EVOLUTION: Of Mice . . .

The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within ...

The Microbiota-Gut-Brain Axis

The various contributions to this book record the remarkable progress that has been made in the understanding and management of pancreatic diseases over the last decade. The improvement in understanding has led in some cases to better management with improved outcome for the patient, whereas in other areas the way is now clear towards a better prospect for the future.

Progress and Prospects

The human microbiota has a fundamental role in host physiology and pathology. Gut microbial alteration, also known as dysbiosis, is a condition associated not only with gastrointestinal disorders but also with diseases affecting other distal organs. Recently it became evident that the intestinal bacteria can affect the central nervous system (CNS) physiology and inflammation. The nervous system and the gastrointestinal tract are communicating through a bidirectional network of signaling pathways called the gut-brain axis, which consists of multiple connections, including the vagus nerve, the immune system, and bacterial metabolites and products. During dysbiosis, these pathways are dysregulated and associated with altered permeability of the blood-brain barrier (BBB) and neuroinflammation. However, numerous mechanisms behind the impact of the gut microbiota in neuro-development and -pathogenesis remain poorly understood. There are several immune pathways involved in CNS homeostasis and inflammation. Among those, the inflammasome pathway has been linked to neuroinflammatory conditions such as multiple sclerosis, Alzheimer's and Parkinson's diseases, but also anxiety and depressive-like disorders. The inflammasome complex assembles upon cell activation due to exposure to microbes, danger signals, or stress and lead to the production of pro-inflammatory cytokines (interleukin-1β and interleukin-18) and to pyroptosis. Evidences suggest that there is a reciprocal influence of microbiota and inflammasome activation in the brain. However, how this influence is precisely working is yet to be discovered. Herein, we discuss the status of the knowledge and the open questions in the field focusing on the function of intestinal microbial metabolites or products on CNS cells during healthy and inflammatory conditions, such as multiple sclerosis, Alzheimer's and Parkinson's diseases, and also neuropsychiatric disorders. In particular, we focus on the innate inflammasome pathway as immune mechanism that can be involved in several of these conditions, upon exposure to certain microbes.

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The Gut-Brain Axis: How Microbiota and Host Inflammasome Influence Brain Physiology and Pathology.

Mounting evidence suggests that the gut microbiome impacts brain development and function. Gut-brain connections may be mediated by an assortment of microbial molecules that are produced in the gastrointestinal tract, which can subsequently permeate many organs, including sometimes the brain. Studies in animal models have identified molecular cues propagated from intestinal bacteria to the brain that can affect neurological function and/or neurodevelopmental and neurodegenerative conditions. Herein, we describe bacterial metabolites with known or suspected neuromodulatory activity, define mechanisms of signalling pathways from the gut microbiota to the brain and discuss direct effects that gut bacterial molecules are likely exerting on specific brain cells. Many discoveries are recent, and the findings described in this Perspective are largely novel and yet to be extensively validated. However, expanding research into the dynamic molecular communications between gut microorganisms and the CNS continues to uncover critical and previously unappreciated clues in understanding the pathophysiology of behavioural, psychiatric and neurodegenerative diseases.

Gut microbial molecules in behavioural and neurodegenerative conditions.

The gut dysbiosis by stressors such as immobilization deteriorates psychiatric disorders through microbiota-gut-brain axis activation. To understand whether probiotics could simultaneously alleviate anxiety/depression and colitis, we examined their effects on immobilization stress (IS)-induced anxiety/depression and colitis in mice. The probiotics Lactobacillus reuteri NK33 and Bifidobacterium adolescentis NK98 were isolated from healthy human feces. Mice with anxiety/depression and colitis were prepared by IS treatment. NK33 and NK98 potently suppressed NF-κB activation in lipopolysaccharide (LPS)-induced BV-2 cells. Treatment with NK33 and/or NK98, which were orally gavaged in mice before or after IS treatment, significantly suppressed the occurrence and development of anxiety/depression, infiltration of Iba1+ and LPS+/CD11b+ cells (activated microglia) into the hippocampus, and corticosterone, IL-6, and LPS levels in the blood. Furthermore, they induced hippocampal BDNF expression while NF-κB activation was suppressed. NK33 and/or NK98 treatments suppressed IS-induced colon shortening, myeloperoxidase activity, infiltration of CD11b+/CD11c+ cells, and IL-6 expression in the colon. Their treatments also suppressed the IS-induced fecal Proteobacteria population and excessive LPS production. They also induced BDNF expression in LPS-induced SH-SY5Y cells in vitro. In conclusion, NK33 and NK98 synergistically alleviated the occurrence and development of anxiety/depression and colitis through the regulation of gut immune responses and microbiota composition.

