Chaihu-Shugan-San (Shihosogansan) alleviates restraint stress-generated anxiety and depression in mice by regulating NF-κB-mediated BDNF expression through the modulation of gut microbiota

Abstract Background Chaihu-Shugan-San (CSS, named Shihosogansan in Korean), a Chinese traditional medicine, is frequently used to treat anxiety and depression. Psychiatric disorders including depression are associated with gut dysbiosis. Therefore, to comprehend gut microbiota-involved anti-depressive effect of CSS, we examined its effect on restraint stress (RS)-induced depression and gut dysbiosis in mice Methods CSS was extracted with water in boiling water bath and freeze-dried. Anxiety and depression was induced in C57BL/6 mice by exposure to RS. Anxiety- and depression-like behaviors were measured in the light/dark transition and elevated plus maze tasks, forced swimming test, and tail suspension test. Biomarkers were assayed by using the enzyme-linked immunosorbent assay and immunoblotting. The gut microbiota composition was analyzed by Illumina iSeq sequencer. Results CSS significantly reduced the RS-induced anxiety- and depression-like behaviors in mice. CSS suppressed the RS-induced activation of NF-κB and expression of interleukin (IL)-6 and increased the RS-suppressed expression of brain-derived neurotrophic factor (BDNF). Furthermore, CSS suppressed the RS-induced IL-6 and corticosterone level in the blood and IL-6 expression and myeloperoxidase activity in the colon. CSS decreased the RS-induced γ-Proteobacteria population in gut microbiota, while the RS-suppressed Lactobacillaceae, Prevotellaceae, and AC160630_f populations increased. Fecal transplantation of vehicle-treated control or RS/CSS-treated mice into RS-exposed mice significantly mitigated RS-induced anxity- and depression-like behaviors, suppressed the NF-κB activation in the hippocampus and colon, and reduced the IL-6 and corticosterone levels in the blood. These fecal microbiota transplantations suppressed RS-induced Desulfovibrionaceae and γ-Proteobacteria populations and increased RS-suppressed Lactobacillaceae and Prevotellaceae poulation in the gut microbiota. Conclusions CSS alleviated anxiety and depression by inducing NF-κB-involved BDNF expression through the regulation of gut inflammation and microbiota.

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Lacticaseibacillus paracasei NK112 mitigates Escherichia coli-induced depression and cognitive impairment in mice by regulating IL-6 expression and gut microbiota

Beneficial Microbes ◽

10.3920/bm2020.0109 ◽

2021 ◽

pp. 1-12

Author(s):

S.-W. Yun ◽

J.-K. Kim ◽

M.J. Han ◽

D.-H. Kim

Keyword(s):

Escherichia Coli ◽

Cognitive Impairment ◽

Gut Microbiota ◽

Psychiatric Disorders ◽

Myeloperoxidase Activity ◽

Bdnf Expression ◽

Strain Collection ◽

Tnf Α ◽

Faecal Bacteria ◽

Anxiety Depression

The gut microbiota communicates with the brain through microbiota-gut-brain (MGB) and hypothalamus-pituitary-adrenal (HPA) axes and other pathways. Excessive expression of interleukin (IL)-6 is closely associated with the occurrence of the psychiatric disorders depression and dementia. Therefore, to understand whether IL-6 expression-suppressing probiotics could alleviate psychiatric disorders, we isolated IL-6 expression-inhibiting Lacticaseibacillus paracasei (formerly Lactobacillus paracasei) NK112 from the human faecal bacteria strain collection (Neurobiota Research Center, Seoul, Korea) and examined its therapeutic effect for the depression and cognitive impairment in mice. C57 BL/6J mice with depression and cognitive impairment were prepared by exposure to Escherichia coli K1. Oral gavage of NK112 significantly alleviated K1-induced anxious, depressive, and memory-impaired behaviours in the elevated plus maze, tail-suspension and Y-maze tasks, IL-1β, IL-6, and tumour necrosis factor (TNF)-α expression, and nuclear factor kappa beta (NF-κB) activation in the hippocampus, while K1-suppressed brain-derived neurotrophic factor (BDNF) expression increased. Treatment with NK112 also improved K1-induced myeloperoxidase activity, IL-6 and TNF-α expression, and NF-κB activation in the colon and reduced K1-induced Proteobacteria population in the gut microbiota. Heat-killed NK112 and its lysate supernatant, and precipitate fractions also improved anxiety/depression, cognitive impairment, and colitis in mice. In conclusion, NK112, even if heat-killed or lysed, alleviated K1 stress-induced colitis, anxiety/depression, and cognitive impairment by suppressing IL-6, TNF-α, and BDNF expression through the regulation of gut microbiota and NF-κB activation.

