scholarly journals The impact of gut microbiota on depressive-like behaviors and adult hippocampal neurogenesis requires the endocannabinoid system

2019 ◽  
Author(s):  
Grégoire Chevalier ◽  
Eleni Siopi ◽  
Laure Guenin-Macé ◽  
Maud Pascal ◽  
Thomas Laval ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Gut Microbiota ◽  
Fecal Microbiota Transplantation ◽  
Endocannabinoid System ◽  
Chronic Mild Stress ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Mild Stress ◽  
Microbiota Composition ◽  
The Impact

SUMMARYDepression is the leading cause of disability worldwide. Recent observations have revealed an association between mood disorders and alterations of the intestinal microbiota, but causality remains yet to be established. Here, using unpredictable chronic mild stress (UCMS) as a mouse model of depression, we show that the UCMS mice display phenotypic alterations — characterized by an altered gut microbiota composition, a reduced adult hippocampal neurogenesis and a depressive-like behaviors — which could be transferred from UCMS donors to naïve recipient mice by fecal microbiota transplantation. The cellular and behavioral alterations observed in recipient mice were accompanied by a decrease in the endocannabinoid (eCB) signaling due to lower peripheral levels of fatty acid precursors of eCB ligands. The adverse effects of UCMS-transferred microbiota on adult neurogenesis and behavior in naïve recipient mice were alleviated by selectively enhancing the central eCB tone or by adding arachidonic acid, a fatty acid precursor of eCB ligands, to the diet. In the gut of both UCMS donors and recipients, the microbiota composition was characterized by a relative decrease in Lactobacilli abundance, and complementation of the UCMS recipient microbiota with a strain of the Lactobacilli genus was sufficient to restore normal eCB brain levels, hippocampal neurogenesis and to alleviate depressive-like behaviors. Our findings provide a mechanistic scenario for how chronic stress, diet and gut microbiota dysbiosis generate a pathological feed-forward loop that contributes to despair behavior via the central eCB system.

scholarly journals Effect of gut microbiota on depressive-like behaviors in mice is mediated by the endocannabinoid system

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Grégoire Chevalier ◽  
Eleni Siopi ◽  
Laure Guenin-Macé ◽  
Maud Pascal ◽  
Thomas Laval ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Adverse Effects ◽  
Mouse Model ◽  
Gut Microbiota ◽  
Fecal Microbiota Transplantation ◽  
Endocannabinoid System ◽  
Chronic Mild Stress ◽  
Fecal Microbiota ◽  
Mild Stress ◽  
Behavioral Alterations

AbstractDepression is the leading cause of disability worldwide. Recent observations have revealed an association between mood disorders and alterations of the intestinal microbiota. Here, using unpredictable chronic mild stress (UCMS) as a mouse model of depression, we show that UCMS mice display phenotypic alterations, which could be transferred from UCMS donors to naïve recipient mice by fecal microbiota transplantation. The cellular and behavioral alterations observed in recipient mice were accompanied by a decrease in the endocannabinoid (eCB) signaling due to lower peripheral levels of fatty acid precursors of eCB ligands. The adverse effects of UCMS-transferred microbiota were alleviated by selectively enhancing the central eCB or by complementation with a strain of the Lactobacilli genus. Our findings provide a mechanistic scenario for how chronic stress, diet and gut microbiota generate a pathological feed-forward loop that contributes to despair behavior via the central eCB system.

scholarly journals Ginsenoside Rb1 Induces a Pro-Neurogenic Microglial Phenotype via PPARγ Activation in Male Mice Exposed to Chronic Mild Stress

2021 ◽  
Author(s):  
Zili You ◽  
Lijuan Zhang ◽  
Minmin Tang ◽  
Xiaofang Xie ◽  
Qiuying Zhao ◽  
...  
Keyword(s):  
Chronic Mild Stress ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Immunofluorescence Staining ◽  
Mild Stress ◽  
Ginsenoside Rb1 ◽  
Male Mice ◽  
Antidepressant Effects

