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Molecular Neurodegeneration Jul 2023Braak's hypothesis states that sporadic Parkinson's disease (PD) follows a specific progression of pathology from the peripheral to the central nervous system, and this...
BACKGROUND
Braak's hypothesis states that sporadic Parkinson's disease (PD) follows a specific progression of pathology from the peripheral to the central nervous system, and this progression can be monitored by detecting the accumulation of alpha-Synuclein (α-Syn) protein. Consequently, there is growing interest in understanding how the gut (commensal) microbiome can regulate α-Syn accumulation, as this could potentially lead to PD.
METHODS
We used 16S rRNA and shotgun sequencing to characterise microbial diversity. H-NMR was employed to understand the metabolite production and intestinal inflammation estimated using ELISA and RNA-sequencing from feces and the intestinal epithelial layer respectively. The Na channel current and gut permeability were measured using an Ussing chamber. Immunohistochemistry and immunofluorescence imaging were applied to detect the α-Syn protein. LC-MS/MS was used for characterization of proteins from metabolite treated neuronal cells. Finally, Metascape and Ingenuity Pathway Analysis (IPA) bioinformatics tools were used for identification of dysregulated pathways.
RESULTS
We studied a transgenic (TG) rat model overexpressing the human SNCA gene and found that a progressive gut microbial composition alteration characterized by the reduction of Firmicutes to Bacteroidetes ratio could be detected in the young TG rats. Interestingly, this ratio then increased with ageing. The dynamics of Lactobacillus and Alistipes were monitored and reduced Lactobacillus and increased Alistipes abundance was discerned in ageing TG rats. Additionally, the SNCA gene overexpression resulted in gut α-Syn protein expression and increased with advanced age. Further, older TG animals had increased intestinal inflammation, decreased Na current and a robust alteration in metabolite production characterized by the increase of succinate levels in feces and serum. Manipulation of the gut bacteria by short-term antibiotic cocktail treatment revealed a complete loss of short-chain fatty acids and a reduction in succinate levels. Although antibiotic cocktail treatment did not change α-Syn expression in the enteric nervous system of the colon, however, reduced α-Syn expression was detected in the olfactory bulbs (forebrain) of the TG rats.
CONCLUSION
Our data emphasize that the gut microbiome dysbiosis synchronous with ageing leads to a specific alteration of gut metabolites and can be modulated by antibiotics which may affect PD pathology.
Topics: Humans; Rats; Animals; Parkinson Disease; alpha-Synuclein; Chromatography, Liquid; RNA, Ribosomal, 16S; Tandem Mass Spectrometry; Aging; Microbiota; Animals, Genetically Modified; Inflammation; Anti-Bacterial Agents
PubMed: 37403161
DOI: 10.1186/s13024-023-00628-1 -
American Journal of Transplantation :... Oct 2023Obesity is associated with dysbiosis and a state of chronic inflammation that contributes to the pathogenesis of metabolic diseases, including diabetes. We have...
Obesity is associated with dysbiosis and a state of chronic inflammation that contributes to the pathogenesis of metabolic diseases, including diabetes. We have previously shown that obese mice develop glucose intolerance, increased alloreactivity, and accelerated transplant rejection. In the present study, we investigated the influence of the microbiota on diet-induced obesity (DIO)-associated transplant rejection and hyperglycemia. Antibiotic treatment prolonged graft survival and reduced fasting glycemia in high-fat diet (HFD)-fed specific-pathogen-free (SPF) mice, supporting a role for the microbiota in promoting accelerated graft rejection and hyperglycemia induced by DIO. Further supporting a microbiota-dependent effect, fecal microbiota transfer from DIO SPF mice into germ-free mice also accelerated graft rejection when compared with lean mice-fecal microbiota transfer. Notably, HFD could be also detrimental to the graft independently from microbiota, obesity, and hyperglycemia. Thus, whereas HFD-associated hyperglycemia was exclusively microbiota-dependent, HFD affected transplant outcomes via both microbiota-dependent and -independent mechanisms. Importantly, hyperglycemia in DIO SPF mice could be reduced by the addition of the gut commensal Alistipes onderdonkii, which alleviated both HFD-induced inflammation and glucose intolerance. Thus, microbial dysbiosis can be manipulated via antibiotics or select probiotics to counter some of the pathogenic effects of obesity in transplantation.