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Ginkgo biloba modulates hippocampal BDNF expression in a rat model of chronic restraint stress-induced depression

Physiology and Pharmacology ◽

10.32598/ppj.24.4.20 ◽

2020 ◽

Vol 24 (4) ◽

pp. 285-297

Author(s):

Seyed Abdolmajid Ayatollahi ◽

◽

Shahrokh Khoshsirat ◽

Ali Asghar Peyvandi ◽

Omidvar Rezaei ◽

...

Keyword(s):

Dna Methylation ◽

Protein Expression ◽

Ginkgo Biloba ◽

Restraint Stress ◽

Corticosterone Level ◽

The Body ◽

Male Rats ◽

Bdnf Expression ◽

Serum Corticosterone ◽

Repeated Restraint Stress

Introduction: Mood disorders such as depression and anxiety disorders have been affecting a relatively high proportion of the world's population. Neuroplasticity hypothesis of depression proposes that lack of brain-derived neurotrophic factor (BDNF) can cause structural changes in the brain. The extract of Ginkgo biloba (Gb) leaves can restore much of the damage in the nervous system. We examined the antidepressant role of Gb extract (EGb 761) on BDNF expression modulation in the hippocampus of rats subjected to repeated restraint stress (RRS). Methods: Adult male rats were randomly divided into 10 groups: control, control-vehicle treated, stress, stress-vehicle treated, as well as three control and three experimental groups pretreated with EGb (15, 30, 60mg/kg, IP daily) for 21 days. They underwent restraint stress on a daily basis, 6 hours for 21 consecutive days. Weight changes, locomotor activity and forced swim test (FST) were employed to assess depressive-like symptoms. The serum corticosterone level was also measured by ELISA. Hippocampal BDNF DNA methylation and protein expression were assayed by methylation sensitive restriction enzymes (Real Time PCR) and Western-blotting respectively in all groups. Results: Pre-treatment with 30 and 60 mg/kg/day of Gb extract significantly attenuated depressive-like effects in the body weight, FST and serum corticosterone level in RSS rats compared to control groups. Further, it inhibited chronic stress-induced alterations in the hippocampal BDNF DNA methylation and protein expression. Conclusion: These findings suggest that Gb can induce an antidepressant role through its modulation effect on the hippocampal BDNF expression.

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Links between gut dysbiosis and neurotransmitter disturbance in chronic restraint stress-induced depressive behaviours: the role of inflammation

10.21203/rs.3.rs-469197/v1 ◽

2021 ◽

Author(s):

Hai-long Yang ◽

Meng-Meng Li ◽

Man-Fei Zhou ◽

Huai-Sha Xu ◽

Fei Huan ◽

...

