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Advertisement Advertisement Nature Aging * View all journals * Search * Log in * Explore content * About the journal * Publish with us * Subscribe * Sign up for alerts * RSS feed 1. nature 2. nature aging 3. articles 4. article * Article * Published: 09 November 2023 Chiral nanoparticle-remodeled gut microbiota alleviates neurodegeneration via the gut-brain axis * Xiao Guo^1, * Chen Li^1, * Jia Zhang^1, * Maozhong Sun^1, * Jun Xu^2, * Chuanlai Xu ORCID: orcid.org/0000-0002-5639-7102^1, * Hua Kuang ORCID: orcid.org/0000-0002-2724-8722^1 & * ... * Liguang Xu ORCID: orcid.org/0000-0001-9453-7703^1 Show authors Nature Aging (2023)Cite this article * 8 Accesses * 8 Altmetric * Metrics details Subjects * Ageing * Alzheimer's disease * Nanobiotechnology Abstract Alzheimer's disease (AD) is characterized by amyloid-b accumulation in the brain and hyperphosphorylated tau aggregation, as well as neuroinflammation. The gut-brain axis has emerged as a therapeutic target in neurodegenerative diseases by modulating metabolic activity, neuroimmune functions and sensory neuronal signaling. Here we investigate interactions between orally ingested chiral Au nanoparticles and the gut microbiota in AD mice. Oral administration of chiral Au nanoparticles restored cognitive abilities and ameliorated amyloid-b and hyperphosphorylated tau pathologies in AD mice via alterations in the gut microbiome composition and an increase in the gut metabolite, indole-3-acetic acid, which was lower in serum and cerebrospinal fluid of patients with AD compared with age-matched controls. Oral administration of indole-3-acetic acid was able to penetrate the blood-brain barrier and alleviated cognitive decline and pathology including neuroinflammation in AD mice. These findings provide a promising therapeutic target for the amelioration of neuroinflammation and treatment of neurodegenerative diseases. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution Access options Access through your institution Access through your institution Change institution Buy or subscribe Access Nature and 54 other Nature Portfolio journals Get Nature+, our best-value online-access subscription $29.99 / 30 days cancel any time Learn more Subscribe to this journal Receive 12 digital issues and online access to articles $119.00 per year only $9.92 per issue Learn more Rent or buy this article Prices vary by article type from$1.95 to$39.95 Learn more Prices may be subject to local taxes which are calculated during checkout Additional access options: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support Fig. 1: Restoration of cognitive abilities of APP/PS1 AD mice through oral administration of l-, d- and t-Au NPs by altering gut microbiota (n = 6). [43587_2023_516_Fig1_HTML] Fig. 2: Alteration of the gut microbiome and the composition of metabolites in APP/PS1 AD mice after oral administration of chiral Au NPs (n = 6). [43587_2023_516_Fig2_HTM] Fig. 3: The function of IAA in the restoration of cognition abilities of AD mice (n = 6). [43587_2023_516_Fig3_HTML] Fig. 4: The levels of IAA in serum and CSF of mice and patients. [43587_2023_516_Fig4_HTML] Fig. 5: Changed neuroinflammation by IAA in vivo and in vitro (n = 6). [43587_2023_516_Fig5_HTM] Fig. 6: Mechanism of increasing IAA, IAM and IE in the microbiota after treated with l-, d- and t-Au NPs (n = 6). [43587_2023_516_Fig6_HTML] Data availability Source data are provided with this paper. Any additional data generated and analyzed in this study are available from the corresponding authors upon reasonable request. 