scholarly journals Metformin modulates microbiota-derived inosine and ameliorates methamphetamine-induced anxiety and depression-like withdrawal symptoms in mice

2021 ◽  
Author(s):  
Jiqing Yang ◽  
Zunyue Zhang ◽  
Zhenrong Xie ◽  
Ling Bai ◽  
Pu Xiong ◽  
...  
Keyword(s):  
Mouse Model ◽  
Gut Microbiota ◽  
Relative Abundance ◽  
Therapeutic Potential ◽  
Withdrawal Symptoms ◽  
Anxiety And Depression ◽  
Therapeutic Effects ◽  
List Type ◽  
Psychiatric Manifestations ◽  
Behavioural Deficits

ABSTRACTObjectiveMetformin exhibits therapeutic potential in behavioural deficits induced by methamphetamine (METH) in rats. Emerging studies suggest gut microbiota may impact psychiatric symptoms, but there is no direct evidence supporting metformin’s participation in the pathophysiology of withdrawal symptoms via modulation of gut microbiota.MehodsIn order to define the functional contributions by gut microbiota and metformin to the behavioural deficits during METH withdrawal, we utilized a combination of fecal microbiota transplantation (FMT), high-throughput sequencing, and untargeted metabolomics technologies.ResultsFirst, METH addicts exhibited higher α diversity and distinct microbial structures compared to heathy controls. In particular, the relative abundance of Rikenellaceae was positively correlated with the severity of anxiety and depression. Second, both human-to-mouse and mouse-to-mouse FMTs confirmed that METH-altered-microbiota transplantation is sufficient to promote anxiety and depression-like behaviours in recipient germ-free mice, and these behavioural disturbances could be ameliorated by metformin. In-depth analysis revealed that METH significantly altered the bacterial composition and structure as well as relative abundance of several bacterial taxa and metabolites, including Rikenellaceae and inosine, respectively, whereas add-on metformin could remodel these alterations. Finally, the inosine complementation successfully restored METH-induced anxiety and depression-like behaviours in mice.DiscussionThis study demonstrates that METH withdrawal-induced anxiety and depression-like behaviours are convertible and transmissible via gut microbiota in a mouse model. The therapeutic effects of metformin on psychiatric manifestations are associated with microbiota-derived metabolites, highlighting the role of the gut microbiota in substance use disorders and the pathophysiology of withdrawal symptoms.Study HighlightsWhat is known?There are no targeted therapies for substance withdrawal syndrome, but there is considerable evidence that withdrawal-associated psychiatric manifestations contribute to the poor adherence to rehabilitation treatment as well as the relapse rates.Metformin has shown its therapeutic potential against METH-induced neurobehavioural changes and neurodegeneration in rats through CREB/BDNF and Akt/GSK3 signaling pathways in the anxiety-related brain nuclei.What is new here?METH withdrawal-induced anxiety and depression-like behaviours are convertible and transmissible via gut microbiota in a mouse model.The therapeutic effects of metformin on psychiatric manifestations are associated with microbiota derived metabolites.Inosine complementation could restore METH withdrawal-induced anxiety and depression-like behaviours.

scholarly journals Oleuropein Ameliorates Advanced Stage of Type 2 Diabetes in db/db Mice by Regulating Gut Microbiota

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2131
Author(s):  
Shujuan Zheng ◽  
Yanan Wang ◽  
Jingjing Fang ◽  
Ruixuan Geng ◽  
Mengjie Li ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Gut Microbiota ◽  
Relative Abundance ◽  
Fasting Blood Glucose ◽  
Therapeutic Effects ◽  
Model Assessment ◽  
Advanced Stage ◽  
Intestinal Microbes ◽  
Promising Therapeutic Approach

Previous studies have reported the therapeutic effects of oleuropein (OP) consumption on the early stage of type 2 diabetes. However, the efficacy of OP on the advanced stage of type 2 diabetes has not been investigated, and the relationship between OP and intestinal flora has not been studied. Therefore, in this study, to explore the relieving effects of OP intake on the advanced stage of type 2 diabetes and the regulatory effects of OP on intestinal microbes, diabetic db/db mice (17-week-old) were treated with OP at the dose of 200 mg/kg for 15 weeks. We found that OP has a significant effect in decreasing fasting blood glucose levels, improving glucose tolerance, lowering the homeostasis model assessment–insulin resistance index, restoring histopathological features of tissues, and promoting hepatic protein kinase B activation in db/db mice. Notably, OP modulates gut microbiota at phylum level, increases the relative abundance of Verrucomicrobia and Deferribacteres, and decreases the relative abundance of Bacteroidetes. OP treatment increases the relative abundance of Akkermansia, as well as decreases the relative abundance of Prevotella, Odoribacter, Ruminococcus, and Parabacteroides at genus level. In conclusion, OP may ameliorate the advanced stage of type 2 diabetes through modulating the composition and function of gut microbiota. Our findings provide a promising therapeutic approach for the treatment of advanced stage type 2 diabetes.

