Physiomimetic model of the human Gut-Liver axis for studies of inflammatory diseases
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE135428 | GEO | 2021/06/03
REPOSITORIES: GEO
Similar Datasets
Project description:Early life exposure to antibiotics alters the gut microbiome. These alterations lead to changes in metabolic homeostasis and an increase in host adiposity. We used microarrays to identify metabolic genes that may be up- or down-regulated secondary to antibiotic exposure. Low dose antibiotics have been widely used as growth promoters in the agricultural industry since the 1950’s, yet the mechanisms for this effect are unclear. Because antimicrobial agents of different classes and varying activity are effective across several vertebrate species, we hypothesized that such subtherapeutic administration alters the population structure of the gut microbiome as well as its metabolic capabilities. We generated a model of adiposity by giving subtherapeutic antibiotic therapy (STAT) to young mice and evaluated changes in the composition and capabilities of the gut microbiome. STAT administration increased adiposity in young mice and altered hormones related to metabolism. We observed substantial taxonomic changes in the microbiome, changes in copies of key genes involved in the metabolism of carbohydrates to short-chain fatty acids (SCFA), increases in colonic SCFA levels, and alterations in the regulation of hepatic metabolism of lipids and cholesterol. In this model, we demonstrate the alteration of early life murine metabolic homeostasis through antibiotic manipulation. C57BL6 mice were divided into low-dose penicillin or control groups. Given antibiotics via drinking water after weaning. Sacrificed and liver sections collected for RNA extraction.
2012-06-30 | E-GEOD-38880 | biostudies-arrayexpress
Project description:Recent evidence has demonstrated that the gut microbiome has marked effects on neuronal function and behavior. Disturbances to microbial populations within the gut have been linked to myriad models of neuropsychiatric disorders. However, the role of the microbiome in substance use disorders remains understudied. Here we show that male mice with their gut microbiome depleted by nonabsorbable antibiotics (Abx) exhibit decreased formation of morphine conditioned place preference across a range of doses (2.5-15 mg/kg), have decreased locomotor sensitization to morphine, and demonstrate marked changes in gene expression within the nucleus accumbens (NAc) in response to high-dose morphine (20 mg/kg × 7 days). Replacement of short-chain fatty acid (SCFA) metabolites, which are reduced by microbiome knockdown, reversed the behavioral and transcriptional effects of microbiome depletion. This identifies SCFA as the crucial mediators of microbiome-brain communication responsible for the effects on morphine reward caused by microbiome knockdown. These studies add important new behavioral, molecular, and mechanistic insight to the role of gut-brain signaling in substance use disorders
2023-05-18 | GSE232836 | GEO
Project description:Significant gut microbiota heterogeneity exists amongst UC patients though the clinical implications of this variance are unknown. European and South Asian UC patients exhibit distinct disease risk alleles, many of which regulate immune function and relate to variation in gut microbiota β-diversity. We hypothesized ethnically distinct UC patients exhibit discrete gut microbiotas with unique luminal metabolic programming that influence adaptive immune responses and relate to clinical status. Using parallel bacterial 16S rRNA and fungal ITS2 sequencing of fecal samples (UC n=30; healthy n=13), we corroborated previous observations of UC-associated depletion of bacterial diversity and demonstrated significant gastrointestinal expansion of Saccharomycetales as a novel UC characteristic. We identified four distinct microbial community states (MCS 1-4), confirmed their existence using microbiota data from an independent UC cohort, and show they co-associate with patient ethnicity and degree of disease severity. Each MCS was predicted to be uniquely enriched for specific amino acid, carbohydrate, and lipid metabolism pathways and exhibited significant luminal enrichment of metabolic products from these pathways. Using a novel in vitro human DC/T-cell assay we show that DC exposure to patient fecal water led to MCS -specific changes in T-cell populations, particularly the Th1:Th2 ratio, and that patients with the most severe disease exhibited the greatest Th2 skewing. Thus, based on ethnicity, microbiome composition, and associated metabolic dysfunction, UC patients may be stratified in a clinically and immunologically meaningful manner, providing a platform for the development of FMC-focused therapy. Fecal microbiome was assessed with Affymetrix PhyloChip arrays from patients with ulcerative colitis and healthy controls.