Abstract BackgroundAnti-inflammatory approaches are emerging as a new strategy for treatment of depressive disorders. Ginsenoside Rb1 (GRb1), a major component of Panax ginseng, can inhibit inflammatory cascade and alleviate depressive behaviors. Microglia can promote or inhibit adult hippocampal neurogenesis according to their functional phenotypes. Here, we examined whether GRb1 may exert antidepressant effects by promoting a pro-neurogenic phenotype of microglia and thereby increasing neurogenesis. MethodsThe antidepressant effects of GRb1 or the licensed antidepressant imipramine (IMI) were assessed in chronic mild stress (CMS)-exposed male mice. The depressive-like behaviors of mice were evaluated by sucrose preference test, forced swimming test (FST), and tail suspension test (TST). The microglial phenotypes were identified by molecular markers and morphological properties, analyzed by RT-qPCR, western blotting and immunofluorescence staining. Effect of GRb1-treated microglia on adult hippocampal neurogenesis in vivo and in vitro were detected using immunofluorescence staining. ResultsBehavioral assessment indicated that GRb1 or IMI treatment alleviated depressive-like behaviors in CMS-exposed mice. Immunofluorescence examinationdemonstrated that GRb1 induced a pro-neurogenic phenotype of microglia via activating PPARγ in vivo and in vitro, which were reversed by PPARγ inhibitor GW9662. In addition, GRb1-treated microglia increased the proliferation and differentiation of neural precursor cells.ConclusionsThese findings demonstrated that GRb1 alleviated depressive-like behaviors of CMS-exposed male mice mainly through PPARγ-mediated microglial activation and improvement of adult hippocampus neurogenesis.

scholarly journals Increasing Adult Hippocampal Neurogenesis Promotes Resilience in a Mouse Model of Depression

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 972
Author(s):  
Barbara Planchez ◽  
Natalia Lagunas ◽  
Anne-Marie Le Guisquet ◽  
Marc Legrand ◽  
Alexandre Surget ◽  
...  
Keyword(s):  
Mouse Model ◽  
Water Maze ◽  
Chronic Mild Stress ◽  
Tail Suspension Test ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Maze Procedure ◽  
Mild Stress ◽  
Protective Effects ◽  
Stress Resilience

Many studies evaluated the functional role of adult hippocampal neurogenesis (AHN) and its key role in cognitive functions and mood regulation. The effects of promoting AHN on the recovery of stress-induced symptoms have been well studied, but its involvement in stress resilience remains elusive. We used a mouse model enabling us to foster AHN before the exposure to unpredictable chronic mild stress (UCMS) to evaluate the potential protective effects of AHN on stress, assessing the depressive-like phenotype and executive functions. For this purpose, an inducible transgenic mouse model was used to delete the pro-apoptotic gene Bax from neural progenitors four weeks before UCMS, whereby increasing the survival of adult-generated neurons. Our results showed that UCMS elicited a depressive-like phenotype, highlighted by a deteriorated coat state, a higher immobility duration in the tail suspension test (TST), and a delayed reversal learning in a water maze procedure. Promoting AHN before UCMS was sufficient to prevent the development of stressed-induced behavioral changes in the TST and the water maze, reflecting an effect of AHN on stress resilience. Taken together, our data suggest that increasing AHN promotes stress resilience on some depressive-like symptoms but also in cognitive symptoms, which are often observed in MD.

scholarly journals Ginsenoside Rb1 induces a pro-neurogenic microglial phenotype via PPARγ activation in male mice exposed to chronic mild stress

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Lijuan Zhang ◽  
Minmin Tang ◽  
Xiaofang Xie ◽  
Qiuying Zhao ◽  
Nan Hu ◽  
...  
Keyword(s):  
Chronic Mild Stress ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Immunofluorescence Staining ◽  
Mild Stress ◽  
Ginsenoside Rb1 ◽  
Male Mice ◽  
Antidepressant Effects