scholarly journals Therapeutic Potential of a Novel Bifidobacterium Identified Through Microbiome Profiling of RA Patients With Different RF Levels

2021 ◽  
Vol 12 ◽  
Author(s):  
Yunju Jeong ◽  
JooYeon Jhun ◽  
Seon-Yeong Lee ◽  
Hyun Sik Na ◽  
JeongWon Choi ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Relative Abundance ◽  
Th17 Cells ◽  
Mononuclear Cells ◽  
Therapeutic Potential ◽  
Human Peripheral Blood ◽  
Cartilage Damage ◽  
Therapeutic Effects ◽  
Bioinformatics Analyses ◽  
Proinflammatory Mediators

The potential therapeutic effects of probiotic bacteria in rheumatoid arthritis (RA) remain controversial. Thus, this study aimed to discover potential therapeutic bacteria based on the relationship between the gut microbiome and rheumatoid factor (RF) in RA. Bacterial genomic DNA was extracted from the fecal samples of 93 RA patients and 16 healthy subjects. Microbiota profiling was conducted through 16S rRNA sequencing and bioinformatics analyses. The effects of Bifidobacterium strains on human peripheral blood mononuclear cells and collagen-induced arthritis (CIA) mice were assessed. Significant differences in gut microbiota composition were observed in patients with different RF levels. The relative abundance of Bifidobacterium and Collinsella was lower in RF-high than in RF-low and RF-negative RA patients, while the relative abundance of Clostridium of Ruminococcaceae family was higher in RF-high than in RF-low and RF-negative patients. Among 10 differentially abundant Bifidobacterium, B. longum RAPO exhibited the strongest ability to inhibit IL-17 secretion. Oral administration of B. longum RAPO in CIA mice, obese CIA, and humanized avatar model significantly reduced RA incidence, arthritis score, inflammation, bone damage, cartilage damage, Th17 cells, and inflammatory cytokine secretion. Additionally, B. longum RAPO significantly inhibited Th17 cells and Th17-related genes—IL-17A, IRF4, RORC, IL-21, and IL-23R—in the PBMCs of rheumatoid arthritis patients. Our findings suggest that B. longum RAPO may alleviate RA by inhibiting the production of IL-17 and other proinflammatory mediators. The safety and efficacy of B. longum RAPO in patients with RA and other autoimmune disorders merit further investigation.

scholarly journals Therapeutic Effects of Intravitreously Administered Bacteriophage in a Mouse Model of Endophthalmitis Caused by Vancomycin-Sensitive or -Resistant Enterococcus faecalis

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Tatsuma Kishimoto ◽  
Waka Ishida ◽  
Ken Fukuda ◽  
Isana Nakajima ◽  
Takashi Suzuki ◽  
...  
Keyword(s):  
Mouse Model ◽  
Enterococcus Faecalis ◽  
Structural Integrity ◽  
Vision Loss ◽  
Therapeutic Potential ◽  
Therapeutic Effects ◽  
Myeloperoxidase Activity ◽  
Content Type ◽  
Viable Bacteria ◽  
Vancomycin Resistant

ABSTRACT Endophthalmitis due to infection with Enterococcus spp. progresses rapidly and often results in substantial and irreversible vision loss. Given that the frequency of this condition caused by vancomycin-resistant Enterococcus faecalis has been increasing, the development of novel therapeutics is urgently required. We have demonstrated the therapeutic potential of bacteriophage ΦEF24C-P2 in a mouse model of endophthalmitis caused by vancomycin-sensitive (EF24) or vancomycin-resistant (VRE2) strains of E. faecalis. Phage ΦEF24C-P2 induced rapid and pronounced bacterial lysis in turbidity reduction assays with EF24, VRE2, and clinical isolates derived from patients with E. faecalis-related postoperative endophthalmitis. Endophthalmitis was induced in mice by injection of EF24 or VRE2 (1 × 104 cells) into the vitreous. The number of viable bacteria in the eye increased to >1 × 107 CFU, and neutrophil infiltration into the eye was detected as an increase in myeloperoxidase activity at 24 h after infection. A clinical score based on loss of visibility of the fundus as well as the number of viable bacteria and the level of myeloperoxidase activity in the eye were all significantly decreased by intravitreous injection of ΦEF24C-P2 6 h after injection of EF24 or VRE2. Whereas histopathologic analysis revealed massive infiltration of inflammatory cells and retinal detachment in vehicle-treated eyes, the number of these cells was greatly reduced and retinal structural integrity was preserved in phage-treated eyes. Our results thus suggest that intravitreous phage therapy is a potential treatment for endophthalmitis caused by vancomycin-sensitive or -resistant strains of E. faecalis.