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Article CAS PubMed Google Scholar Download references Acknowledgements H.K., C.X. and L.X. acknowledge support from the National Natural Science Foundation of China, grant nos. 21925402, 92156003 and 32071400, respectively. Author information Authors and Affiliations 1. State Key Laboratory of Food Science and Resources, International Joint Research Laboratory for Biointerface and Biodetection, School of Food Science and Technology, International Joint Research Center for Photo-responsive Molecules and Materials, Jiangnan University, Wuxi, People's Republic of China Xiao Guo, Chen Li, Jia Zhang, Maozhong Sun, Chuanlai Xu, Hua Kuang & Liguang Xu 2. Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, China National Clinical Research Center for Neurological Diseases, Beijing, People's Republic of China Jun Xu Authors 1. Xiao Guo View author publications You can also search for this author in PubMed Google Scholar 2. Chen Li View author publications You can also search for this author in PubMed Google Scholar 3. Jia Zhang View author publications You can also search for this author in PubMed Google Scholar 4. Maozhong Sun View author publications You can also search for this author in PubMed Google Scholar 5. Jun Xu View author publications You can also search for this author in PubMed Google Scholar 6. Chuanlai Xu View author publications You can also search for this author in PubMed Google Scholar 7. Hua Kuang View author publications You can also search for this author in PubMed Google Scholar 8. Liguang Xu View author publications You can also search for this author in PubMed Google Scholar Contributions L.X., H.K. and C.X. conceived the project and planned the experiments. X.G. and C.L. fabricated and characterized chiral NPs. X.G. and J.Z. carried out experiments in vivo and in vitro. M.S. assisted with the animal behavioral tests. J.X. provided assistance in collecting clinical samples and information. L.X., H.K. and C.X. conceptualized the work. All authors wrote the manuscript and compiled figures, with discussion of results and feedback on the manuscript. Corresponding authors Correspondence to Chuanlai Xu, Hua Kuang or Liguang Xu. Ethics declarations Competing interests The authors declare no competing financial interest. Peer review Peer review information Nature Aging thanks the anonymous reviewers for their contribution to the peer review of this work. Additional information Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Extended data Extended Data Fig. 1 Pathologies of APP/PS1 AD mice through FMT (n = 6). (A) Immunofluorescence of Ab (red) and p-tau (green) in the hippocampus. (B) Representative immunostaining for Ab (black arrows) and p-tau (black arrows) protein. (C) Nissl staining of neuro cells in the brains (hippocampus of mice with treatments for 60 days). l- Au-AD: fecal microbiota was transplanted from the donor mice, APP/PS1 AD mice orally administered l-Au NPs, into receptor APP/PS1 AD mice. HT of l-Au-AD: Heat-treatment (HT) of fecal microbiota from the donor mice, APP/PS1 AD mice orally administered l-Au NPs, were transplanted into receptor APP/PS1 AD mice. Scale bars, 50 mm. 'AD' stands for APP /PS1 AD model mice. Each 'n' represents an independent biological sample. Extended Data Fig. 2 Restoration of cognition abilities and pathologies of 3xTg AD mice through oral administration of IAA (n = 6). (A) Immunofluorescence of Ab (red) and p-tau (green) in the hippocampus. (B) Representative immunostaining for Ab (black arrows) and p-tau (black arrows) protein. (C) Nissl staining of neuro cells in the brains (hippocampus of mice with treatments for 45 days). Scale bars, 50 mm. CH-223191, the AHR inhibitor. Each 'n' represents an independent biological sample. Extended Data Fig. 3 Restoration of cognition abilities and pathologies of APP/PS1 AD mice through oral administration of IAA and co-housed with WT or APP/PS1 AD mice (n = 6). (A) Overview of the experimental design in the effects of microbiota on IAA function. (B) The latent period to find the escape platform in water maze of mice with different treatments for 15 days, 30 days, and 45 days, respectively. (C) Track