Abstract Background Anti-inflammatory approaches are emerging as a new strategy for the treatment of depressive disorders. Ginsenoside Rb1 (GRb1), a major component of Panax ginseng, can inhibit inflammatory cascade and alleviate depressive-like behaviors. Microglia can promote or inhibit adult hippocampal neurogenesis according to their functional phenotypes. Here, we examine whether GRb1 may exert antidepressant effects by promoting a pro-neurogenic phenotype of microglia and thereby increasing neurogenesis. Methods The antidepressant effects of GRb1 or the licensed antidepressant imipramine (IMI) were assessed in chronic mild stress (CMS)-exposed male mice. The depressive-like behaviors of mice were evaluated by sucrose preference test, forced swimming test (FST), and tail suspension test (TST). The microglial phenotypes were identified by pro- and anti-inflammatory cytokine expression and morphological properties, analyzed by RT-qPCR, western blotting, and immunofluorescence staining. The effect of GRb1-treated microglia on adult hippocampal neurogenesis in vivo and in vitro was detected using immunofluorescence staining. Results Behavioral assessment indicated that GRb1 or IMI treatment alleviated depressive-like behaviors in CMS-exposed mice. Immunofluorescence examination demonstrated that GRb1 induced a pro-neurogenic phenotype of microglia via activating PPARγ in vivo and in vitro, which were effectively reversed by the PPARγ inhibitor GW9662. In addition, GRb1-treated microglia increased the proliferation and differentiation of neural precursor cells. Conclusions These findings demonstrated that GRb1 alleviated depressive-like behaviors of CMS-exposed male mice mainly through PPARγ-mediated microglial activation and improvement of adult hippocampus neurogenesis.

scholarly journals Changes in the functional connectome and behavior after exposure to chronic stress and increasing neurogenesis

2020 ◽  
Author(s):  
Luka Culig ◽  
Patrick E. Steadman ◽  
Justin W. Kenney ◽  
Sandra Legendre ◽  
Frédéric Minier ◽  
...  
Keyword(s):  
Chronic Stress ◽  
Granule Cells ◽  
Brain Networks ◽  
Chronic Mild Stress ◽  
Protective Role ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Mild Stress ◽  
Brain Circuitry ◽  
Newborn Neurons

AbstractAddition of new neurons to the dentate gyrus might change the activity of neural circuitry in the areas which the hippocampus projects to. The size of the hippocampus and the number of adult newborn granule cells are decreased by unpredictable chronic mild stress (UCMS). Additionally, one of the notable effects of chronic stress is the induction of ΔFosB, an unusually stable transcription factor which accumulates over time in several brain areas. This accumulation has been observed in many animal models of depression and it could have a protective role against stress, but no studies so far have explored how a specific increase in neurogenesis might regulate the induction and which brain networks might be predominately affected.We attempted to investigate the role of increasing adult hippocampal neurogenesis on stress-related behavior and the functional brain circuitry involved in mice exposed to UCMS. We used iBax mice, in which the pro-apoptotic gene Bax can be selectively ablated in neural stem cells, therefore inducibly enhancing survival of newborn neurons after tamoxifen administration. The animals were exposed to UCMS for 9 weeks and treated with tamoxifen in week 3 after the beginning of UCMS. In week 8, they were submitted to a battery of behavioral tests to assess depressive-like and anxiety-like behavior. In week 9, blood was collected to assess basal corticosterone levels, and the animals were sacrificed and their brain collected for ΔFosB immunohistochemistry. Brain-wide maps of ΔFosB expression were constructed and graph theoretical analyses were used to study the changes in brain networks after stress.UCMS induced negative correlations between the lateral entorhinal cortex and both the hippocampal structures and the nucleus accumbens in the VEH-treated mice, which were not present in other groups. Ranking nodes by degree reveals a strong thalamic-cortical signature in both non-stress (NS) groups. Exposure to UCMS seems to induce activity in thalamic areas and cerebral nuclei, with a different signature in the UCMS TAM group, which seems to completely “disengage” the neocortex and has most of its nodes with the most connections in the thalamic areas.

scholarly journals Gut microbiota requires vagus nerve integrity to promote depression

2019 ◽  
Author(s):  
Eleni Siopi ◽  
Soham Saha ◽  
Carine Moigneu ◽  
Mathilde Bigot ◽  
Pierre-Marie Lledo
Keyword(s):  
Risk Factors ◽  
Gut Microbiota ◽  
Brain Plasticity ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Vagal Afferents ◽  
Microbiota Composition ◽  
Induced Changes ◽  
And Behavior ◽  
Gut Microbiota Composition

Chronic stress constitutes one of the strongest risk factors for depression and can disrupt various aspects of homeostasis, including gut microbiota composition. We found that stress-induced changes in gut microbiota promote depression and decrease adult hippocampal neurogenesis upon transfer to antibiotic-treated recipient mice. Subdiaphragmatic vagotomy abrogated the microbiota-induced effects on behavior and neurogenesis, suggesting that gut microbiota can influence brain plasticity and behavior through vagal afferents.