Topics: Animals; Mice; Graft Rejection; Glucose Intolerance; Dysbiosis; Gastrointestinal Microbiome; Obesity; Diet, High-Fat; Hyperglycemia; Inflammation; Mice, Inbred C57BL
PubMed: 37356668
DOI: 10.1016/j.ajt.2023.06.011 -
The Science of the Total Environment Dec 2023Iron plays a pivotal role in various physiological processes, including intestinal inflammation, ferroptosis, and the modulation of the gut microbiome. However, the way...
BACKGROUND
Iron plays a pivotal role in various physiological processes, including intestinal inflammation, ferroptosis, and the modulation of the gut microbiome. However, the way these factors interact with each other is unclear.
METHODS
Mice models were fed with low, normal and high iron diets to assess their impacts on colitis, ferroptosis and gut microbiota. Untargeted fecal metabolomics analysis, 16S rRNA sequencing, histopathology analysis, real-time quantitative PCR and western blot were performed to analyze the differences in the intestinal inflammatory response and understanding its regulatory mechanisms between low, normal and high iron groups.
RESULTS
The iron overload changed the serum iron, colon iron and fecal iron. In addition, the iron overload induced the colitis, induced the ferroptosis and altered the microbiome composition in the fecal of mice. By using untargeted fecal metabolomics analysis to screen of metabolites in the fecal, we found that different metabolomics profiles in the fecal samples between iron deficiency, normal iron and iron overload groups. The correlation analysis showed that both of iron deficiency and overload were closely related to Dubosiella. The relationship between microbial communities (e.g., Akkermansia, Alistipes, and Dubosiella) and colitis-related parameters was highly significant. Additionally, Alistipes and Bacteroides microbial communities displayed a close association with ferroptosis-related parameters. Iron overload reduced the concentration of metabolites, which exert the anti-inflammatory effects (e.g., (+)-.alpha.-tocopherol) in mice. The nucleotide metabolism, enzyme metabolism and metabolic diseases were decreased and the lipid metabolism was increased in iron deficiency and iron overload groups compared with normal iron group.
CONCLUSION
Iron overload exacerbated colitis in mice by modulating ferroptosis and perturbing the gut microbiota. Iron overload-induced ferroptosis was associated with NRF2/GPX-4 signaling pathway. Specific microbial taxa and their associated metabolites were closely intertwined with both colitis and ferroptosis markers.
Topics: Animals; Mice; Gastrointestinal Microbiome; Ferroptosis; RNA, Ribosomal, 16S; Iron Overload; Colitis; Iron; Bacteroidetes; Firmicutes; Iron Deficiencies; Mice, Inbred C57BL
PubMed: 37717771
DOI: 10.1016/j.scitotenv.2023.167043 -
Food & Function Oct 2023Ulcerative colitis (UC) is a common inflammatory bowel disease, whose incidence is on the rise worldwide. The drugs commonly used for UC are often associated with a...
Ulcerative colitis (UC) is a common inflammatory bowel disease, whose incidence is on the rise worldwide. The drugs commonly used for UC are often associated with a number of side effects. Therefore, the development of effective, food-borne substances for UC is in line with the current needs. Egg yolk phosphatidylcholine (EYPC) is one of the abundant lipids in egg yolk and possesses various biological activities. However, its protective effect against UC has not been clarified. In this study, the anti-UC activity of EYPC was investigated using a dextran sodium sulfate (DSS)-induced colitis model of BALB/c mice. The results showed that EYPC supplementation inhibited DSS-induced colon shortening, the spleen index and disease activity index increase and intestinal structural damage. EYPC could down-regulate the levels of TNF-α, IL-1β, IL-6 and MPO in the colon and restore the number of goblet cells and the level of tight junction (TJ) proteins. Besides, EYPC modulated the composition of the gut microbiota, lowered the relative abundance of the pathogenic bacterium and upregulated the abundance of the beneficial bacteria and . These results evidenced that EYPC could attenuate DSS-induced colitis in mice and had the potential to prevent and treat UC.
