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Gut microbiota dysbiosis is associated with hippocampal neuronal damage and behavioral alterations in APP/PS1 mice with high-salt diet

Overview

Authors: Huanmin Zhang1, Jinxin Kou1, Pengfei Ge2, Lingzhuan Gong3, Wen Zhang3, Yulang Fei4,5
  1. Department of Clinical Rehabilitation, School of Medicine, Xi’an Siyuan University, Xi’an, China
  2. Department of Neurology, Shiyan Taihe Hospital, Affiliated Hospital of Hubei University of Medicine, Shiyan, China
  3. Department of Rehabilitation Medicine, Ordnance Industry General Hospital, Xi’an, China
  4. The First Affiliated Hospital of Nanyang Medical College, Nanyang, Henan Province, China
  5. Zhang Zhongjing Chinese Medical Research Institute, Nanyang Medical College, Nanyang, Henan Province, China
Journal: Frontiers in microbiology, volume 17, article 1884427
Dates: received 18 May 2026; accepted 14 August 2026; published online 11 September 2026
Type: Research article · Language: English
License: CC BY
Identifiers: DOI · PMCID PMC13612445
Status: data only
Categories: genetics / omics (modality), histology / microscopy (modality), mouse (organism), Alzheimer's / dementia (population)
Methods: Statistics, Machine learning, Connectivity
Keywords: Alzheimer’s disease, cognitive impairment, gut microbiota, high-salt diet, neuronal damage
Citations: not cited yet (Europe PMC); 61 references in the paper

Abstract

Introduction: High-salt diet (HSD) has been shown to influence cognition and emotional behavior in mice via gut microbiota modulation, yet its chronic effects in Alzheimer’s disease (AD) pathology remain poorly understood. This study aimed to investigate whether long-term HSD exacerbates cognitive and emotional deficits in APP/PS1 transgenic mice and to explore the underlying gut–brain axis mechanisms involving microbiota dysbiosis, peripheral and central inflammation, hippocampal neuronal integrity, and metabolic alterations.

Methods: Six-month-old male APP/PS1 mice were randomly assigned to a normal diet (ND, 0.4% NaCl, n = 43) or high-salt diet (HSD, 8% NaCl, n = 41) for 6 months. Body weight, water intake, and blood pressure were monitored regularly (n = 10 per group). Behavioral phenotypes were assessed via open field, elevated plus maze, marble burying, light–dark box, and novel object recognition tests (n = 10). Hippocampal neuronal density was quantified by Nissl staining in CA1 and CA2, and dendritic complexity was evaluated by Golgi staining with Sholl analysis (n = 4). Gut microbiota composition was profiled by 16S rRNA sequencing (ND: n=13; HSD: n = 12), and inflammatory cytokine expression (TNF-α, IL-6, and IL-1β) in brain and liver was measured by RT-PCR and ELISA (n = 4). Hippocampal metabolomics was performed using LC–MS (ND: n = 8; HSD: n = 7). Correlation analyses integrated microbial, inflammatory, metabolic, and neuropathological data.

Results: HSD significantly altered gut microbiota structure, as shown by reduced α-diversity, distinct β-diversity (PCoA), and differential abundance of taxa including Prevotellaceae, Rikenellaceae, and Ruminococcaceae (LEfSe). Concurrently, HSD elevated pro-inflammatory cytokine expression in both brain and liver, reduced neuronal density in hippocampal CA1/CA2, and impaired dendritic arborization. Behaviorally, HSD-treated mice exhibited aggravated emotional disorders (anxiety- and compulsive-like behaviors) and worsened cognitive impairment in novelty recognition. Hippocampal metabolomics revealed substantial shifts in amino acid, energy, and neurotransmitter metabolic pathways. Spearman correlation analyses demonstrated significant interconnections among specific gut microbial genera, inflammatory markers, neuronal damage indices, and differential metabolites.

Discussion and conclusion: Long-term high-salt intake exacerbates cognitive decline and emotional disturbances in APP/PS1 mice, likely through a cascading gut–brain axis pathway: HSD-induced microbiota dysbiosis promotes peripheral and central inflammation, which in turn drives hippocampal neuronal damage and metabolic reprogramming. The strong correlations among microbial shifts, metabolic alterations, and neuropathological changes suggest that gut microbiota may serve as a critical mediator of HSD’s deleterious effects on AD-related brain functions. These findings provide new mechanistic insights into dietary risk factors in AD and highlight potential microbiota–metabolite targets for therapeutic intervention.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

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Data availability statement

The data analyzed in this study are available in the NCBI SRA under accession number PRJNA1520793: https://www.ncbi.nlm.nih.gov/sra/PRJNA1520793.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 6 authors, 5 keywords, 61 references.

Cite

This paper

Zhang, H., Kou, J., Ge, P., Gong, L., Zhang, W., & Fei, Y. (2026). Gut microbiota dysbiosis is associated with hippocampal neuronal damage and behavioral alterations in APP/PS1 mice with high-salt diet. Frontiers in microbiology, 17, 1884427.

BibTeX

@article{zhang2026gut,
author = {Zhang, Huanmin and Kou, Jinxin and Ge, Pengfei and Gong, Lingzhuan and Zhang, Wen and Fei, Yulang},
title = {{Gut microbiota dysbiosis is associated with hippocampal neuronal damage and behavioral alterations in APP/PS1 mice with high-salt diet}},
journal = {Frontiers in microbiology},
year = {2026},
month = sep,
volume = {17},
pages = {1884427},
publisher = {Frontiers Media SA},
issn = {1664-302X},
pmcid = {PMC13612445}
}

RIS

TY - JOUR
AU - Zhang, Huanmin
AU - Kou, Jinxin
AU - Ge, Pengfei
AU - Gong, Lingzhuan
AU - Zhang, Wen
AU - Fei, Yulang
TI - Gut microbiota dysbiosis is associated with hippocampal neuronal damage and behavioral alterations in APP/PS1 mice with high-salt diet
T2 - Frontiers in microbiology
J2 - Front Microbiol
PY - 2026
DA - 2026/09/26
VL - 17
SP - 1884427
SN - 1664-302X
PB - Frontiers Media SA
LA - en
ER -

CSL-JSON

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