Abstract
Dietary supplement silver nanoparticles have recently drawn attention following reports of hazards associated with long-term use. However, their biosafety, especially their effects on the gut-brain axis, remains largely unexplored. This study demonstrated that dietary supplement silver nanoparticles can accumulate in the intestines, brain, and liver of mice. Chronic exposure to these nanoparticles leads to Alzheimer-like lesions, primarily by disrupting gut microbiota balance. Specifically, this exposure depletes Bifidobacterium and Ruminococcaceae, resulting in reduced intestinal metabolites such as sphingomyelin (d18:1/20:0), tryptophan, and indole. Consequently, this disruption causes neuroinflammation, cognitive impairment, and amyloid-β deposition in mice. Moreover, Bifidobacterium was identified as a key microbial group contributing to Alzheimer-like lesions after exposure, whereas supplementation with Bifidobacterium breve MCC1274 effectively alleviated these lesions. Therefore, the potential risks of silver nanoparticles in dietary supplements should be carefully evaluated. This study provides a promising new direction for the prevention and treatment of Alzheimer-like lesions through microbial interventions.

Data availability
The data that support the findings of this study are available from the corresponding author upon reasonable request.
References
Landsiedel, R. et al. Gut microbiome and plasma metabolome changes in rats after oral gavage of nanoparticles: sensitive indicators of possible adverse health effects. Part. Fibre Toxicol. 19, 21 (2022).
Temizel-Sekeryan, S. & Hicks, A. L. Global environmental impacts of silver nanoparticle production methods supported by life cycle assessment. Resour. Conserv. Recycl. 156, 104676 (2020).
Research and Markets. Silver Nanoparticles Market Size, Share & Trends Analysis Report By Application (Electronics & Electrical, Healthcare, Food & Beverages, Textiles, Others), By Region, And Segment Forecasts, 2024—2030. https://www.researchandmarkets.com/reports/5998829/silver-nanoparticles-market-size-share-and-trends (2024).
Ratan, Z. A. et al. Silver nanoparticles as potential antiviral agents. Pharmaceutics 13, 2034 (2021).
Archer, S. L. Dilated cardiomyopathy and left bundle branch block associated with ingestion of colloidal gold and silver is reversed by British antiLewisite and vitamin E: the potential toxicity of metals used as health supplements. Can. J. Cardiol. 24, 397–399 (2008).
Bracey, N. A., Zipursky, J. S. & Juurlink, D. N. Argyria caused by chronic ingestion of silver. CMAJ 190, E139 (2018).
Hu, D. & Yuen, C. Seizures following self-medication with colloidal silver: a case report. Hosp. Pharm. 58, 350–352 (2023).
Keung, Y.-K., Wang, T. & Hong-Lung Hu, E. Acute myeloid leukemia with complex cytogenetic abnormalities associated with long-term use of oral colloidal silver as nutritional supplement—Case report and review of literature. J. Oncol. Pharm. Pr. 26, 212–215 (2020).
Mohan, N., Gomez, C., Khawar, N., Narula, P. & John, M. Colloidal silver ingestion associated with leukocytoclastic vasculitis in an adolescent female. Am. J. Case Rep. 20, 730–734 (2019).
Over-the-counter drug products containing colloidal silver ingredients or silver salts. Department of Health and Human Services (HHS), Public Health Service (PHS), Food and Drug Administration (FDA). Final rule. Fed. Regist. 64, 44653–44658 (1999).
EFSA Panel on Food Additives and Nutrient Sources added to Food (EFSA ANS Panel) et al. Safety and bioavailability of silver hydrosol as a source of silver added for nutritional purposes to food supplements. EFSA J. 16, e05237 (2018).
EFSA Scientific Committee et al. Guidance on risk assessment of the application of nanoscience and nanotechnologies in the food and feed chain: Part 1, human and animal health. EFSA J. 16, e05327 (2018).
EFSA Panel on Food Contact Materials, Enzymes and Processing Aids (CEP) et al. Safety assessment of the substance silver nanoparticles for use in food contact materials. EFSA J. 19, e06790 (2021).
EFSA Scientific Committee et al. Guidance on risk assessment of nanomaterials to be applied in the food and feed chain: human and animal health. EFSA J. 19, e06768 (2021).