Topics: Animals; Mice; Lecithins; Mice, Inbred BALB C; Egg Yolk; Colitis; Colitis, Ulcerative; Colon; Dextran Sulfate; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 37781872
DOI: 10.1039/d3fo02885b -
Renal Failure Dec 2023Vascular calcification (VC) is an independent risk factor for cardiovascular mortality in end-stage renal disease (ESRD) patients. The pathogenesis of VC is complicated...
INTRODUCTION
Vascular calcification (VC) is an independent risk factor for cardiovascular mortality in end-stage renal disease (ESRD) patients. The pathogenesis of VC is complicated and unclear. Uremic toxins produced by gut microbiota can promote VC. This study aims to identify the differences in gut microbiota between the different VC groups and the main bacteria associated with VC in hemodialysis (HD) patients in an attempt to open up new preventive and therapeutic approaches and define the probable mechanism for VC in HD patients in the future.
METHODS
A total of 73 maintenance HD patients were enrolled in this cross-sectional study. According to the abdominal aortic calcification (AAC) scores, the participants were divided into the high AAC score group and the low AAC score group. High-throughput sequencing of the gut microbiota was performed and the results were evaluated by alpha diversity, beta diversity, species correlation, and model predictive analyses.
RESULTS
The prevalence of VC was 54.79% (40/73) in the study. The majority of phyla in the two groups were the same, including , , , and . The microbial diversity in the high AAC score group had a decreasing trend ( = 0.050), and the species abundance was significantly lower ( = 0.044) than that in the low AAC score group. The HD patients with high AAC scores showed an increased abundance of and decreased abundances of and at the phylum level; increased abundances of and and decreased abundances of and at the genus level (0.05). and were positively correlated with VC, and , and were negatively correlated with VC. had the greatest influence on VC in HD patients, followed by and
CONCLUSIONS
Our results provide clinical evidence that there was a difference in gut microbiota between the different VC groups in HD patients. a lipopolysaccharide (LPS)-producing bacterium, was positively correlated with VC and had the greatest influence on VC. a short-chain fatty acid (SCFA)-producing bacterium, was negatively correlated with VC and had the second strongest influence on VC in HD patients. The underlying mechanism is worth studying. These findings hint at a new therapeutic target.
Topics: Humans; Gastrointestinal Microbiome; Cross-Sectional Studies; Renal Dialysis; Kidney Failure, Chronic; Vascular Calcification; Bacteria
PubMed: 36632746
DOI: 10.1080/0886022X.2022.2148538 -
Clinical Immunology (Orlando, Fla.) Oct 2023The clinical relevance and pathogenic role of gut microbiome in both myositis and its associated interstitial lung disease (ILD) are still unclear. The purpose of this...
PURPOSE
The clinical relevance and pathogenic role of gut microbiome in both myositis and its associated interstitial lung disease (ILD) are still unclear. The purpose of this study was to investigate the role of gut microbiome in myositis through comprehensive metagenomic-wide association studies (MWAS).
METHODS
We conducted MWAS of the myositis gut microbiome in a Chinese cohort by using whole-genome shotgun sequencing of high depth, including 30 myositis patients and 31 healthy controls (HC). Among the myositis patients, 11 developed rapidly progressive interstitial lung disease (RP-ILD) and 10 had chronic ILD (C-ILD).
RESULTS
Analysis for overall distribution level of the bacteria showed Alistipes onderdonkii, Parabacteroides distasonis and Escherichia coli were upregulated, Lachnospiraceae bacterium GAM79, Roseburia intestinalis, and Akkermansia muciniphila were downregulated in patients with myositis compared to HC. Bacteroides thetaiotaomicron, Parabacteroides distasonis and Escherichia coli were upregulated, Bacteroides A1C1 and Bacteroides xylanisolvens were downregulated in RP-ILD cases compared with C-ILD cases. A variety of biological pathways related to metabolism were enriched in the myositis and HC, RP-ILD and C-ILD comparison. And in the analyses for microbial contribution in metagenomic biological pathways, we have found that E. coli played an important role in the pathway expression in both myositis group and myositis-associated RP-ILD group. Anti-PL-12 antibody, anti-Ro-52 antibody, and anti-EJ antibody were found to have positive correlation with bacterial diversity (Shannon-wiener diversity index and Chao1, richness estimator) between myositis group and control groups. The combination of E. coli and R. intestinalis could distinguish myositis group from HC effectively. R. intestinalis can also be applied in the distinguishment of RP-ILD group vs. C-ILD group in myositis patients.
