Enriched environmental conditions modify the gut microbiome composition and fecal markers of inflammation in Parkinson’s disease
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ABSTRACT:
PROVIDER: PRJNA564818 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10095909.fastq.gz | Fastqsanger.gz | |||
| SRR10095910.fastq.gz | Fastqsanger.gz | |||
| SRR10095911.fastq.gz | Fastqsanger.gz | |||
| SRR10095912.fastq.gz | Fastqsanger.gz | |||
| SRR10095913.fastq.gz | Fastqsanger.gz |
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Project description:We used a transgenic mouse model overexpressing the complete human SNCA genes modeling familial and sporadic forms of Parkinson’s disease to study whether environmental conditions such as standard versus enriched environment changes the gut microbiome and influences disease progression.
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Project description:Recent findings suggest an implication of the gut microbiome in Parkinson's disease (PD) patients. PD onset and progression has also been linked with various environmental factors such as physical activity, exposure to pesticides, head injury, nicotine, and dietary factors. In this study, we used a mouse model, overexpressing the complete human SNCA gene (SNCA-TG mice) modeling familial and sporadic forms of PD to study whether environmental conditions such as standard vs. enriched environment changes the gut microbiome and influences disease progression. We performed 16S rRNA DNA sequencing on fecal samples for microbiome analysis and studied fecal inflammatory calprotectin from the colon of control and SNCA-TG mice kept under standard environment (SE) and enriched environment (EE) conditions. The overall composition of the gut microbiota was not changed in SNCA-TG mice compared with WT in EE with respect to SE. However, individual gut bacteria at genus level such as Lactobacillus sp. was a significant changed in the SNCA-TG mice. EE significantly reduced colon fecal inflammatory calprotectin protein in WT and SNCA-TG EE compared to SE. Moreover, EE reduces the pro-inflammatory cytokines in the feces and inflammation inducing genes in the colon. Our data suggest that an enriched social environment has a positive effect on the induction of SNCA mediated inflammation in the intestine and by modulating anti-inflammatory gut bacteria.
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Project description:Environmental enteropathy (EE), a subclinical intestinal disorder characterized by mucosal inflammation, reduced barrier integrity, and malabsorption, appears to be associated with increased risk of stunting in children in low- and middle-income countries. Fecal biomarkers indicative of EE (neopterin [NEO], myeloperoxidase [MPO], and alpha-1-antitrypsin [AAT]) have been negatively associated with 6-month linear growth. Associations between fecal markers (NEO, MPO, and AAT) and short-term linear growth were examined in a birth cohort of 246 children in Bangladesh. Marker concentrations were categorized in stool samples based on their distribution (< first quartile, interquartile range, > third quartile), and a 10-point composite EE score was calculated. Piecewise linear mixed-effects models were used to examine the association between markers measured quarterly (in months 3-21, 3-9, and 12-21) and 3-month change in length-for-age z-score (?LAZ). Children with high MPO levels at quarterly time points lost significantly more LAZ per 3-month period during the second year of life than those with low MPO (?LAZ = -0.100; 95% confidence interval = -0.167 to -0.032). AAT and NEO were not associated with growth; however, composite EE score was negatively associated with subsequent 3-month growth. In this cohort of children from an urban setting in Bangladesh, elevated MPO levels, but not NEO or AAT levels, were associated with decreases in short-term linear growth during the second year of life, supporting previous data suggesting the relevance of MPO as a marker of EE.