sheets in water maze of mice with treatments for 45 days. (D) Novel object recognition (NOR) test of mice with different treatments for 45 days. (E) Track sheets in NOR test of mice with treatments for 45 days. (F) Ab and (G) p-tau concentrations in CSF in 45 days. (H) Immunofluorescence of Ab (red) and p-tau (green) in the hippocampus. (I) Representative immunostaining for Ab (black arrows) and p-tau (black arrows) protein. (J) Nissl staining of neuro cells in the brains (hippocampus of mice with treatments for 45 days). i.g: Intragastric administration. IAA co-housed with AD: APP/PS1 AD mice oral administrated of IAA that were housed with APP/PS1 AD mice without treatment. Scale bars, 50 mm. 'AD' stands for APP/PS1 AD model mice. Each 'n' represents an independent biological sample. One dot represents one mouse. Data are represented as the mean +- SD. *p < 0.05, **p < 0.01, ***p < 0.001. Two-tailed unpaired Student's t -test (D), one-way (B, F, and G) ANOVA, followed by Tukey's multiple comparisons test. Source data Extended Data Fig. 4 Alteration of the ability of tryptophan metabolism to produce IAA in APP/PS1 AD mice after oral administration l-Au NPs (n = 6). (A) Schematic of the ^13C[10]-IAA produced by ^13C[11]- Trp in APP/ PS1 AD mice experimental design. (B-C) Relative abundance of ^13C[10] -IAA in APP/PS1 AD mice serum after oral administration of ^13C[11]- Trp, or ^13C[11]- Trp and l-Au NPs 8 h. i.g: Intragastric administration. Each 'n' represents an independent biological sample. One dot represents one mouse. Data are represented as the mean +- SD. ***p < 0.001. Two-tailed unpaired Student's t-test. Source data Extended Data Fig. 5 Neuroinflammations in mice oral administration with Au NPs and FMT mice (n = 6). Contents of (A) IL6, (B) TNF-a, and (C) IL1b in the CSF of APP/PS1 AD mice after oral administration of l-, d-, and t-Au NPs. Contents of (D) IL6, (E) TNF-a, and (F) IL1b in the CSF of FMT mice. l-Au-AD: fecal microbiota were transplanted from the donor mice, APP/PS1 AD mice orally administered l-Au NPs, into receptor APP/PS1 AD mice. HT of l-Au-AD: Heat-treatment (HT) of fecal microbiota from the donor mice, APP/PS1 AD mice orally administered l-Au NPs, were transplanted into receptor APP/PS1 AD mice. 'AD' stands for APP/PS1 AD model mice. Each 'n' represents an independent biological sample. One dot represents one mouse. Data are represented as the mean +- SD. *p < 0.05, **p < 0.01, ***p < 0.001. One-way ANOVA followed by Tukey's multiple comparisons test. Source data Extended Data Fig. 6 Activated state of microglia cells line BV2, astrocytes cells line MA-c in vitro after IAA treatment (n = 6). Detection of activated (A) M1(CD68^+CD86^+), (B) M2 (CD206^+CD163^+) microglia cell line BV2 and (C) A1, (D) A2 astrocyte cell line MA-c by flow cytometry. (E) Detection of activated M1, M2 microglia cell line BV2 and A1, A2 astrocyte cell line MA-c by confocal. Scale bars, 20 mm. CH-223191, the AHR inhibitor. Box plots extend from the 25th to the 75th percentile with the median value shown as a black line in the middle, and whiskers denote the minima and maxima values. Each 'n' represents an independent biological sample. One dot represents one sample. Data are represented as the mean +- SD. *p < 0.05, **p < 0.01, ***p < 0.001. One-way (A-D) ANOVA followed by Tukey's multiple comparisons test. Source data Extended Data Fig. 7 The cognition abilities and pathologies of 3xTg AD mice through oral administration of IAA after depleted T[reg] or microglia cells (n = 6). (A) Overview of the experimental design to explore the key targets of IAA. (B) The latent period to find the escape platform in water maze of mice with different treatments for 15 days, 30 days, and 45 days, respectively. (C) Track sheets in water maze of mice with treatments for 45 days. (D) Novel object recognition (NOR) test of mice with different treatments for 45 