scholarly journals Development of an imaging toolbox to assess the therapeutic potential and biodistribution of macrophages in a mouse model of multiple organ dysfunction

2018 ◽  
Author(s):  
Jack Sharkey ◽  
Lorenzo Ressel ◽  
Nathalie Brillant ◽  
Bettina Wilm ◽  
B. Kevin Park ◽  
...  
Keyword(s):  
Liver Function ◽  
Mouse Model ◽  
Organ Dysfunction ◽  
Therapeutic Potential ◽  
Cardiac Injury ◽  
Multiple Organ ◽  
Therapeutic Effects ◽  
M2 Macrophages ◽  
Optoacoustic Tomography ◽  
Kidney Liver

AbstractCell-based regenerative medicine therapies require robust preclinical safety, efficacy, biodistribution and engraftment data prior to clinical testing. To address these challenges, we have developed an imaging toolbox comprising multi-spectral optoacoustic tomography and ultrasonography, which allows the degree of kidney, liver and cardiac injury and the extent of functional recovery to be assessed non-invasively in a mouse model of multi-organ dysfunction. This toolbox allowed us to determine the therapeutic effects of adoptively transferred M2 macrophages. Using bioluminescence imaging, we could then investigate the association between amelioration and biodistribution. Macrophage therapy improved kidney and liver function to a limited extent, but did not ameliorate histological damage. No improvement in cardiac function was observed. Biodistribution analysis showed that macrophages homed and persisted in the injured kidneys and liver, but did not populate the heart. Our data suggest that the limited improvement observed in kidney and liver function could be mediated by M2 macrophages.

scholarly journals Perampanel Reduces Hyperthermia-Induced Seizures in Dravet Syndrome Mouse Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Shih-Yin Ho ◽  
Li Lin ◽  
I-Chun Chen ◽  
Che-Wen Tsai ◽  
Fang-Chia Chang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Model Potential ◽  
Temperature Tolerance ◽  
Epileptic Activity ◽  
Dravet Syndrome ◽  
Therapeutic Effects ◽  
Discharge Duration ◽  
Spontaneous Recurrent Seizures

Treatment options for Dravet syndrome are limited. The aim of this study was to evaluate the antiepileptic effect of the AMPA receptor antagonist perampanel (PER) on a mouse model of Dravet syndrome (Scn1aE1099X/+). We report here that the PER (2 mg/kg) treatment inhibited the spontaneous recurrent seizures and attenuated epileptic activity in Scn1aE1099X/+ mice. In the hyperthermia-induced seizure experiment, PER clearly increased temperature tolerance and significantly ameliorated seizure frequency and discharge duration. PER also demonstrated antiepileptic effects in a cross-over study and a synergistic effect for attenuating heat-induced seizure when given in combination with stiripentol or valproic acid. The results showed that PER effectively decreased the occurrence of spontaneous recurrent seizures and showed significant therapeutic potential for hyperthermia-induced seizures with regard to both susceptibility and severity in a Dravet syndrome mouse model. Potential therapeutic effects of PER for treatment of Dravet syndrome were demonstrated.

scholarly journals Reducing tau ameliorates behavioural and transcriptional deficits in a novel model of Alzheimer’s disease

2018 ◽  
Author(s):  
Eleanor K Pickett ◽  
Abigail G Herrmann ◽  
Jamie McQueen ◽  
Kimberly Abt ◽  
Owen Dando ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Synaptic Function ◽  
List Type ◽  
Wild Type ◽  
Disease Phenotypes ◽  
Model Of Alzheimer’S Disease ◽  
Novel Model ◽  
Behavioural Deficits