State Food and Drug Administration. Announcement of the State Food and Drug Administration on Regulating Matters Related to the Registration and Management of Medical Devices Containing Silver Salts (No. 225 of 2015), https://www.nmpa.gov.cn/xxgk/ggtg/ylqxggtg/ylqxqtggtg/20151109120001276.html (accessed October 16, 2024).
Camilla, R. et al. Repeated oral administration of low doses of silver in mice: tissue distribution and effects on central nervous system. Part. Fibre Toxicol. 18, 23 (2021).
Suthar, J. K., Vaidya, A. & Ravindran, S. Toxic implications of silver nanoparticles on the central nervous system: a systematic literature review. J. Appl. Toxicol. 43, 4–21 (2023).
Wu, W. et al. Transformation and speciation analysis of silver nanoparticles of dietary supplement in simulated human gastrointestinal tract. Environ. Sci. Technol. 52, 8792–8800 (2018).
Mirsattari, S. M., Hammond, R. R., Sharpe, M. D., Leung, F. Y. & Young, G. B. Myoclonic status epilepticus following repeated oral ingestion of colloidal silver. Neurology 62, 1408–1410 (2004).
Ebabe Elle, R. et al. Dietary exposure to silver nanoparticles in Sprague–Dawley rats: effects on oxidative stress and inflammation. Food Chem. Toxicol. 60, 297–301 (2013).
Moghadam, H. et al. Toxicological effects of dietary silver nanoparticles (AgNPs) and zinc oxide nanoparticles (ZnONPs) on zebrafish (Danio rerio): a comprehensive study on mixture toxicity. Mar. Pollut. Bull. 219, 118354 (2025).
O’Riordan, K. J., Moloney, G. M., Keane, L., Clarke, G. & Cryan, J. F. The gut microbiota-immune-brain axis: Therapeutic implications. Cell Rep. Med. 6, 101982 (2025).
Martin, C. R., Osadchiy, V., Kalani, A. & Mayer, E. A. The brain-gut-microbiome Axis. Cell. Mol. Gastroenterol. Hepatol. 6, 133–148 (2018).
Guilloteau, E. et al. Exposure to atmospheric Ag, TiO2, Ti and SiO2 engineered nanoparticles modulates gut inflammatory response and microbiota in mice. Ecotoxicol. Environ. Saf. 236, 113442 (2022).
Lamas, B., Martins Breyner, N. & Houdeau, E. Impacts of foodborne inorganic nanoparticles on the gut microbiota-immune axis: potential consequences for host health. Part Fibre Toxicol. 17, 19 (2020).
Perez, L. et al. Dietary nanoparticles alter the composition and function of the gut microbiota in mice at dose levels relevant for human exposure. Food Chem. Toxicol. 154, 112352 (2021).
Rogers, K. R. et al. Characterization of engineered nanoparticles in commercially available spray disinfectant products advertised to contain colloidal silver. Sci. Total Environ. 619–620, 1375–1384 (2018).
Oćwieja, M., Barbasz, A., Walas, S., Roman, M. & Paluszkiewicz, C. Physicochemical properties and cytotoxicity of cysteine-functionalized silver nanoparticles. Colloids Surf. B Biointerfaces 160, 429–437 (2017).
Bergin, I. L. & Witzmann, F. A. Nanoparticle toxicity by the gastrointestinal route: evidence and knowledge gaps. Int. J. Biomed. Nanosci. Nanotechnol. 3, https://doi.org/10.1504/IJBNN.2013.054515 (2013).
Nair, A. B. & Jacob, S. A simple practice guide for dose conversion between animals and human. J. Basic Clin. Pharm. 7, 27–31 (2016).
Gibson, R. S. & Scythes, C. A. Chromium, selenium, and other trace element intakes of a selected sample of Canadian premenopausal women. Biol. Trace Elem. Res. 6, 105–116 (1984).
Whiteley, C. M., Dalla Valle, M., Jones, K. C. & Sweetman, A. J. Challenges in assessing release, exposure and fate of silver nanoparticles within the UK environment. Environ. Sci. Process Impacts 15, 2050–2058 (2013).
Shahare, B., Yashpal, M. & Gajendra. Toxic effects of repeated oral exposure of silver nanoparticles on small intestine mucosa of mice. Toxicol. Mech. Methods https://www.tandfonline.com/doi/abs/10.3109/15376516.2013.764950 (2013).
