The extracellular vesicle of gut microbial Paenalcaligenes hominis is a risk factor for vagus nerve-mediated cognitive impairment.

BACKGROUND: In a pilot study, we found that feces transplantation from elderly individuals to mice significantly caused cognitive impairment. Paenalcaligenes hominis and Escherichia coli are increasingly detected in the feces of elderly adults and aged mice. Therefore, we isolated Paenalcaligenes hominis and Escherichia coli from the feces of elderly individuals and aged mice and examined their effects on the occurrence of age-related degenerative cognitive impairment and colonic inflammation in mice. RESULTS: The transplantation of feces collected from elderly people and aged mice caused significantly more severe cognitive impairment in transplanted young mice than those from young adults and mice. Oral gavage of Paenalcaligenes hominis caused strong cognitive impairment and colitis in specific pathogen-free (SPF) and germ-free mice. Escherichia coli also induced cognitive impairment and colitis in SPF mice. Oral gavage of Paenalcaligenes hominis, its extracellular vesicles (EVs), and/or lipopolysaccharide caused cognitive impairment and colitis in mice. However, celiac vagotomy significantly inhibited the occurrence of cognitive impairment, but not colitis, in mice exposed to Paenalcaligenes hominis or its EVs, whereas its lipopolysaccharide or Escherichia coli had no such effects. Vagotomy also inhibited the infiltration of EVs into the hippocampus. CONCLUSIONS: Paenalcaligenes hominis, particularly its EVs, can cause cognitive function-impaired disorders, such as Alzheimer's disease, and its EVs may penetrate the brain through the blood as well as the vagus nerve. Video Abstract.

Suppression of gut dysbiosis by Bifidobacterium longum alleviates cognitive decline in 5XFAD transgenic and aged mice.

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-ß, ß/γ-secretases, and caspase-3 expression and amyloid-ß 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.

Immobilization stress-induced Escherichia coli causes anxiety by inducing NF-κB activation through gut microbiota disturbance.

The present study aimed to understand the crosstalk between anxiety and gut microbiota. Exposure of mice to immobilization stress (IS) led to anxiety-like behaviors, increased corticosterone and tumor necrosis factor-α levels in the blood, increased nuclear factor (NF)-κB activation and microglia/monocyte populations in the hippocampus, and suppressed brain-derived neurotrophic factor (BDNF) expression in the hippocampus. Furthermore, IS exposure increased NF-κB activation and monocyte population in the colon and increased Proteobacteria and Escherichia coli populations in the gut microbiota and fecal and blood lipopolysaccharide (LPS) levels while decreasing the lactobacilli population. Oral administration of the fecal microbiota of mice treated with IS (FIS) or E. coli led to the increased NF-κB activation and monocyte population in the colon. These treatments increased blood corticosterone and LPS levels and anxiety-like behaviors, decreased BDNF expression, and induced NF-κB activation and microglia/monocyte populations in the hippocampus. Intraperitoneal injection of LPS purified from E. coli also led to anxiety and colitis in mice. Oral administration of commensal lactobacilli, particularly Lactobacillus johnsonii, attenuated IS- or E. coli-induced colitis and anxiety-like behaviors and biomarkers. These findings suggest that exposure to stressors can increase Proteobacteria populations and fecal LPS levels and cause gastrointestinal inflammation, resulting in the deterioration of anxiety through NF-κB activation. However, the amelioration of gastrointestinal inflammation by treatment with probiotics including L. johnsonii can alleviate anxiety.

Lactobacillus plantarum C29-Fermented Soybean (DW2009) Alleviates Memory Impairment in 5XFAD Transgenic Mice by Regulating Microglia Activation and Gut Microbiota Composition.

SCOPE: The study aims to determine whether Lactobacillus plantarum C29-fermented defatted soybean (FDS, DW2009) can attenuate memory impairment in 5XFAD transgenic (Tg) mice. METHODS AND RESULTS: Oral administration of FDS or C29 increases cognitive function in Tg mice in passive avoidance, Y-maze, novel object recognition, and Morris water maze tasks. FDS or C29 treatment significantly suppresses amyloid-ß, ß/γ-secretases, caspase-3 expression, and NF-κB activation, and activates microglia and apoptotic neuron cell populations, and increases BDNF expression in the brain. FDS or C29 treatment suppresses blood and fecal lipopolysaccharide levels and Enterobacteriaceae population and increases lactobacilli/bifidobacteria populations. CONCLUSION: FDS and C29 alleviates the decrease in cognitive function and inhibited amyloid-ß expression in Tg mice by regulating microglia activation and gut microbiota composition.

Lactobacillus johnsonii CJLJ103 Attenuates Scopolamine-Induced Memory Impairment in Mice by Increasing BDNF Expression and Inhibiting NF-κB Activation.

