Abstract
To understand the role of commensal gut bacteria on the progression of cognitive decline in Alzheimer’s disease via the microbiota-gut-brain axis, we isolated anti-inflammatory Bifidobacterium longum (NK46) from human gut microbiota, which potently inhibited gut microbiota endotoxin production and suppressed NF-κB activation in lipopolysaccharide (LPS)-stimulated BV-2 cells, and examined whether NK46 could simultaneously alleviate gut dysbiosis and cognitive decline in male 5xFAD-transgenic (5XFAD-Tg, 6 months-old) and aged (18 months-old) mice. Oral administration of NK46 (1 × 109 CFU/mouse/day for 1 and 2 months in aged and Tg mice, respectively) shifted gut microbiota composition, particularly Proteobacteria, reduced fecal and blood LPS levels, suppressed NF-κB activation and TNF-α expression, and increased tight junction protein expression in the colon of 5XFAD-Tg and aged mice. NK46 treatment also alleviated cognitive decline in 5XFAD-Tg and aged mice. Furthermore, NK46 treatment suppressed amyloid-β, β/γ-secretases, and caspase-3 expression and amyloid-β accumulation in the hippocampus of 5XFAD-Tg mice. NK46 treatment also reduced Iba1+, LPS+/CD11b+, and caspase-3+/NeuN+ cell populations and suppressed NF-κB activation in the hippocampus of 5XFAD-Tg and aged mice, while BDNF expression was increased. These findings suggest that the suppression of gut dysbiosis and LPS production by NK46 can mitigate cognitive decline through the regulation of microbiota LPS-mediated NF-κB activation.
Highlights
Alzheimer’s disease (AD), which is the leading cause of dementia, is a highly prevalent, progressive, and neurodegenerative disorder in the elderly[1,2]
We examined the inhibitory effects of 25 Lactobacilli and 25 Bifidobacteria strains on gut microbiota LPS production
To understand the balance of beneficial to harmful bacteria in the gut microbiota composition, we investigated the ratio of live Enterobacteriaceae to Bifidobaceria plus Lactobacilli (E/BL) by using selective media, glucose blood liver (BL) and deoxycholate hydrogen sulfide lactose (DHL) agar plates (Fig. 2D)
Summary
Alzheimer’s disease (AD), which is the leading cause of dementia, is a highly prevalent, progressive, and neurodegenerative disorder in the elderly[1,2]. These characteristics make 5xFAD-tg mice useful for evaluating the efficacy of anti-AD drugs. To understand the role of commensal gut Bifidobacteria in the occurrence of AD, we isolated anti-inflammatory Bifidobacterium longum NK46, which suppressed human gut microbiota LPS production and NF-κB activation in LPS-stimulated microglial BV-2 cells, from healthy human fecal microbiota and examined whether NK46 could alleviate cognitive decline and gut microbiota dysbiosis in 5XFAD-Tg and aged mice
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