Antsiferova, A. A., Buzulukov, Y.uP., Kashkarov, P. K. & Kovalchuk, M. V. Experimental and theoretical study of the transport of silver nanoparticles at their prolonged administration into a mammal organism. Crystallogr. Rep. 61, 1020–1026 (2016).
van der Zande, M. et al. Distribution, elimination, and toxicity of silver nanoparticles and silver ions in rats after 28-day oral exposure. ACS Nano 6, 7427–7442 (2012).
Shrestha, P. & Klann, E. Alzheimer’s disease: lost memories found. Nature 531, 450–451 (2016).
Hemonnot, A.-L., Hua, J., Ulmann, L. & Hirbec, H. Microglia in Alzheimer disease: well-known targets and new opportunities. Front. Aging Neurosci. 11, 233 (2019).
Sarlus, H. & Heneka, M. T. Microglia in Alzheimer’s disease. J. Clin. Investig. 127, 3240–3249 (2017).
Zhao, J. et al. Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice. Sci. Rep. 9, 5790 (2019).
Choi, J., Lee, H.-W. & Suk, K. Increased plasma levels of lipocalin 2 in mild cognitive impairment. J. Neurol. Sci. 305, 28–33 (2011).
Lee, S., Lee, W.-H., Lee, M.-S., Mori, K. & Suk, K. Regulation by lipocalin-2 of neuronal cell death, migration, and morphology. J. Neurosci. Res. 90, 540–550 (2012).
Lodeiro, M. et al. Aggregation of the Inflammatory S100A8 Precedes Aβ Plaque Formation in Transgenic APP Mice: Positive Feedback for S100A8 and Aβ Productions. J. Gerontol A Biol. Sci. Med Sci. 72, 319–328 (2017).
Colonna, M. TREMs in the immune system and beyond. Nat. Rev. Immunol. 3, 445–453 (2003).
Nguyen, T. T. T. et al. Tryptophanyl-tRNA synthetase 1 signals activate TREM-1 via TLR2 and TLR4. Biomolecules 10, 1283 (2020).
Yang, J., Wise, L. & Fukuchi, K. TLR4 cross-talk with NLRP3 inflammasome and complement signaling pathways in Alzheimer’s disease. Front. Immunol. 11, 724 (2020).
Mizoguchi, H. et al. Matrix metalloprotease-9 inhibition improves amyloid beta-mediated cognitive impairment and neurotoxicity in mice. J. Pharm. Exp. Ther. 331, 14–22 (2009).
Vahsen, B. F. et al. C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9. Nat. Commun. 14, 5898 (2023).
Hernandes-Alejandro, M. et al. Analysis of the relationship between metalloprotease-9 and Tau protein in Alzheimer’s disease. J. Alzheimer’s. Dis. 76, 553–569 (2020).
Ringland, C. et al. MMP9 modulation improves specific neurobehavioral deficits in a mouse model of Alzheimer’s disease. BMC Neurosci. 22, 39 (2021).
Li, X.-F. et al. Ulinastatin protects brain against cerebral ischemia/reperfusion injury through inhibiting MMP-9 and alleviating loss of ZO-1 and occludin proteins in mice. Exp. Neurol. 302, 68–74 (2018).
Gasche, Y. et al. Early appearance of activated matrix metalloproteinase-9 after focal cerebral ischemia in mice: a possible role in blood-brain barrier dysfunction. J. Cereb. Blood Flow. Metab. 19, 1020–1028 (1999).
Agirman, G., Yu, K. B. & Hsiao, E. Y. Signaling inflammation across the gut-brain axis. Science 374, 1087–1092 (2021).
van den Brule, S. et al. Dietary silver nanoparticles can disturb the gut microbiota in mice. Part. Fibre Toxicol. 13, 38 (2016).
Vogt, N. M. et al. Gut microbiome alterations in Alzheimer’s disease. Sci. Rep. 7, 13537 (2017).
Cattò, C. et al. Impacts of dietary silver nanoparticles and probiotic administration on the microbiota of an in-vitro gut model. Environ. Pollut. 245, 754–763 (2019).
Ueda, A. et al. Identification of Faecalibacterium prausnitzii strains for gut microbiome-based intervention in Alzheimer’s-type dementia. Cell Rep. Med. 2, 100398 (2021).