CONCLUSION
Our MWAS study first revealed the link between gut microbiome and pathgenesis of myositis, which may help us understand the role of gut microbiome in the etiology of myositis and myositis-associated RP-ILD.
Topics: Humans; Gastrointestinal Microbiome; Metagenome; Escherichia coli; Myositis; Lung Diseases, Interstitial; Bacteria; Autoantibodies; Retrospective Studies
PubMed: 37595937
DOI: 10.1016/j.clim.2023.109738 -
Chemico-biological Interactions Jul 2023Methamphetamine (METH) is a psychotropic drug known to cause cardiotoxicity. The gut-heart axis is emerging as an important pathway linking gut microbiota to...
Methamphetamine (METH) is a psychotropic drug known to cause cardiotoxicity. The gut-heart axis is emerging as an important pathway linking gut microbiota to cardiovascular disease, but the precise association between METH-induced cardiotoxicity and gut microbiota has yet to be elucidated. In this study, we established an escalating dose-multiple METH administration model in male BALB/c mice, examined cardiac injury and gut microbiota, and investigated the contribution of gut microbiota to cardiotoxicity induced by METH. Additionally, we treated mice with antibiotics and fecal microbiota transplantation (FMT) to assess the impact of gut microbiota on cardiotoxicity. Our results showed that METH exposure altered the p53 and PI3K/Akt signaling pathways and modulated the apoptosis pathway in heart tissue, accompanied by elevated levels of Bax/BCL-2 expression and cleaved caspase-3 proteins. METH exposure increased the diversity and richness of gut microbiota, and significantly changed the microbial community composition, accompanied by elevated abundance of Lactobacillus, Bifidobacterium, and decreased abundance of Bacteroides, norank_f_Muribaculaceae and Alistipes. Eliminating gut microbiota by antibiotics treatment alleviated METH-induced cardiotoxicity, while FMT treatment transferred similar cardiac injury manifestations from METH-exposed mice to healthy recipient mice. Our study unveils the crucial involvement of gut microbiota in the development of cardiotoxicity induced by METH and provides potential strategies for treating cardiac complications caused by METH.
Topics: Male; Mice; Animals; Methamphetamine; Gastrointestinal Microbiome; Cardiotoxicity; Phosphatidylinositol 3-Kinases; Anti-Bacterial Agents
PubMed: 37116852
DOI: 10.1016/j.cbi.2023.110512 -
Microorganisms Jul 2023Gestational diabetes, affecting about 10% of pregnancies, is characterized by impaired glucose regulation and can lead to complications for health of pregnant women and... (Review)
Review
Gestational diabetes, affecting about 10% of pregnancies, is characterized by impaired glucose regulation and can lead to complications for health of pregnant women and their offspring. The microbiota, the resident microbes within the body, have been linked to the development of several metabolic conditions. This systematic review with meta-analysis aims to summarize the evidence on the differences in microbiota composition in pregnant women with gestational diabetes and their offspring compared to healthy pregnancies. A thorough search was conducted in the PubMed, Scopus, and Web of Science databases, and data from 21 studies were analyzed utilizing 41 meta-analyses. In the gut microbiota, Bifidobacterium and Alistipes were found to be more abundant in healthy pregnancies, while Roseburia appears to be more abundant in gestational diabetes. The heterogeneity among study findings regarding the microbiota in the meconium is considerable. The placental microbiota exhibited almost no heterogeneity, with an increased abundance of Firmicutes in the gestational diabetes group and a higher abundance of Proteobacteria in the control. The role of the microbiota in gestational diabetes is reinforced by these findings, which additionally point to the potential of microbiome-targeted therapies. To completely comprehend the interactions between gestational diabetes and the microbiome, standardizing methodologies and further research is necessary.