SummaryOne of the key knowledge gaps blocking development of effective therapeutics for Alzheimer’s disease (AD) is the lack of understanding of how amyloid beta (Aβ) and tau cooperate in causing disease phenotypes. Within a mouse tau deficient background, we probed the molecular, cellular and behavioural disruption triggered by wild-type human tau’s influence on human Aβ-induced pathology. We find that Aβ and tau work cooperatively to cause a hyperactivity phenotype and to cause downregulation of gene transcription including many involved in synaptic function. In both our mouse model and in human post-mortem tissue, we observe accumulation of pathological tau in synapses, supporting the potential importance of synaptic tau. Importantly, tau depletion in the mice, initiated after behavioural deficits emerge, was found to correct behavioural deficits, reduce synaptic tau levels, and substantially reverse transcriptional perturbations, suggesting that lowering tau levels, particularly at the synapse, may be beneficial in AD.Highlights- Expression of human familial Alzheimer’s associated mutant amyloid precursor protein and presenillin 1 with wild-type human tau in the absence of endogenous tau in a novel MAPT-AD mouse model results in behavioural deficits and downregulation of genes involved in synaptic function.- Tau is present in pre and postsynaptic terminals in MAPT-AD mice and human AD brain. In mice, lowering synaptic tau levels was associated with improved cognition and recovered gene expression.- These data suggest that Aβ and tau act cooperatively in impairing synaptic function and that lowering tau at synapses could be a beneficial therapeutic approach in AD.

scholarly journals ShenLing BaiZhu San alleviates Ulcerative Colitis in Rats by Regulating Gut Microbiota

2020 ◽  
Author(s):  
Daxing Gu ◽  
Shanshan Zhou ◽  
Lili Yao ◽  
Ying Tan ◽  
Xingzi Chi ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Gut Microbiota ◽  
Relative Abundance ◽  
Rat Model ◽  
High Throughput Sequencing ◽  
Intestinal Barrier Function ◽  
Enzyme Linked Immunosorbent Assay ◽  
Trinitrobenzene Sulfonic Acid ◽  
Rrna Gene ◽  
Therapeutic Effects

Abstract Background: Recent studies have suggested that Shenling Baizhu San (SLBZS), an complementary and alternative medical therapy for ulcerative colitis (UC), alleviate clinic symptoms by the improvement of biochemical criteria and restoration of the intestinal barrier function. SLBZS as a famous Chinese herbal formula has been reportedly used to treat UC, of which mechanism is unknown. This study investigated the therapeutic effects of SLBZS on restoring the gut microbiota in a UC rat model. Methods: We proposed a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced UC rat model to monitor the structural modulation of the gut microbiota. The test period was 10 days (observation for two days after modeling, treatment for 8 days by SLBZS). In this study, the level of inflammatory cytokines and activity of antioxidant enzymes in serum were ascertained by enzyme-linked immunosorbent assay (ELISA) and histological changes of colon were observed. Feces were collected for high-throughput sequencing of 16S rRNA gene. Results: SLBZS partly reduced the diversity of the gut microbiota, while the abundance of that is increased. Furthermore, at the genus level, the relative abundance of short chain fatty acids (SCFA) producing bacteria including Prevotella and Oscillospira increased, while the relative abundance of harmful bacteria including Desulfovibrio, and Bilophila decreased. Additionally, SLBZS could improve the lesions of colon and significantly reduce the expression of Interleukin-6 (IL-6) and Myeloperoxidase (MPO) and increase the activities of Superoxide dismutase (SOD) and Catalase (CAT) in rats serum. Conclusions: These results demonstrate that SLBZS may treat UC effectively by inhibiting inflammation, enhancing antioxidant capacity and regulating gut microbiota.

scholarly journals Modulation of Gut Microbiota by Lonicera caerulea L. Berry Polyphenols in a Mouse Model of Fatty Liver Induced by High Fat Diet

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3213 ◽  
Author(s):  
Shusong Wu ◽  
Ruizhi Hu ◽  
Hironobu Nakano ◽  
Keyu Chen ◽  
Ming Liu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Gut Microbiota ◽  
Fatty Liver ◽  
Relative Abundance ◽  
High Fat Diet ◽  
Rrna Gene ◽  
Protective Effects ◽  
High Fat ◽  
Lonicera Caerulea ◽  
Alcoholic Fatty Liver

Polyphenols from the Lonicera caerulea L. berry have shown protective effects on experimental non-alcoholic fatty liver disease (NAFLD) in our previous studies. As endotoxins from gut bacteria are considered to be the major trigger of inflammation in NAFLD, this study aims to clarify the regulatory effects of L. caerulea L. berry polyphenols (LCBP) on gut microbiota in a high fat diet (HFD)-induced mouse model. C57BL/6N mice were fed with a normal diet, HFD, or HFD containing 0.5–1% of LCBP for 45 days. The results revealed that supplementation with LCBP decreased significantly the levels of IL-2, IL-6, MCP-1, and TNF-α in serum, as well as endotoxin levels in both serum and liver in HFD-fed mice. Fecal microbiota characterization by high throughput 16S rRNA gene sequencing revealed that a HFD increased the Firmicutes/Bacteroidetes ratio, and LCBP reduced this ratio by increasing the relative abundance of Bacteroides, Parabacteroides, and another two undefined bacterial genera belonging to the order of Bacteroidales and family of Rikenellaceae, and also by decreasing the relative abundance of six bacterial genera belonging to the phylum Firmicutes, including Staphylococcus, Lactobacillus, Ruminococcus, and Oscillospira. These data demonstrated that LCBP potentially attenuated inflammation in NAFLD through modulation of gut microbiota, especially the ratio of Firmicutes to Bacteroidetes.