In the present study, we examined whether Lactobacillus johnsonii CJLJ103 (LJ) could alleviate cholinergic memory impairment in mice. Oral administration of LJ alleviated scopolamine-induced memory impairment in passive avoidance and Y-maze tasks. Furthermore, LJ treatment increased scopolamine-suppressed BDNF expression and CREB phosphorylation in the hippocampi of the brain, as well as suppressed TNF-α expression and NF-κB activation. LJ also increased BDNF expression in corticosterone-stimulated SH-SY5Y cells and inhibited NF-κB activation in LPS-stimulated microglial BV2 cells. However, LJ did not inhibit acetylcholinesterase activity. These findings suggest that LJ, a member of human gut microbiota, may mitigate cholinergic memory impairment by increasing BDNF expression and inhibiting NF-κB activation.

Evidence for interplay among antibacterial-induced gut microbiota disturbance, neuro-inflammation, and anxiety in mice.

The aim of the present study was to determine whether there is the mechanistic connection between antibacterial-dependent gut microbiota disturbance and anxiety. First, exposure of mice to ampicillin caused anxiety and colitis and increased the population of Proteobacteria, particularly Klebsiella oxytoca, in gut microbiota and fecal and blood lipopolysaccharide levels, while decreasing lactobacilli population including Lactobacillus reuteri. Next, treatments with fecal microbiota of ampicillin-treated mouse (FAP), K. oxytoca, or lipopolysaccharide isolated from K. oxytoca (KL) induced anxiety and colitis in mice and increased blood corticosterone, IL-6, and lipopolysaccharide levels. Moreover, these treatments also increased the recruitment of microglia (Iba1+), monocytes (CD11b+/CD45+), and dendritic cells (CD11b+/CD11c+) to the hippocampus, as well as the population of apoptotic neuron cells (caspase-3+/NeuN+) in the brain. Furthermore, ampicillin, K. oxytoca, and KL induced NF-κB activation and IL-1ß and TNF-α expression in the colon and brain as well as increased gut membrane permeability. Finally, oral administration of L. reuteri alleviated ampicillin-induced anxiety and colitis. These results suggest that ampicillin exposure can cause anxiety through neuro-inflammation which can be induced by monocyte/macrophage-activated gastrointestinal inflammation and elevated Proteobacteria population including K. oxytoca, while treatment with lactobacilli suppresses it.

Lactobacillus plantarum C29 Alleviates TNBS-Induced Memory Impairment in Mice.

In a preliminary study, Lactobacillus plantarum C29 was found to suppress 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in mice. Therefore, to understand whether an anti-colitic probiotic C29 could attenuate memory impairment, we examined the effects of C29 on TNBS-induced memory impairment in mice. Orally administered Lactobacillus plantarum C29 attenuated TNBS-induced memory impairment in mice in the Y-maze, noble object, and passive avoidance task tests. C29 treatment increased TNBS-suppressed hippocampal brain-derived neurotrophic factor expression and inhibited TNBS-induced hippocampal NF-kappaB activation and blood LPS levels. Moreover, C29 restored the TNBS-disturbed gut microbiota composition. These findings suggest that C29 can alleviate memory impairment presumably by restoring the gut microbiota composition.

Soyasapogenol B and Genistein Attenuate Lipopolysaccharide-Induced Memory Impairment in Mice by the Modulation of NF-κB-Mediated BDNF Expression.

Lactobacillus plantarum C29-fermented defatted soybean (FDS), which contains soyasaponins such as soyasaponin I (SI) and soyasapogenol B (SB) and isoflavones such as genistin (GE) and genistein (GT), attenuated memory impairment in mice. Moreover, in the preliminary study, FDS and its soyasaponins and isoflavones significantly inhibited NF-κB activation in LPS-stimulated microglial BV2 cells. Therefore, we examined the effects of FDS and its constituents SI, SB, GT, and GE on LPS-induced memory impairment in mice. Oral administration of FDS (80 mg/kg), which has higher concentrations of SB and GE than DS, recovered LPS-impaired cognitive function in Y-maze (55.1 ± 3.5%) and passive avoidance tasks (50.9 ± 19.2 s) to 129.2% (74.1 ± 3.5%) and 114.2% (290.0 ± 22.4 s) of normal mice, respectively (P < 0.05). SB and GE (10 µM) also more potently attenuated LPS-impaired cognitive behavior than SI and GT, respectively. SB (10 mg/kg) was the most effective: treatment recovered LPS-impaired spontaneous alternation and latency time to 105.7% and 126.8% of normal control mice, respectively (P < 0.05). SB and GE significantly increased BDNF expression and CREB phosphorylation in LPS-treated mice and corticosterone-stimulated SH-SY5Y cells. Furthermore, SB and GE (10 µM) also significantly inhibited NF-κB activation in LPS-treated mice. These findings suggested that FDS and its constituent soyasaponins and isoflavones may attenuate memory impairment by the regulation of NF-κB-mediated BDNF expression.