scholarly journals Insights into the Impact of Microbiota in the Treatment of NAFLD/NASH and Its Potential as a Biomarker for Prognosis and Diagnosis

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 145
Author(s):  
Julio Plaza-Díaz ◽  
Patricio Solis-Urra ◽  
Jerónimo Aragón-Vela ◽  
Fernando Rodríguez-Rodríguez ◽  
Jorge Olivares-Arancibia ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Fecal Microbiota Transplantation ◽  
Liver Steatosis ◽  
Intestinal Barrier ◽  
Fecal Microbiota ◽  
Current Treatment ◽  
Immune Defense ◽  
Alcoholic Fatty Liver ◽  
The Impact

Non-alcoholic fatty liver disease (NAFLD) is an increasing cause of chronic liver illness associated with obesity and metabolic disorders, such as hypertension, dyslipidemia, or type 2 diabetes mellitus. A more severe type of NAFLD, non-alcoholic steatohepatitis (NASH), is considered an ongoing global health threat and dramatically increases the risks of cirrhosis, liver failure, and hepatocellular carcinoma. Several reports have demonstrated that liver steatosis is associated with the elevation of certain clinical and biochemical markers but with low predictive potential. In addition, current imaging methods are inaccurate and inadequate for quantification of liver steatosis and do not distinguish clearly between the microvesicular and the macrovesicular types. On the other hand, an unhealthy status usually presents an altered gut microbiota, associated with the loss of its functions. Indeed, NAFLD pathophysiology has been linked to lower microbial diversity and a weakened intestinal barrier, exposing the host to bacterial components and stimulating pathways of immune defense and inflammation via toll-like receptor signaling. Moreover, this activation of inflammation in hepatocytes induces progression from simple steatosis to NASH. In the present review, we aim to: (a) summarize studies on both human and animals addressed to determine the impact of alterations in gut microbiota in NASH; (b) evaluate the potential role of such alterations as biomarkers for prognosis and diagnosis of this disorder; and (c) discuss the involvement of microbiota in the current treatment for NAFLD/NASH (i.e., bariatric surgery, physical exercise and lifestyle, diet, probiotics and prebiotics, and fecal microbiota transplantation).

scholarly journals Antibiotics at birth and later antibiotic courses: effects on gut microbiota

2021 ◽  
Author(s):  
Sofia Ainonen ◽  
Mysore V Tejesvi ◽  
Md. Rayhan Mahmud ◽  
Niko Paalanne ◽  
Tytti Pokka ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Control Group ◽  
List Type ◽  
Antibiotic Exposure ◽  
Microbiota Composition ◽  
Long Term Effects ◽  
The Impact ◽  
Antibiotic Courses ◽  
Gut Microbiota Composition

Abstract Background Intrapartum antibiotic prophylaxis (IAP) is widely used, but the evidence of the long-term effects on the gut microbiota and subsequent health of children is limited. Here, we compared the impacts of perinatal antibiotic exposure and later courses of antibiotic courses on gut microbiota. Methods This was a prospective, controlled cohort study among 100 vaginally delivered infants with different perinatal antibiotic exposures: control (27), IAP (27), postnatal antibiotics (24), and IAP and postnatal antibiotics (22). At 1 year of age, we performed next-generation sequencing of the bacterial 16S ribosomal RNA gene of fecal samples. Results Exposure to the perinatal antibiotics had a clear impact on the gut microbiota. The abundance of the Bacteroidetes phylum was significantly higher in the control group, whereas the relative abundance of Escherichia coli was significantly lower in the control group. The impact of the perinatal antibiotics on the gut microbiota composition was greater than exposure to later courses of antibiotics (28% of participants). Conclusions Perinatal antibiotic exposure had a marked impact on the gut microbiota at the age of 1 year. The timing of the antibiotic exposure appears to be the critical factor for the changes observed in the gut microbiota. Impact Infants are commonly exposed to IAP and postnatal antibiotics, and later to courses of antibiotics during the first year of life. Perinatal antibiotics have been associated with an altered gut microbiota during the first months of life, whereas the evidence regarding the long-term impact is more limited. Perinatal antibiotic exposure had a marked impact on the infant’s gut microbiota at 1 year of age. Impact of the perinatal antibiotics on the gut microbiota composition was greater than that of the later courses of antibiotics at the age of 1 year.

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