Keyword(s):

Gut Microbiota ◽

Restraint Stress ◽

Forced Swim Test ◽

Preference Test ◽

16S Rrna Gene Sequencing ◽

Rrna Gene ◽

Chronic Restraint Stress ◽

Bdnf Expression ◽

Behavioural Tests ◽

Neurotransmitter Metabolism

Abstract Accumulating evidence has shown that inflammation, the gut microbiota and neurotransmitters are closely associated with the pathophysiology of depression. However, the links between the gut microbiota and neurotransmitter metabolism remain poorly understood. The present study aimed to investigate the neuroinflammatory reactions in chronic restraint stress (CRS)-induced depression and to delineate the potential links between the gut microbiota and neurotransmitter metabolism. C57BL/6 mice were subjected to chronic restraint stress for 5 weeks, followed by behavioural tests (the sucrose preference test, forced swim test, open field test and elevated plus maze) and analysis. The results showed that CRS significantly increased IL-1β, IL-2, IL-6 and TNFα levels and decreased BDNF expression, accompanied by the activation of IκBα-p-NF-κB signalling in the mouse hippocampus. In addition, the neurotransmitter metabolomics results showed that CRS resulted in decreased levels of plasma 5-HT, DA, and NE and their corresponding metabolites, and gut microbiota fecal metabolites with the 16S rRNA gene sequencing indicated that CRS caused marked microbiota dysbiosis in mice, with a significant increase in Helicobacter, Lactobacillus, and Oscillibacter and a decrease in Parabacteroides, Ruminococcus, and Prevotella. Notably, CRS-induced depressive behaviours and the disturbance of neurotransmitter metabolism and microbiota dysbiosis can be substantially restored by dexamethasone (DXMS) administration. Furthermore, a Pearson heatmap focusing on correlations between the microbiota, behaviours and neurotransmitters showed that Helicobacter, Lactobacillus, and Oscillibacter were positively correlated with depressive behaviours but were negatively correlated with neurotransmitter metabolism, and Parabacteroides and Ruminococcus were negatively correlated with depressive behaviours but were positively correlated with neurotransmitter metabolism. Taken together, the results suggest that inflammation is involved in microbiota dysbiosis and the disturbance of neurotransmitter metabolism in CRS-induced depressive changes, and the delineation of the potential links between the microbiota and neurotransmitter metabolism will provide novel strategies for depression treatment.

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Bifidobacteria-Fermented Red Ginseng and Its Constituents Ginsenoside Rd and Protopanaxatriol Alleviate Anxiety/Depression in Mice by the Amelioration of Gut Dysbiosis

Nutrients ◽

10.3390/nu12040901 ◽

2020 ◽

Vol 12 (4) ◽

pp. 901 ◽

Cited By ~ 1

Author(s):

Sang-Kap Han ◽

Min-Kyung Joo ◽

Jeon-Kyung Kim ◽

Woonhee Jeung ◽

Heerim Kang ◽

...

Keyword(s):

Cell Population ◽

Myeloperoxidase Activity ◽

Red Ginseng ◽

Trinitrobenzenesulfonic Acid ◽

Bdnf Expression ◽

Ginsenoside Rd ◽

Gut Dysbiosis ◽

Plus Maze ◽

Anxiety Depression ◽

The Brain

Gut dysbiosis is closely connected with the outbreak of psychiatric disorders with colitis. Bifidobacteria-fermented red ginseng (fRG) increases the absorption of ginsenoside Rd and protopanxatriol into the blood in volunteers and mice. fRG and Rd alleviates 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice. Therefore, to understand the gut microbiota-mediated mechanism of fRG against anxiety/depression, we examined the effects of red ginseng (RG), fRG, ginsenoside Rd, and protopanaxatriol on the occurrence of anxiety/depression, colitis, and gut dysbiosis in mice. Mice with anxiety/depression were prepared by being exposed to two stressors, immobilization stress (IS) or Escherichia coli (EC). Treatment with RG and fRG significantly mitigated the stress-induced anxiety/depression-like behaviors in elevated plus maze, light-dark transition, forced swimming (FST), and tail suspension tasks (TST) and reduced corticosterone levels in the blood. Their treatments also suppressed the stress-induced NF-κB activation and NF-κB+/Iba1+ cell population in the hippocampus, while the brain-derived neurotrophic factor (BDNF) expression and BDNF+/NeuN+ cell population were increased. Furthermore, treatment with RG or fRG suppressed the stress-induced colitis: they suppressed myeloperoxidase activity, NF-κB activation, and NF-κB+/CD11c+ cell population in the colon. In particular, fRG suppressed the EC-induced depression-like behaviors in FST and TST and colitis more strongly than RG. fRG treatment also significantly alleviated the EC-induced NF-κB+/Iba1+ cell population and EC-suppressed BDNF+/NeuN+ cell population in the hippocampus more strongly than RG. RG and fRG alleviated EC-induced gut dysbiosis: they increased Bacteroidetes population and decreased Proteobacteria population. Rd and protopanaxatriol also alleviated EC-induced anxiety/depression and colitis. In conclusion, fRG and its constituents Rd and protopanaxatriol mitigated anxiety/depression and colitis by regulating NF-κB-mediated BDNF expression and gut dysbiosis.