days. (E) Track sheets in NOR test of mice with treatments for 45 days. (F) Ab and (G) p-tau concentrations in CSF in 45 days. (H) Immunofluorescence of Ab (red) and p-tau (green) in the hippocampus. (I) Representative immunostaining for Ab (black arrows) and p-tau (black arrows) protein. (J) Nissl staining of neuro cells in the brains (hippocampus of mice with treatments for 45 days). Scale bars, 50 mm. PLX, PLX3397. i.g: Intragastric administration. Each 'n' represents an independent biological sample. One dot represents one mouse. Data are represented as the mean +- SD. *p < 0.05, **p < 0.01, ***p < 0.001. Two-tailed unpaired Student's t -test (D), one-way (B, F, and G) ANOVA, followed by Tukey's multiple comparisons test. To explore the role of cells, we transiently depleted T[reg] or microglia cells in 3xTg AD mice (Extended Data Fig. 7a). After depletion of T[reg] by anti-CD25, 3xTg AD mice showed the improved cognitive function in both Morris water maze experiment and novel object recognition test after treatment with IAA for approximately 45 days, whereas 3xTg AD depleted microglia cells did not (Extended Data Fig. 7b-e). The contents of Ab and p-tau in the CSF of 3xTg AD mice depleted T[reg] cells after treatment with IAA for 45 days were the same as those of the WT mice (Extended Data Fig. 7f,g), which also verified by immunohistochemical and immunofluorescence analyses (Extended Data Fig. 7h,i). Nissl staining of the hippocampus in 3xTg AD mice depleted T[reg] cells showed that the nuclei of the neurons were intact and that the number of neurons had increased after oral administrated of IAA for 45 days, compared with those of 3xTg AD mice (Extended Data Fig. 7j). To be noticed, the concentrations of Ab and p-tau in CSF, immunohistochemical and immunofluorescence analysis of 3xTg AD mice depleted microglia cells have no any improvements on oral administration with IAA for 45 days. Source data Extended Data Fig. 8 Impact of IAA on the systemic immune cell population of the 3xTg AD mice (n = 6). Percentages of (A)T[reg] cells in CD4^+ T cells, (B)T[H]17 in CD4^+ T cells, and (C) IL17^+gdT cells in gd T cells in the colon of 3xTg AD mice. Percentages of (D)T[reg] cells in CD4^+ T cells, (E)T[H]17 in CD4^+ T cells, and (F) IL17^+gdT cells in gd T cells in the periphery of 3xTg AD mice. Percentages of (G)T[reg] cells in CD4^+ T cells, (H) T[H]17 in CD4^+ T cells, and (I) IL17^+gdT cells in gd T cells in the meninges of 3xTg AD mice. Percentages of (J)T[reg] cells in CD4^+ T cells, (K)T[H]17 in CD4^+ T cells, and (L) IL17^+gdT cells in gd T cells in the brain of 3xTg AD mice. CH-223191, the AHR inhibitor. Each 'n' represents an independent biological sample. One dot represents one mouse. Data are represented as the mean +- SD. *p < 0.05, **p < 0.01, ***p < 0.001. One-way ANOVA followed by Tukey's multiple comparisons test. The results displayed the increase in T [reg] cells and decrease in T[H]17 and IL17gdT cells in the colon, peripheral and meninges of 3xTg AD mice after treatment with IAA for 45 days. On the contrary, 3xTg AD mice without IAA treatment triggered the decrease in T[reg] cells and the increase in T[H]17 and IL17gdT cells in colon, peripheral and meninges. While 3xTg AD mice treated with IAA and CH-223191(an AHR inhibitor), the percentage of T [reg] cells, T[H]17 cells, and IL17gdT cells had no changes, which was the same as 3xTg AD mice without IAA treatment. Noticeably, these cells in brain parenchyma were almost no affected. Source data Extended Data Fig. 9 The inflammasome activity of primary microglia, primary astrocytes cell, microglial cells line BV2, and astrocyte cell line MA-c after treated with IAA in vitro (n = 6). (A) levels of NLRP3 in microglia cell line BV2 and astrocyte cell line MA-c were determined confocally. Scale bars, 20 mm. (B) Western blot analysis of microglia cell line BV2 and astrocyte cell line MA-c for