Chen, G., Zhou, X., Zhu, Y., Shi, W. & Kong, L. Gut microbiome characteristics in subjective cognitive decline, mild cognitive impairment and Alzheimer’s disease: a systematic review and meta-analysis. Eur. J. Neurol. 30, 3568–3580 (2023).
Yang, J. et al. Dysregulation of Ruminococcaceae and Megamonas could be predictive markers for rapid progression of mild cognitive impairment. Micro. Pathog. 183, 106272 (2023).
Verhaar, B. J. H. et al. Gut microbiota composition is related to AD pathology. Front. Immunol. 12, 794519 (2021).
Underwood, M. A., German, J. B., Lebrilla, C. B. & Mills, D. A. Bifidobacterium longum subspecies infantis: champion colonizer of the infant gut. Pediatr. Res. 77, 229–235 (2015).
Kobayashi, Y. et al. Therapeutic potential of Bifidobacterium breve strain A1 for preventing cognitive impairment in Alzheimer’s disease. Sci. Rep. 7, 13510 (2017).
Barrett, E., Ross, R. P., O’Toole, P. W., Fitzgerald, G. F. & Stanton, C. γ-Aminobutyric acid production by culturable bacteria from the human intestine. J. Appl. Microbiol. 113, 411–417 (2012).
Koh, A., Vadder, F. D., Kovatcheva-Datchary, P. & Bäckhed, F. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell 165, 1332–1345 (2016).
Osadchiy, V., Martin, C. R. & Mayer, E. A. The gut–brain axis and the microbiome: mechanisms and clinical implications. Clinical gastroenterology and hepatology: the official clinical practice. J. Am. Gastroenterol. Assoc. 17, 322 (2018).
Maceyka, M. & Spiegel, S. Sphingolipid metabolites in inflammatory disease. Nature 510, 58–67 (2014).
Haughey, N. J., Bandaru, V. V., Bai, M. & Mattson, M. P. Roles for dysfunctional sphingolipid metabolism in Alzheimer’s disease neuropathogenesis. Biochim. Biophys. Acta 1801, 878 (2010).
He, X., Huang, Y., Li, B., Gong, C.-X. & Schuchman, E. H. Deregulation of sphingolipid metabolism in Alzheimer’s disease. Neurobiol. aging 31, 398 (2008).
Cutler, R. G. et al. Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 101, 2070 (2004).
Han, X. et al. Substantial sulfatide deficiency and ceramide elevation in very early Alzheimer’s disease: potential role in disease pathogenesis. J. Neurochem 82, 809–818 (2002).
Zhang, H., Hui, X., Wang, Y., Wang, Y. & Lu, X. Angong Niuhuang Pill ameliorates cerebral ischemia/reperfusion injury in mice partly by restoring gut microbiota dysbiosis. Front. Pharm. 13, 1001422 (2022).
Griffin, J. W. D. & Bradshaw, P. C. Amino acid catabolism in Alzheimer’s disease brain: friend or foe?. Oxid. Med. Cell. Longev. 2017, 5472792 (2017).
Trushina, E., Dutta, T., Persson, X.-M. T., Mielke, M. M. & Petersen, R. C. Identification of altered metabolic pathways in plasma and CSF in mild cognitive impairment and Alzheimer’s disease using metabolomics. PLoS ONE 8, e63644 (2013).
Tang, Z. et al. Urinary metabolomics reveals alterations of aromatic amino acid metabolism of Alzheimer’s disease in the transgenic CRND8 mice. Curr. Alzheimer Res. 13, 764–776 (2016).
Bekdash, R. A. The cholinergic system, the adrenergic system and the neuropathology of Alzheimer’s disease. Int. J. Mol. Sci. 22, 1273 (2021).
Richard, D. M. et al. L-Tryptophan: basic metabolic functions, behavioral research and therapeutic indications. Int J. Tryptophan Res. 2, 45–60 (2009).
Doifode, T. et al. The impact of the microbiota-gut-brain axis on Alzheimer’s disease pathophysiology. Pharm. Res. 164, 105314 (2021).
Cheng, Y. et al. Leucine Deprivation Stimulates Fat Loss via Increasing CRH Expression in the Hypothalamus and Activating The Sympathetic Nervous System. Mol. Endocrinol. 25, 1624–1635 (2011).
Xiong, Y. et al. The associations of serum valine with mild cognitive impairment and Alzheimer’s disease. Aging Clin. Exp. Res. 34, 1807–1817 (2022).