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Orally Administered Antibiotics Vancomycin and Ampicillin Cause Cognitive Impairment With Gut Dysbiosis in Mice With Transient Global Forebrain Ischemia

Frontiers in Microbiology ◽

10.3389/fmicb.2020.564271 ◽

2020 ◽

Vol 11 ◽

Author(s):

Kyung-Eon Lee ◽

Jeon-Kyung Kim ◽

Dong-Hyun Kim

Keyword(s):

Cognitive Impairment ◽

Cognitive Function ◽

Gut Microbiota ◽

Brain Ischemia ◽

Prophylactic Antibiotic ◽

Forebrain Ischemia ◽

Fecal Transplantation ◽

Gut Dysbiosis ◽

Y Maze ◽

The Impact

Gut microbiota is closely associated with the occurrence of neuropsychiatric disorders. Antibiotics are frequently used to prevent pathogen infection in patients with brain ischemia. To understand the impact of prophylactic antibiotic treatment for patients with brain ischemia, we examined the effects of orally administered vancomycin and ampicillin on cognitive function and gut microbiota composition in mice with transient global forebrain ischemia (tIsc). tIsc operation and orally gavaged vancomycin mildly and moderately caused cognitive impairment, respectively. However, the exposure of mice with tIsc to vancomycin or ampicillin severely impaired cognitive function in the Y-maze, novel object recognition, and Banes maze tasks. Furthermore, their treatments induced NF-κB activation as well as active microglia (NF-κB+/Iba1+ and LPS+/Iba1+ cells) and apoptotic (caspase 3+/NeuN+) cell population in the hippocampus, whereas the brain-derived neurotrophic factor (BDNF)+/NeuN+ cell populations decreased. These treatments also caused colitis and gut dysbiosis. They increased the population of Proteobacteria including Enterobacter xiangfangenesis. Orally delivered fecal transplantation of vancomycin-treated mice with or without tIsc and oral gavage of Enterobacter xiangfangenesis also significantly deteriorated the cognitive impairment and colitis in transplanted mice with tIsc. These findings suggest that oral administration of antibiotics can deteriorate cognitive impairment with gut dysbiosis in patients with brain ischemia.

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Microbiota-Immune System Interactions in Human Neurological Disorders

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666200726222138 ◽

2020 ◽

Vol 19 (7) ◽

pp. 509-526

Author(s):

Qin Huang ◽

Fang Yu ◽

Di Liao ◽

Jian Xia

Keyword(s):

