Outer membrane vesicles enhance tau phosphorylation and contribute to cognitive impairment.

Outer membrane vesicles (OMVs) are nanosized vesicles produced by the gut microbiota (GM). The GM is well-known to be involved in the pathological process of Alzheimer's disease (AD). However, the mechanism of OMVs is not clear. In the present study, we demonstrated the involvement of OMVs in the development of cognitive (learning and memory) dysfunction induced by blood-brain barrier (BBB) disruption. More important, further study showed that OMVs induced tau phosphorylation by activating glycogen synthase kinase 3ß (GSK-3ß) in the hippocampus. OMVs activated astrocytes and microglia, increased secretion of inflammatory cytokines (nuclear factor κB, interleukin-1ß, and tumour necrosis factor-α) in the hippocampus. Therefore, OMVs increase the permeability of the BBB and promote the activation of astrocytes and microglia, inducing an inflammatory response and tau hyperphosphorylation by activating the GSK-3ß pathway and finally leading to cognitive impairment.

Protection of Fecal Microbiota Transplantation in a Mouse Model of Multiple Sclerosis.

Given the growing evidence of a link between gut microbiota (GM) dysbiosis and multiple sclerosis (MS), fecal microbiota transplantation (FMT), aimed at rebuilding GM, has been proposed as a new therapeutic approach to MS treatment. To evaluate the viability of FMT for MS treatment and its impact on MS pathology, we tested FMT in mice with experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We provide evidence that FMT can rectify altered GM to some extent with a therapeutic effect on EAE. We also found that FMT led to reduced activation of microglia and astrocytes and conferred protection on the blood-brain barrier (BBB), myelin, and axons in EAE. Taken together, our data suggest that FMT, as a GM-based therapy, has the potential to be an effective treatment for MS.

Excretion of Amyloid-ß in the Gastrointestinal Tract and Regulation by the Gut Microbiota.

BACKGROUND: Amyloid-ß (Aß) is important in the etiology of Alzheimer's disease (AD). Removal of Aß from the brain is a major strategy for the prevention and treatment of AD. OBJECTIVE: To clarify whether Aß42 can be cleared by intestinal excretion and whether the gut microbiota (GM) can affect the excretory clearance of Aß42 in the peripheral blood and intestines. METHODS: Male 8-month-old C57BL6 mice were maintained on either normal chow or received broad-spectrum antibiotics in their drinking water for one week. Sterile saline, fluorescein isothiocyanate (FITC), or FITC-Aß42 (fluorescein isothiocyanate-labeled amyloid-ß42 peptides) was injected 1 h before sampling. Related changes of Aß42 before and after injection were evaluated. RESULTS: FITC-Aß42 was injected into mice through the tail vein and could later be detected in feces. Furthermore, the fecal concentrations of FITC-Aß42 were higher in mice that had been fed antibiotics to alter their GM than in normal mice. However, the FITC-Aß42 concentrations in blood showed the opposite pattern. CONCLUSION: Aß42 can be excreted into the intestinal lumen and is regulated by the GM.

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

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-1ß, 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.

SCD rs41290540 single-nucleotide polymorphism modifies miR-498 binding and is associated with a decreased risk of coronary artery disease.

BACKGROUND: Atherosclerosis is the primary cause of coronary artery disease (CAD), and stearoyl-CoA desaturase (SCD) is associated with atherosclerosis. However, the associations between variants of SCD and CAD have not yet been decided. METHODS: This study analyzed SCD rs41290540 single-nucleotide polymorphism (SNP) in the 3'-untranslated region for an association with a risk of CAD among the Chinese Han population. CAD patients and controls were genotyped for SNP rs41290540 in SCD by SNaPshot. The binding affinity of miR-498 to rs41290540 was determined by a luciferase assay, and SCD expression was assessed using Western blot. RESULTS: A total of 969 CAD patients and 1,095 control subjects were involved in this study. The SCD rs41290540CC genotype is associated with a decreased risk of CAD compared with the AA genotype. Furthermore, the CC genotype is associated with lower serum total cholesterol (TC). Western blot analysis demonstrated that miR-498 suppressed the expression of SCD. A luciferase assay confirmed that rs41290540 A>C variation in the SCD 3'UTR inhibits miR-498 binding. CONCLUSION: This study demonstrates that the SCD rs41290540 may be associated with a decreased risk of CAD, lower serum TC, and decreased miR-498 binding.

Vascular Cognitive Impairment and the Gut Microbiota.

Vascular cognitive impairment (VCI), the second most common cause of dementia in elderly people, is a term that refers to all forms of cognitive disorders that can be attributed to cerebrovascular disease such as manifestations of discrete infarctions, brain hemorrhages, and white matter lesions. The gut microbiota (GM) has emerged recently as an essential player in the development of VCI. The GM may affect the brain's physiological, behavioral, and cognitive functions through the brain-gut axis via neural, immune, endocrine, and metabolic pathways. Therefore, microbiota dysbiosis may mediate or affect atherosclerosis, cerebrovascular disease, and endothelial dysfunction, which are the predominant risk factors for VCI. Moreover, the composition of the GM includes the bacterial component lipopolysaccharides and their metabolic products including trimethylamine-N-oxide and short-chain fatty acids. These products may increase the permeability of the intestinal epithelium, leading to systemic immune responses, low-grade inflammation, and altered signaling pathways that are associated with the pathogenesis of VCI. In this review, we discuss the proposed mechanisms of the GM in the maintenance of VCI and how it is implicated in acquired metabolic diseases, particularly in VCI regulation.

The Prevalence of Alzheimer's Disease in China: A Systematic Review and Meta-analysis.

BACKGROUND: Several studies have investigated the prevalence of Alzheimer's disease (AD) among the general population in several parts of China. However, the results have been inconsistent. This meta-analysis was conducted to estimate the overall prevalence of AD between 2007 and 2017 in China. METHODS: English and Chinese electronic databases were searched with a date range from Nov 2007 to Nov 2017 and the reference lists of the included studies were screened as well. Cross-sectional studies addressing the prevalence of AD among the general Chinese population were retrieved irrespective of the age, location or sex of the participants. Study quality was assessed using the recommended checklist of STROBE. RESULTS: Overall, 184058 subjects and 7445 patients with AD were included from 17 studies in this meta-analysis. The overall prevalence of AD in China was calculated to be 0.04(95% CI:0.04-0.05). The prevalence was higher in older age groups, among females, and in the rural areas of the country, with an increasing trend in recent years. CONCLUSION: AD is a common problem among those in the Chinese population older than 65 yr. Furthermore, an increasing trend of the disease over the past 10 years is indicative of a critical public health problem in China in the near future. Further evidence based on a national survey is needed to estimate the exact prevalence of the disease in the country.