High Salt Elicits Brain Inflammation and Cognitive Dysfunction, Accompanied by Alternations in the Gut Microbiota and Decreased SCFA Production

Article type: Research Article

Authors: Hu, Li^{c; d; 1} | Zhu, Shaoping^{b; 1} | Peng, Xiaoping^{a; 1} | Li, Kanglan^d | Peng, Wanjuan^d | Zhong, Yu^e | Kang, Chenyao^d | Cao, Xingxing^d | Liu, Zhou^{a; d; *} | Zhao, Bin^{a; d; *}

Affiliations: [a] Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China | [b] Institute of Laboratory Animal Center, Guangdong Medical University, Zhanjiang, China | [c] Department of Histology and Embryology, Guangdong Medical University, Zhanjiang, China | [d] Guangdong Key Laboratory of Age-Related Cardiac and Cerebral Diseases, Institute of Neurology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China | [e] Analysis Center of Guangdong Medical University, Zhanjiang, China

Correspondence: [*] Correspondence to: Zhou Liu and Bin Zhao, Guangdong Medical University, Zhanjiang, China. Tel.: +8613543558835 (Z. Liu); E-mails: liuzhou@gdmu.edu.cn (Z. Liu); binzhaoe@163.com (B. Zhao)

Note: [1] These authors contributed equally to this work.

Abstract: Background:Excessive salt intake is considered as an important risk factor for cognitive impairment, which might be the consequence of imbalanced intestinal homeostasis. Objective:To investigate the effects of dietary salt on the gut microbiota and cognitive performance and the underlying mechanisms. Methods:Adult female C57BL/6 mice were maintained on either normal chow (control group, CON) or sodium-rich chow containing 8% NaCl (high-salt diet, HSD) for 8 weeks. Spatial learning and memory ability, short-chain fatty acids (SCFAs) concentrations, gut bacterial flora composition, blood-brain barrier permeability, and proinflammatory cytokine levels and apoptosis in the brain were evaluated. Results:The mice fed a HSD for 8 weeks displayed impaired learning and memory abilities. HSD significantly reduced the proportions of Bacteroidetes (S24-7 and Alloprevotella) and Proteobacteria and increased that of Firmicutes (Lachnospiraceae and Ruminococcaceae). SCFA concentrations decreased in the absolute concentrations of acetate, propionate, and butyrate in the fecal samples from the HSD-fed mice. The HSD induced both BBB dysfunction and microglial activation in the mouse brain, and increased the IL-1β, IL-6, and TNF-α expression levels in the cortex. More importantly, the degree of apoptosis was higher in the cortex and hippocampus region of mice fed the HSD, and this effect was accompanied by significantly higher expression of cleaved caspase-3, caspase-3, and caspase-1. Conclusion:The HSD directly causes cognitive dysfunction in mice by eliciting an inflammatory environment and triggering apoptosis in the brain, and these effects are accompanied by gut dysbiosis, particularly reduced SCFA production.

Keywords: Blood-brain barrier, cognition, gut microbiota, high-salt diet, microglia, short-chain fatty acids

DOI: 10.3233/JAD-200035

Journal: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 629-640, 2020