Immune System ◽

Gut Microbiota ◽

Neurological Disorders ◽

Brain Function ◽

Neurological Diseases ◽

Host Immune System ◽

Gut Dysbiosis ◽

Characteristic Features ◽

Novel Therapeutic Strategies

: Recent studies implicate microbiota-brain communication as an essential factor for physiology and pathophysiology in brain function and neurodevelopment. One of the pivotal mechanisms about gut to brain communication is through the regulation and interaction of gut microbiota on the host immune system. In this review, we will discuss the role of microbiota-immune systeminteractions in human neurological disorders. The characteristic features in the development of neurological diseases include gut dysbiosis, the disturbed intestinal/Blood-Brain Barrier (BBB) permeability, the activated inflammatory response, and the changed microbial metabolites. Neurological disorders contribute to gut dysbiosis and some relevant metabolites in a top-down way. In turn, the activated immune system induced by the change of gut microbiota may deteriorate the development of neurological diseases through the disturbed gut/BBB barrier in a down-top way. Understanding the characterization and identification of microbiome-immune- brain signaling pathways will help us to yield novel therapeutic strategies by targeting the gut microbiome in neurological disease.

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Gut Microbiota and Dysbiosis in Alzheimer’s Disease: Implications for Pathogenesis and Treatment

Molecular Neurobiology ◽

10.1007/s12035-020-02073-3 ◽

2020 ◽

Vol 57 (12) ◽

pp. 5026-5043 ◽

Cited By ~ 2

Author(s):

Shan Liu ◽

Jiguo Gao ◽

Mingqin Zhu ◽

Kangding Liu ◽

Hong-Liang Zhang

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gut Microbiota ◽

Gut Dysbiosis ◽

Bidirectional Communication ◽

Significant Research ◽

Novel Therapeutic Strategies ◽

The Brain ◽

Brain Homeostasis ◽

Gut Microbiota Composition

Abstract Understanding how gut flora influences gut-brain communications has been the subject of significant research over the past decade. The broadening of the term “microbiota-gut-brain axis” from “gut-brain axis” underscores a bidirectional communication system between the gut and the brain. The microbiota-gut-brain axis involves metabolic, endocrine, neural, and immune pathways which are crucial for the maintenance of brain homeostasis. Alterations in the composition of gut microbiota are associated with multiple neuropsychiatric disorders. Although a causal relationship between gut dysbiosis and neural dysfunction remains elusive, emerging evidence indicates that gut dysbiosis may promote amyloid-beta aggregation, neuroinflammation, oxidative stress, and insulin resistance in the pathogenesis of Alzheimer’s disease (AD). Illustration of the mechanisms underlying the regulation by gut microbiota may pave the way for developing novel therapeutic strategies for AD. In this narrative review, we provide an overview of gut microbiota and their dysregulation in the pathogenesis of AD. Novel insights into the modification of gut microbiota composition as a preventive or therapeutic approach for AD are highlighted.

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Modulation of Gut Microbiota for the Prevention and Treatment of COVID-19

Journal of Clinical Medicine ◽

10.3390/jcm10132903 ◽

2021 ◽

Vol 10 (13) ◽

pp. 2903

Author(s):

Jiezhong Chen ◽

Luis Vitetta

Keyword(s):

Clinical Trials ◽

Trace Elements ◽

Gut Microbiota ◽

Human Health ◽

Intestinal Microbiota ◽

Narrative Review ◽

Bacterial Metabolites ◽

Gut Dysbiosis ◽

Prevention And Treatment

The gut microbiota is well known to exert multiple benefits on human health including protection from disease causing pathobiont microbes. It has been recognized that healthy intestinal microbiota is of great importance in the pathogenesis of COVID-19. Gut dysbiosis caused by various reasons is associated with severe COVID-19. Therefore, the modulation of gut microbiota and supplementation of commensal bacterial metabolites could reduce the severity of COVID-19. Many approaches have been studied to improve gut microbiota in COVID-19 including probiotics, bacterial metabolites, and prebiotics, as well as nutraceuticals and trace elements. So far, 19 clinical trials for testing the efficacy of probiotics and synbiotics in COVID-19 prevention and treatment are ongoing. In this narrative review, we summarize the effects of various approaches on the prevention and treatment of COVID-19 and discuss associated mechanisms.