scholarly journals Berberine Blocks the Relapse of Clostridium difficile Infection in C57BL/6 Mice after Standard Vancomycin Treatment

2015 ◽  
Vol 59 (7) ◽  
pp. 3726-3735 ◽  
Author(s):  
Zhi Lv ◽  
Guoli Peng ◽  
Weihua Liu ◽  
Hufeng Xu ◽  
JianRong Su
Keyword(s):  
Clostridium Difficile ◽  
Mouse Model ◽  
Gut Microbiota ◽  
Inflammatory Responses ◽  
Relative Weight ◽  
16S Rrna Genes ◽  
Rrna Genes ◽  
Therapeutic Effects ◽  
Content Type ◽  
Vancomycin Treatment

ABSTRACTVancomycin is a preferred antibiotic for treatingClostridium difficileinfection (CDI) and has been associated with a rate of recurrence of CDI of as high as 20% in treated patients. Recent studies have suggested that berberine, an alternative medical therapy for gastroenteritis and diarrhea, exhibits several beneficial effects, including induction of anti-inflammatory responses and restoration of the intestinal barrier function. This study investigated the therapeutic effects of berberine on preventing CDI relapse and restoring the gut microbiota in a mouse model. Berberine was administered through gavage to C57BL/6 mice with established CDI-induced intestinal injury and colitis. The disease activity index (DAI), mean relative weight, histopathology scores, and levels of toxins A and B in fecal samples were measured. An Illumina sequencing-based analysis of 16S rRNA genes was used to determine the overall structural change in the microbiota in the mouse ileocecum. Berberine administration significantly promoted the restoration of the intestinal microbiota by inhibiting the expansion of members of the familyEnterobacteriaceaeand counteracting the side effects of vancomycin treatment. Therapy consisting of vancomycin and berberine combined prevented weight loss, improved the DAI and the histopathology scores, and effectively decreased the mortality rate. Berberine prevented CDIs from relapsing and significantly improved survival in the mouse model of CDI. Our data indicate that a combination of berberine and vancomycin is more effective than vancomycin alone for treating CDI. One of the possible mechanisms by which berberine prevents a CDI relapse is through modulation of the gut microbiota. Although this conclusion was generated in the case of the mouse model, use of the combination of vancomycin and berberine and represent a novel therapeutic approach targeting CDI.

scholarly journals The potential therapeutic effects of the gut microbiome manipulation by synbiotic containing-Lactobacillus plantarum on neuropsychological performance of diabetic rats

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Mohammad Morshedi ◽  
Maryam Saghafi-Asl ◽  
Elaheh-Sadat Hosseinifard
Keyword(s):  
Oxidative Stress ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Therapeutic Potential ◽  
Diabetic Rats ◽  
Therapeutic Effects ◽  
Microbial Composition ◽  
Stress Markers ◽  
Oxidative Stress Status ◽  
The Impact

Abstract Background The manipulation of gut microbiota as a target has been suggested to reduce the risks for a number of diseases such as type 2 diabetes mellitus (T2DM). Conversely, T2DM is associated with complications such as gut and brain disorders. Furthermore, the impact of probiotics and prebiotics to improve T2DM complications are reported. Thus, the present study seeks to investigate the therapeutic and neuropsychological effects of L. plantarum and inulin in diabetic rats. Methods Throughout the investigation, L. plantarum, inulin or their combination (synbiotic) was administered to diabetic rats. in the end, fecal samples were collected to evaluate the gut microbial composition. Then behavioral tests were conducted. Subsequently, the obtainment of the prefrontal cortex (PFC) and hippocampal samples. Results Our data demonstrated that administration of L. plantarum and inulin could improve gut dysbiosis and oxidative stress status. In addition, it could ameliorate serotonin and BDNF/TrkB signaling pathway. Notably, a strong correlation between the gut microbiota changes and cognition responses was observed. Interestingly, synbiotics intake exploited a rather powerful effect on oxidative stress markers. Conclusion The findings confirm that there is a beneficial therapeutic potential of supplements, especially symbiotic. Moreover, neuropsychological improvement associated with balanced gut microbiome.

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