Shiitake Mushroom-Derived Vesicle-like Nanoparticles Improve Cognitive Function and Reshape Gut Microbiota and Fecal Metabolome in Aged Mice

Authors

Xingzhi Li, University of Nebraska-Lincoln and Case Western Reserve UniversityFollow
Baolong Liu, University of Nebraska-LincolnFollow
Deekshika Sekar, University of Nebraska-LincolnFollow
Meghna Sur, University of Nebraska-LincolnFollow
Jay Reddy, University of Nebraska-LincolnFollow
Sathish Kumar Natarajan, University of Nebraska-LincolnFollow
Peder J. Lund, Case Western Reserve UniversityFollow
Jiujiu Yu, University of Nebraska-Lincoln and Case Western UniversityFollow

ORCID IDs

Reddy https://orcid.org/0000-0003-4082-9254

Natarajan https://orcid.org/0000-0001-7491-8592

Lund https://orcid.org/0000-0002-2146-8724

Document Type

Article

Date of this Version

2025

Citation

Nutrients (2025) 17(17): 2902

doi: 10.3390/nu17172902

Comments

Open access

License: CC BY 4.0

Abstract

Background/Objectives: Population aging and its associated chronic conditions have become an unprecedented challenge in the United States and worldwide. Many aged individuals experience certain forms of cognitive decline, which increases their risk of developing a pre-dementia condition called mild cognitive impairment and even dementia. No effective pharmacological treatments are available to treat normal age-associated cognitive decline or mild cognitive impairment. Our previous study has shown the potent anti-inflammatory effects of shiitake mushroom-derived vesicle-like nanoparticles (S-VLNs) in vitro and in an acute inflammatory disease model. In this study, we aimed to investigate the potential benefits of orally administered S-VLNs in aged mice. Methods: S-VLNs were extracted from fresh shiitake mushrooms. S-VLNs in phosphate-buffered saline (PBS) or vehicle only was orally administered to 13-month-old male C57BL/6J mice weekly for 9 months. These mice were subjected to a series of physiological tests, followed by euthanasia at 22 months of age. Their fecal samples were subjected to 16S rRNA and untargeted metabolomics analyses, followed by comprehensive bioinformatics analyses. Results: The long-term oral administration of S-VLNs significantly improved the cognitive function of aged mice. Orally administered S-VLNs did not travel to the brain. Instead, they impacted the composition of the gut microbiota and reshaped the fecal metabolome. Functional predictions of the gut microbiota and fecal metabolome suggested that S-VLNs regulated tryptophan metabolism. Specifically, S-VLNs markedly decreased the tryptophan-related metabolite kynurenic acid (KYNA). The integrative analyses of omics data identified a strong correlation between 18 gut bacterial genera and 66 fecal metabolites. KYNA was found to highly correlate with five genera positively and twelve genera negatively. Conclusions: The oral intake of S-VLNs represents a new and superior dietary approach with the ability to modulate the gut microbiota and fecal metabolome and to improve cognitive function during aging.