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Crosstalk between Gut and Brain in Alzheimer’s Disease: The Role of Gut Microbiota Modulation Strategies

Nutrients ◽

10.3390/nu13020690 ◽

2021 ◽

Vol 13 (2) ◽

pp. 690

Author(s):

Umair Shabbir ◽

Muhammad Sajid Arshad ◽

Aysha Sameen ◽

Deog-Hwan Oh

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gut Microbiota ◽

Dietary Habits ◽

Inflammatory Responses ◽

Fecal Microbiota Transplantation ◽

Fecal Microbiota ◽

Gut Dysbiosis ◽

Dynamic Population

The gut microbiota (GM) represents a diverse and dynamic population of microorganisms and about 100 trillion symbiotic microbial cells that dwell in the gastrointestinal tract. Studies suggest that the GM can influence the health of the host, and several factors can modify the GM composition, such as diet, drug intake, lifestyle, and geographical locations. Gut dysbiosis can affect brain immune homeostasis through the microbiota–gut–brain axis and can play a key role in the pathogenesis of neurodegenerative diseases, including dementia and Alzheimer’s disease (AD). The relationship between gut dysbiosis and AD is still elusive, but emerging evidence suggests that it can enhance the secretion of lipopolysaccharides and amyloids that may disturb intestinal permeability and the blood–brain barrier. In addition, it can promote the hallmarks of AD, such as oxidative stress, neuroinflammation, amyloid-beta formation, insulin resistance, and ultimately the causation of neural death. Poor dietary habits and aging, along with inflammatory responses due to dysbiosis, may contribute to the pathogenesis of AD. Thus, GM modulation through diet, probiotics, or fecal microbiota transplantation could represent potential therapeutics in AD. In this review, we discuss the role of GM dysbiosis in AD and potential therapeutic strategies to modulate GM in AD.

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Dose-Responses Relationship in Glucose Lowering and Gut Dysbiosis to Saskatoon Berry Powder Supplementation in High Fat-High Sucrose Diet-Induced Insulin Resistant Mice

Microorganisms ◽

10.3390/microorganisms9081553 ◽

2021 ◽

Vol 9 (8) ◽

pp. 1553

Author(s):

Ruozhi Zhao ◽

Fei Huang ◽

Garry X. Shen

Keyword(s):

Inflammatory Markers ◽

Plasminogen Activator Inhibitor ◽

Model Assessment ◽

High Fat ◽

Plasminogen Activator Inhibitor 1 ◽

Insulin Resistant ◽

Gut Dysbiosis ◽

Freeze Dried ◽

Factor Α ◽

High Sucrose

Administration of freeze-dried powder of Saskatoon berry (SB), a popular fruit enriched with antioxidants, reduced glucose level, inflammatory markers and gut microbiota disorder in high fat-high sucrose (HFHS) diet-induced insulin resistant mice. The present study examined the dose-response relationship in metabolic, inflammatory and gut microbiotic variables to SB power (SBp) supplementation in HFHS diet-fed mice. Male C57 BL/6J mice were fed with HFHS diet supplemented with 0, 1%, 2.5% or 5% SBp for 11 weeks. HFHS diet significantly increased the levels of fast plasma glucose (FPG), cholesterol, triglycerides, insulin, homeostatic model assessment of insulin resistance (HOMA-IR), tumor necrosis factor-α, monocyte chemotactic protein-1 and plasminogen activator inhibitor-1, but decreased fecal Bacteroidetes phylum bacteria and Muribaculaceae family bacteria compared to low fat diet. SBp dose-dependently reduced metabolic and inflammatory variables and gut dysbiosis in mice compared with mice receiving HFHS diet alone. Significant attenuation of HFHS diet-induced biochemical disorders were detected in mice receiving ≥1% SBp. The abundances of Muribaculaceae family bacteria negatively correlated with body weights, FPG, lipids, insulin, HOMA-IR and inflammatory markers in the mice. The results suggest that SBp supplementation dose-dependently attenuated HFHS diet-induced metabolic and inflammatory disorders, which was associated with the amelioration of gut dysbiosis in the mice.

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