaired Student’s t-test.

Source data

Extended Data Fig. 2 IF suppresses mTOR signaling and activates autophagy in 5XFAD mice.

a, Western blotting analysis of indicated proteins (or modifications) in the hippocampal lysates of WT-AL, 5XFAD-AL, and 5XFAD-IF mice. b, Quantification of indicated protein levels shown in a (n = 4 mice per group). Data are represented as the mean ± SEM. *p < 0.05 and **p < 0.01; N.S., not significant. One-way ANOVA, followed by Tukey’s multiple comparisons test.

Source data

Extended Data Fig. 3 IF leads to significant metabolic changes in gut microbiota.

a, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showing the significantly different biological processes of the gut microbiota. b, Heatmap showing the predicted functions of the gut microbiota involved in the indicated pathways among WT-AL, 5XFAD-AL, and 5XFAD-IF mice.

Extended Data Fig. 4 Effects of IF and ABX on body weight and food intake in 5XFAD mice.

a, Bacterial colony formation of the fecal homogenates from 5XFAD mice after 7 days of oral gavage with vehicle or ABX (left panel) and the bacterium were collected with PBS and the optical density (O.D.) was measure at 600 nm (right panel, n = 3 per group). b, The images of ceca collected from indicated group mice at 6-month-old (left panel), with quantification of the relative cecum volume (right panel, n = 4 per group). c, Body weight of indicated group mice monitoring every day during the experiments. d, Body weight of indicated group mice at the beginning and the end of the experiments. e and f, Food intake per two days (c) and cumulative food intake (d) of indicated group mice. The number of mice were: n = 12 mice for the WT-AL; n = 10 mice for the 5XFAD-AL group; n = 11 mice for the 5XFAD-IF and 5XFAD-IF + ABX groups. Data are represented as the mean ± SEM. **p < 0.01 and ***p < 0.001; N.S., not significant. Two-tailed unpaired Student’s t-test (a and b) or one-way ANOVA (d), followed by Tukey’s multiple comparisons test.

Source data

Extended Data Fig. 5 UPLC-MS analysis of Sar and DMG in the serum and brain of mice.

a and b, Sar and DMG levels in the serum and brain samples of WT-AL, 5XFAD-AL, and 5XFAD-IF mice (n = 3 mice per group). c and d, Sar and DMG levels in the serum and brain samples of mice 1 h post i.p. injected with saline, Sar or DMG (n = 3 mice per group). Data are represented as the mean ± SEM. *p < 0.05 and **p < 0.01. Two-tailed unpaired Student’s t-test (c and d) or one-way ANOVA (a and b), followed by Tukey’s multiple comparisons test.

Source data

Extended Data Fig. 6 Effects of Sar or DMG on body weight, food intake, and cognition in WT mice.

a, Schematic diagram showing the drug treatment strategy in WT mice. b, Body weight of indicated group mice was monitoring every day during the experiments. c and d, Every day food intake (c) and cumulative food intake (d) of indicated group mice. e, Distance travelled to the platform during the training period in the MWM test. f-i, Latency of first time to enter the target (f), target entries (g), time spent in target quadrant (h), and mean swimming speed in the probe trial of the MWM test (i). j, NOR test recognition index of mice. The number of mice were: n = 11 mice for the WT and WT + Sar groups; n = 9 mice for the WT + DMG group. Data are represented as the mean ± SEM. *p < 0.05, **p < 0.01, and ***p < 0.001; N.S., not significant. Two-tailed unpaired Student’s t-test (j) or one-way ANOVA (f-i), followed by Tukey’s multiple comparisons test.

Source data

Extended Data Fig. 7 Sar or DMG treatment reduces the expression levels of Aβ in 5XFAD mice.

Western blotting analysis of Aβ in hippocampal lysates from 5XFAD, 5XFAD + Sar, and 5XFAD + DMG mice (left panel), with quantification of Aβ levels (right panel, n = 4 mice per group). Data are represented as the mean ± SEM. *p < 0.05. Two-tailed unpaired Student’s t-test.

Source data

Supplementary information

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Pan, RY., Zhang, J., Wang, J. et al. Intermittent fasting protects against Alzheimer’s disease in mice by altering metabolism through remodeling of the gut microbiota. Nat Aging 2, 1024–1039 (2022). https://doi.org/10.1038/s43587-022-00311-y

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