Alleviation of Cognitive Impairment-like Behaviors, Neuroinflammation, Colitis, and Gut Dysbiosis in 5xFAD Transgenic and Aged Mice by Lactobacillus mucosae and Bifidobacterium longum

Abstract

Neuropsychiatric disorders including Alzheimer’s disease (AD) may cause gut inflammation and dysbiosis. Gut inflammation-suppressing probiotics alleviate neuropsychiatric disorders. Herein, to understand whether anti-inflammatory probiotics Lactobacillus mucosae NK41 and Bifidobacterium longum NK46, which suppressed tumor necrosis factor (TNF)-α expression in lipopolysaccharide (LPS)-stimulated macrophages, could alleviate cognitive impairment, we first examined their effects on cognitive function, gut inflammation, and gut microbiota composition in 5xFAD-transgenic mice. Oral administration of NK41 or NK46 decreased cognitive impairment-like behaviors, hippocampal amyloid-β (Aβ), TNF-α and interleukin (IL)-1β expression, hippocampal NF-κB+Iba1+ cell population, and Aβ accumulation, while hippocampal brain-derived neurotropic factor (BDNF) and IL-10 expression and BDNF+NeuN+ cell population increased. They also decreased TNF-α and IL-1β expression and NF-κB+CD11c+ cell population in the colon. They also reduced fecal and blood LPS levels and gut Proteobacteria and Verrucomicrobia populations (including Akkkermansiaceae), which are positively associated with hippocampal TNF-α and fecal LPS levels and negatively correlated with hippocampal BDNF level. However, they increased Odoribactericeae, which positively correlated with BDNF expression level and TNF-α to IL-10 expression ratio. The combination of NK41 and NK46 (4:1, NKc), which potently inhibited TNF-α expression in LPS-stimulated macrophages, additively alleviated cognitive impairment-like behaviors in 5xFAD-transgenic or aged mice. NKc increased hippocampal BDNF+NeuN+ cell population and BDNF expression in 5xFAD-transgenic or aged mice, while hippocampal TNF-α and IL-1β expression decreased. NKc also decreased TNF-α and IL-1β expression in the colon and LPS levels in the blood and feces. These findings suggest that gut bacteria and its product LPS may be closely connected with occurrence of cognitive impairment and neuroinflammation and the combination of NK41 and NK46 can additively alleviate cognitive impairment and neuroinflammation by inducing NF-κB-suppressed BDNF expression and suppressing LPS-producing gut bacteria.

A Narrative Review of Psychobiotics: Probiotics That Influence the Gut–Brain Axis

“…In a recent experimental study, Lactobacillus mucosae and Bifidobacterium longum were given to 30 male mice; this combination showed alleviated cognitive decline and neuroinflammation. They also alleviated colitis and gut dysbiosis [57].…”

The Probiotic Properties and Safety of Limosilactobacillus mucosae NK41 and Bifidobacterium longum NK46

“…Limosilactobacillus mucosae (L. mucosae) NK41 and Bifidobacterium longum (B. longum) NK46, which were selected from a human fecal bacterial collection, have been previously reported to induce the expression of brain-derived neurotrophic factor, which promotes the proliferation, survival, and differentiation of neurons in corticosterone-stimulated SH-SY5Y cells [20,21]. Moreover, these strains improve cognitive impairment-like behavior and neuroinflammation in aged or 5xFAD transgenic mice [21], and reduce anxiety and depression and colitis by suppressing gut dysbiosis in immobilization stress-induced mice [20].…”

“…Limosilactobacillus mucosae (L. mucosae) NK41 and Bifidobacterium longum (B. longum) NK46, which were selected from a human fecal bacterial collection, have been previously reported to induce the expression of brain-derived neurotrophic factor, which promotes the proliferation, survival, and differentiation of neurons in corticosterone-stimulated SH-SY5Y cells [20,21]. Moreover, these strains improve cognitive impairment-like behavior and neuroinflammation in aged or 5xFAD transgenic mice [21], and reduce anxiety and depression and colitis by suppressing gut dysbiosis in immobilization stress-induced mice [20]. The aim of this study was to assess the probiotic properties (resistance to gastrointestinal conditions, auto-aggregation, hydrophobicity, adhesion to intestinal epithelial cells, and extracellular enzyme activity) and safety characteristics (hemolysis, gelatinase activity, antimicrobial susceptibility, production of D-/L-lactate, and identification of genes associated with virulence factors) of these strains for potential commercial applications as functional foods.…”