NLRP3, pro-caspase 1, caspase 1, ASC, pro-IL18, IL18, pro-IL1b, IL1b, NF-kB and b-actin, respectively. The expression levels of NLRP3, caspase-1, IL1b and IL18 in (C) microglial cell line BV2 and (D) astrocyte cell line MA-c were detected by RT-qPCR. Contents of IL18 and IL1b in (E) primary microglia and (F) primary astrocytes cell were determined by ELISA. Contents of IL18 and IL1b in (G) microglia cell line BV2 and (H) astrocyte cell line MA-c were determined by ELISA. CH-223191, the AHR inhibitor. Each 'n' represents an independent biological sample. One dot represents one sample. Data are represented as the mean +- SD. *p < 0.05, **p < 0.01, ***p < 0.001. One-way (C-H) ANOVA followed by Tukey's multiple comparisons test. Source data Extended Data Fig. 10 The way of Au NPs interacts with bacteria. (A) Zeta potential of PEGylated Au NPs (n = 3). (B) Confocal and (C) SEM images of L.reuteri incubated with l-Au NPs (n = 6). ITC data and integrated heat data with respect to time for the titration of Trp to (D) l-Au NPs (E) d-Au NPs (F) t-Au NPs. The (G) absorbance (H) CD and (I) Fluorescence of remaining Trp in the supernatant after coincubation of Au NPs with Trp. Scale bars, 2 mm. Each 'n' represents an independent sample. Data are represented as the mean +- SD. ^*p < 0.05, ^**p < 0.01, ^***p < 0.001. One-way (A) followed by Tukey's multiple comparisons test. Source data Supplementary information Supplementary Information Supplementary materials and methods, Figs. 1-18 and references. Reporting summary Supplementary Data 1 Statistical source data for Supplementary Fig. 3. Supplementary Data 2 Statistical source data for Supplementary Fig. 4. Supplementary Data 3 Statistical source data for Supplementary Fig. 7. Supplementary Data 4 Statistical source data for Supplementary Fig. 8. Supplementary Data 5 Statistical source data for Supplementary Fig. 10. Supplementary Data 6 Statistical source data for Supplementary Fig. 11. Supplementary Data 7 Statistical source data for Supplementary Fig. 12. Supplementary Table 1 KEGG pathway enrichment analysis of feces metabolites in APP/PS1 AD mice with or without oral administration of L-Au NPs. Supplementary Table 2 RT-qPCR primer sequence. Source data Source Data Fig. 1 Statistical source data for Fig. 1. Source Data Fig. 2 Statistical source data for Fig. 2. Source Data Fig. 3 Statistical source data for Fig. 3. Source Data Fig. 4 Statistical source data for Fig. 4. Source Data Fig. 5 Statistical source data for Fig. 5. Source Data Fig. 6 Statistical source data for Fig. 6. Source Data All unprocessed western blots. Source Data Extended Data Fig. 3 Statistical source data for Extended Data Fig. 3. Source Data Extended Data Fig. 4 Statistical source data for Extended Data Fig. 4. Source Data Extended Data Fig. 5 Statistical source data for Extended Data Fig. 5. Source Data Extended Data Fig. 6 Statistical source data for Extended Data Fig. 6. Source Data Extended Data Fig. 7 Statistical source data for Extended Data Fig. 7. Source Data Extended Data Fig. 8 Statistical source data for Extended Data Fig. 8. Source Data Extended Data Fig. 9 Statistical source data for Extended Data Fig. 9. Source Data Extended Data Fig. 10 Statistical source data for Extended Data Fig. 10. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. Reprints and Permissions About this article Check for updates. Verify currency and authenticity via CrossMark Cite this article Guo, X., Li, C., Zhang, J. et al. Chiral nanoparticle-remodeled gut microbiota alleviates neurodegeneration via the gut-brain axis. Nat Aging (2023). https://doi.org/10.1038/s43587-023-00516-9 Download citation * Received: 13 October 2022 * Accepted: 28 September 2023 * Published: 09 November 2023 * DOI: https://doi.org/10.1038/s43587-023-00516-9 Share this article Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. 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