https://www.mdpi.com/2072-6643/11/4/819/pdf

The Preventive and Curative Effects of Lactobacillus reuteri NK33 and Bifidobacterium adolescentis NK98 on Immobilization Stress-Induced Anxiety/Depression and Colitis in 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-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.

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

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.

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

To understand the roles of human gut bacteria in the occurrence of neuropsychiatric disorders, we isolated inflammatory Escherichia coli K1 and anti-inflammatory Lactobacillus mucosae from healthy human feces and examined their effects on the occurrence of altered microbiota, cognitive decline, and depression in mice. Oral gavage of Escherichia coli K1 caused colitis, cognitive decline, and depression in mice in the elevated plus maze, tail suspension, and forced swimming tasks. However, NK41 treatment reduced K1-induced cognitive decline and anxiety/depression. Furthermore, NK41 treatment increased K1-suppressed brain-derived neurotrophic factor (BDNF) expression and BDNF+/NeuN+ cell population and suppressed K1-induced NF-κB activation and LPS+/Iba1+ and NF-κB+/Iba1+ (microglial) cell populations in the hippocampus. NK41 treatment also suppressed K1-induced TNF-α and LPS levels in the blood and TNF-α expression, myeloperoxidase activity, NF-κB+/CD11c+ and CD11b+/CD11c+ cell populations in the colon. Furthermore, NK41 treatment decreased K1-induced colonic MUC2 expression, gut Proteobacteria population, and fecal LPS levels and modified the bacterial abundance related to polysaccharide breaking and biosynthesis. In conclusion, the overgrowth of inflammatory bacteria such as Escherichia coli in the gastrointestinal tract can cause neuropsychiatric disorders with gut microbiota alteration and the superiority of anti-inflammatory bacteria such as Lactobacillus mucosae can alleviate neuropsychiatric disorders with the attenuation of altered microbiota.

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Interplay Between Human Gut Bacteria Escherichia coli and Lactobacillus mucosae in the Occurrence of Neuropsychiatric Disorders in Mice

Excessive expression of interleukin (IL)-1β in the brain causes depression and cognitive dysfunction. Herein, we investigated the effect of Lactobacillus gasseri NK109, which suppressed IL-1β expression in activated macrophages, on Escherichia coli K1-induced cognitive impairment and depression in mice. Germ-free and specific pathogen-free mice with neuropsychiatric disorders were prepared by oral gavage of K1. NK109 alleviated K1-induced cognition-impaired and depressive behaviors, decreased the expression of IL-1β and populations of NF-κB+/Iba1+ and IL-1R+ cells, and increased the K1-suppressed population of BDNF+/NeuN+ cells in the hippocampus. However, its effects were partially attenuated by celiac vagotomy. NK109 treatment mitigated K1-induced colitis and gut dysbiosis. Tyndallized NK109, even if lysed, alleviated cognitive impairment and depression. In conclusion, NK109 alleviated neuropsychiatric disorders and colitis by modulating IL-1β expression, gut microbiota, and vagus nerve-mediated gut–brain signaling.

https://www.mdpi.com/2072-6643/12/11/3441/pdf

A Probiotic Lactobacillus gasseri Alleviates Escherichia coli -Induced Cognitive Impairment and Depression in Mice by Regulating IL-1β Expression and Gut Microbiota.

Kyung-Eon Lee

Papers

The Preventive and Curative Effects of Lactobacillus reuteri NK33 and Bifidobacterium adolescentis NK98 on Immobilization Stress-Induced Anxiety/Depression and Colitis in Mice.

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

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

Interplay Between Human Gut Bacteria Escherichia coli and Lactobacillus mucosae in the Occurrence of Neuropsychiatric Disorders in Mice

A Probiotic Lactobacillus gasseri Alleviates Escherichia coli -Induced Cognitive Impairment and Depression in Mice by Regulating IL-1β Expression and Gut Microbiota.