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Project description:The full complement of molecular pathways contributing to Parkinson’s disease (PD) pathogenesis remains unknown. Here, to address this issue, we began by using a high-resolution variant of functional magnetic resonance imaging (fMRI) to pinpoint brainstem regions differentially affected by, and resistant to, the disease. Then, relying on the imaging information as a guide, we profiled gene expression levels of postmortem brain samples and used a factorial statistical model to identify a disease related decrease in the expression of the polyamine enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1). Next, a series of studies were performed to confirm the pathogenic relevance of this finding. First, to test for a causal link between polyamines and α-synuclein toxicity, we investigated a yeast model expressing α-synuclein. Polyamines were found to enhance the toxicity of α-synuclein, and an unbiased genome-wide screen for modifiers of α-synuclein toxicity identified Tpo4, a member of a family of proteins responsible for polyamine transport. Second, to test for a causal link between SAT1 activity and PD histopathology we investigated a mouse model expressing α-synuclein. DENSPM (N1, N11-diethylnorspermine), a polyamine analog that increases SAT1 activity, was found to reduce PD histopathology, while Berenil (diminazene aceturate), a pharmacological agent that reduces SAT1 activity, worsened the histopathology. Third, we genotyped PD patients and controls and isolated a rare but novel variant in the SAT1 gene, although the functional significance of this genetic variant was not identified. Taken together, the results suggest that the polyamine pathway contributes to PD pathogenesis. Imaging-guided microarray In principle, gene expression profiling techniques like microarray are well suited to identify molecular pathways contributing to the pathogenesis of complex diseases. In practice, however, microarray applied to diseases of the brain present a number of analytic challenges. By identifying regions within the same brain structure that are differentially targeted by and resistant to a disease, imaging-guided microarray is an approach designed to address these limitations. Specifically, guided by the spatial information generated from high resolution functional imaging, a 2x2 factorial analysis-of-variance can be designed, including both within and between group factors, and this “double subtraction” model is effective in improving signal-to-noise in a microarray experiment. Relying on imaging findings, we harvested the DMNV from 6 postmortem brains with evidence of PD and from 5 control brains. The postmortem PD cases were evaluated for pathological changes (Lewy body-containing neurons and Lewy neurites evidenced with antibodies directed against α-synuclein aggregates) that matched the pattern proposed by Braak. We relied on the imaging results to identify a neighboring medullary region relatively unaffected by the disease to be used as a within-brain control. We decided on the inferior olivary nucleus (ION), because it is histologically identifiable, and harvested the ION from each of the 6 PD cases and 5 controls. Microarray techniques were used to generate gene expression profiles for each of the 22 tissue samples. A repeated-measures 2x2 factorial ANOVA model constructed for the imaging study was applied to the expression dataset, in which expression levels from two regions of the medulla (DMNV vs. ION) were included as the first within group factor, diagnosis (PD vs. controls) was the between group factor, and age and sex were included as covariates. Based on current literature, one of the top hits (SAT1) was investigated further to determine if it played a role in PD pathogenesis.
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Project description:Since microbiota may influence the physiology of its host including body weight increase, growth rate or feed intake, in this study we determined the microbiota composition in high or low residual feed intake (HRFI and LRFI) pig lines, of different age and/or subjected to sanitary stress by sequencing the V3/V4 variable region of 16S rRNA genes. Allisonella, Megasphaera, Mitsuokella, Acidaminococcus (all belonging to Firmicutes/class Negativicutes), Lactobacillus, Faecalibacterium, Catenibacterium, Butyrivibrio, Erysipelotrichaceae, Holdemania, Olsenella and Collinsella were more abundant in HRFI pigs. On the other hand, 26 genera including Bacteroides, Clostridium sensu stricto, Oscillibacter, Paludibacter, Elusimicrobium, Bilophila, Pyramidobacter and TM7 genera, and Clostridium XI and Clostridium XIVa clusters were more abundant in LRFI than HRFI pigs. Adaptation of microbiota to new diet after weaning was slower in LRFI than in HRFI pigs. Sanitary stress was of relatively minor influence on pig microbiota composition in both tested lines although abundance of Helicobacter increased in LRFI pigs subjected to stress. Selection for residual feed intake thus resulted in a selection of fecal microbiota of different composition. However, we cannot conclude whether residual feed intake was directly affected by different microbiota composition or whether the residual feed intake and microbiota composition are two independent consequences of yet unknown genetic traits differentially selected in the pigs of the two lines.
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Project description:Cell replacement is a long-standing and realistic goal for the treatment of Parkinson’s disease (PD). Cells for transplantation can be obtained from fetal brain tissue or from stem cells. However, after transplantation dopamine (DA) neurons are a minor component of grafts and it has remained difficult to determine the identity of other cell types. Here, we report analysis by single cell RNA sequencing (scRNA-seq) combined with comprehensive histological analyses to characterize intracerebral grafts from human embryonic stem cells (hESCs) and fetal tissue after functional maturation in a pre-clinical rat PD model. We show that neurons and astrocytes are major components in both fetal and stem cell-derived grafts. Additionally, we identify a cell type closely resembling a class of newly identified perivascular-like cells in stem cell-derived grafts. Thus, this study uncovers previously unknown cellular diversity in a clinically relevant cell replacement PD model.
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