PubMed: 37512921
DOI: 10.3390/microorganisms11071749 -
Journal of Agricultural and Food... Dec 2023Ginsenoside Rg1 (G-Rg1) has various pharmacological properties including antiobesity, immunomodulatory, and anti-inflammatory effects. This study aimed to explore the...
Ginsenoside Rg1 (G-Rg1) has various pharmacological properties including antiobesity, immunomodulatory, and anti-inflammatory effects. This study aimed to explore the therapeutic effects and underlying mechanisms of G-Rg1 on colitis complicated by obesity. The results indicate that G-Rg1 effectively alleviates colitis in obese mice and improves serum lipid levels and liver function. Importantly, G-Rg1 improved the composition of gut microbiota in obese mice with colitis, with increases in alpha diversity indexes Sobs, Ace, and Chao, a significant down-regulation of the relative abundance of , and a significant up-regulation of , , , , and . Meanwhile, G-Rg1 improved lipid metabolism in the colonic contents of obese mice with colitis. Additionally, G-Rg1 significantly reduced the percentages of helper T (Th)1, Th17, central memory T (TCM), and effector memory T (TEM) cells in obese mice with colitis while significantly increasing Naïve T and Th2 cells. In conclusion, G-Rg1 could be a promising therapeutic option for alleviating obesity complicated by colitis through regulation of the gut microbiota and lipid metabolism as well as Th1/Th2/Th17 cell differentiation.
Topics: Mice; Animals; Colitis, Ulcerative; Mice, Obese; Lipid Metabolism; Th17 Cells; Gastrointestinal Microbiome; Colitis; Obesity; Mice, Inbred C57BL; Disease Models, Animal; Dextran Sulfate; Colon
PubMed: 38064669
DOI: 10.1021/acs.jafc.3c04811 -
The Science of the Total Environment Dec 2023The past decade has been characterized by increased awareness and de-stigmatization of mental health issues, in particular the most common neuropsychiatric disorders...
The past decade has been characterized by increased awareness and de-stigmatization of mental health issues, in particular the most common neuropsychiatric disorders depression and anxiety. Further, with growing understanding of neurodevelopmental disorders such as attention deficit and hyperactivity disorder and autism spectrum disorder, the number of diagnosed patients has increased. The pathogenesis of these behavioral disorders is multifactorial and early-life exposure to environmental chemicals has been proposed to be a relevant risk factor that might mediate these effects by disturbances on the gut-brain-axis. However, for glyphosate, the most widely used pesticide worldwide, there are only limited and inconsistent findings that link chronic low-dose exposure in particular during early life to neurobehavioral disorders. Here, we explored the impact of maternal oral glyphosate exposure (0.5 and 50 mg/kg body weight/day) during pregnancy and the lactational period on offspring's behavior, brain gene expression and gut microbiota using a cross-generational mouse model. Behavioral analyses revealed a depression- and anxiety-like behavior as well as social deficits most notably in adult female offspring of glyphosate-exposed dams. Furthermore, the expression of tryptophan hydroxylase 2, an enzyme discussed to be linked to behavioral problems, was reduced in the hippocampus of female offspring and correlated to a glyphosate-induced DNA hypermethylation of the gene. Moreover, maternal glyphosate exposure significantly altered the gut microbiota in the female offspring including a decreased abundance of Akkermansia and increased abundance of Alistipes and Blautia, bacteria involved in tryptophan metabolism and associated with depression- and anxiety-like disorders. Our results suggest that glyphosate might influence the gut-brain axis crosstalk following in-utero and lactational exposure. This study underlines the importance of understanding the impact of exposure to pesticides on the gut-brain axis and further emphasizes the need for microbiome analyses to be compulsorily included in health risk assessments of pesticides.
Topics: Humans; Adult; Pregnancy; Animals; Mice; Female; Maternal Exposure; Depression; Brain-Gut Axis; Autism Spectrum Disorder; Anxiety; Pesticides; Glyphosate
PubMed: 37709081
DOI: 10.1016/j.scitotenv.2023.167034