Muraoka, S. et al. Proteomic profiling of extracellular vesicles separated from plasma of former National Football League players at risk for chronic traumatic encephalopathy. Aging Dis. 12, 1363–1375 (2021).
Liu, P. et al. Phenylalanine metabolism is dysregulated in human hippocampus with alzheimer’s disease related pathological changes. J. Alzheimers Dis. 83, 609–622 (2021).
Hampel, J. K. A. et al. Differential modulation of cell cycle, apoptosis and PPARgamma2 gene expression by PPARgamma agonists ciglitazone and 9-hydroxyoctadecadienoic acid in monocytic cells. Prostaglandins Leukot. Ess. Fat. Acids 74, 283–293 (2006).
Shi, L. et al. Early interleukin-6 enhances hepatic ketogenesis in APPSWE/PSEN1dE9 mice via 3-hydroxy-3-methylglutary-CoA synthase 2 signaling activation by p38/nuclear factor κB p65. Neurobiol. Aging 56, 115–126 (2017).
Wollmer, M. A. et al. Association study of cholesterol-related genes in Alzheimer’s disease. Neurogenetics 8, 179–188 (2007).
Serpente, M. et al. Role of OLR1 and its regulating hsa-miR369-3p in Alzheimer’s disease: genetics and expression analysis. J. Alzheimers Dis. 26, 787–793 (2011).
Abdelhamid, M., Zhou, C., Jung, C.-G. & Michikawa, M. Probiotic Bifidobacterium breve MCC1274 mitigates Alzheimer’s disease-related pathologies in wild-type mice. Nutrients 14, 2543 (2022).
Kim, H. et al. Administration of Bifidobacterium bifidum BGN4 and Bifidobacterium longum BORI improves cognitive and memory function in the mouse model of Alzheimeras disease. Front. Aging Neurosci. 13, 709091 (2021).
Lu, X., Li, J., Lou, H., Cao, Z. & Fan, X. Genome-wide DNA methylation alterations and potential risk induced by subacute and subchronic exposure to food-grade nanosilica in mice. ACS Nano 15, 8225–8243 (2021).
Authority (EFSA), E. F. S Existing approaches incorporating replacement, reduction and refinement of animal testing: applicability in food and feed risk assessment. EFSA J. 7, 1052 (2009).
Shang, J. et al. Oral exposure to food-grade nanoparticles poses a risk of Alzheimer’s disease-like symptoms by triggering autophagy defects in neurons. Adv. Sci. 13, e08096 (2025).
Liang, B. et al. Brain single-nucleus transcriptomics highlights that polystyrene nanoplastics potentially induce Parkinson’s disease-like neurodegeneration by causing energy metabolism disorders in mice. J. Hazard. Mater. 430, 128459 (2022).
Ennaceur, A. & Delacour, J. A new one-trial test for neurobiological studies of memory in rats. 1: behavioral data. Behav. Brain Res. 31, 47–59 (1988).
Acknowledgements
This work was supported by the Key R&D Program of Zhejiang (No.2024SDXT001-7), the Zhejiang Provincial Natural Science Foundation of China (No. LY23B070004), and the National Natural Science Foundation of China (No. 82374136 & No. 82574631). The authors gratefully acknowledge D. Song and G. Zhu in the Center of Cryo-Electron Microscopy (CCEM), Zhejiang University with assistance on STEM.
Author information
Authors and Affiliations
Contributions
Rongshang Shou: Methodology, validation, formal analysis, investigation, data curation, writing—original draft, visualization. Ziyue Wang: Investigation, data curation, validation, writing—review and editing. Zig Han, Anyao Li, Jiaxin Shang, He Lou, Fangmin Zhang, Yingqi Zhan, Guofang Shen: Investigation, validation, data curation. Xiaoyan Lu: Conceptualization, supervision, project administration, resources, writing—review and editing, funding acquisition. Haiping Jiang: Supervision, project administration, resources, writing—review and editing. Xiaohui Fan: Conceptualization, supervision, project administration, resources, writing—review and editing, funding acquisition.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Shou, R., Wang, Z., Han, Z. et al. Dietary silver nanoparticle supplementation induces Alzheimer-like lesions through Bifidobacterium deficiency-dominated gut microbiota dysbiosis and neuroinflammation. npj Sci Food (2026). https://doi.org/10.1038/s41538-026-00820-9
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41538-026-00820-9