2016-07-25 | E-GEOD-78724 | biostudies-arrayexpress
Project description:Cocaine use disorder represents a public health crisis with no FDA-approved medications for its treatment. A growing body of research has detailed the important connections between the brain and the resident population of bacteria in the gut, the gut microbiome in psychiatric disease models. Acute depletion of gut bacteria results in enhanced reward in a mouse cocaine place preference model, and repletion of bacterially-derived short-chain fatty acid (SCFA) metabolites reverses this effect. However, the role of the gut microbiome and its metabolites in modulating cocaine-seeking behavior after prolonged abstinence is unknown. Given that relapse prevention is the most clinically challenging issue in treating substance use disorders, studies examining the effects of microbiome manipulations in relapse-relevant models are critical. Here, Sprague-Dawley rats received either untreated water or antibiotics to deplete the gut microbiome and its metabolites. Rats were trained to self-administer cocaine and subjected to either within-session threshold testing to evaluate motivation for cocaine or 21 days of abstinence followed by a cue-induced cocaine-seeking task to model relapse behavior. Microbiome depletion did not affect cocaine acquisition on an FR1 schedule. However, microbiome-depleted subjects exhibited significantly enhanced motivation for low dose cocaine on a within-session threshold task. Similarly, microbiome depletion increased cue-induced cocaine-seeking following prolonged abstinence. In the absence of a normal microbiome, repletion of bacterially-derived SCFA metabolites reversed the behavioral and transcriptional changes associated with microbiome depletion. These findings suggest that gut bacteria, via their metabolites, are key regulators of drug-seeking behaviors, positioning the microbiome as a potential translational research target.
2024-05-01 | GSE227980 | GEO
Project description:Alterations in the composition of the gut microbiome have an emerging role in brain function and behaviour. We have porposed that short chain fatty acids (SCFA) including propionate and butyrate which are present in the diet and are fermantation products of many gastrointestinal bacteria are contributing environmental factors in autism spectrum disorders (ASD). Here we used the microarray technology to compare global changes in gene expression profiles following exposure of PC12 cells to structurally related SCFA propionate and butyrate each in two different concentrations. Large number of affected genes, common for both SCFA were identified, including genetic networks and GO processes implicated in ASD. PC12 cells were exposed to propionate or butyrate. RNA was isolated from each experimental group (n=6, pooled samples) and subjected to genome-wide expression profiling using Affymetrix microarrays to reveal dose- and SCFA-specific changes in gene expression and specific molecular pathways or processes affected as compared to vehicle treated controls.
2014-06-02 | E-GEOD-56516 | biostudies-arrayexpress
Project description:Differences in male vs. female immune responses are well-documented and have significant clinical implications. While the immunomodulatory effects of sex hormones are well established, the contributions of sex chromosome complement (XX vs. XY) and gut microbiome diversity on immune sexual dimorphisms have only recently become appreciated. Here we investigate the individual and collaborative influences of sex chromosome complements and gut microbiome bacteria on humoral immune activation. Sham-operated and gonadectomized male and female Four Core Genotype (FCG) mice were immunized with heat-killed Streptococcus pneumoniae (HKSP). Humoral immune responses were assessed and X-linked immune-related gene expression was evaluated to explain the identified XX-dependent phenotypes. Ex vivo studies investigated the functional role of Kdm6a, an X-linked epigenetic regulatory gene of interest, in mitogenic B cell activation. We further evaluated whether gut microbiome communities, or their metabolites, differentially influence immune cell activation in a sex chromosome-dependent manner. Endogenous gut microbiomes were antibiotically depleted and reconstituted with select short-chain fatty acid (SCFA)-producing bacteria prior to HKSP immunization and immune responses assessed. XX mice exhibited higher HKSP-specific IgM-secreting B cells and plasma cell frequencies than XY mice, regardless of gonadal sex. Although Kdm6a was identified as an X-linked gene overexpressed in XX B cells, inhibition of its enzymatic activity did not affect mitogen-induced plasma cell differentiation or antibody production in a sex chromosome-dependent manner ex vivo. Enhanced humoral responses in XX vs. XY immunized FCG mice were eliminated after microbiome depletion, indicating that the microbiome contributes to the identified XX-dependent immune enhancement. Reconstituting microbiota-depleted mice with select SCFA-producing bacteria increased humoral responses in XX, but not XY, FCG mice. This XX-dependent enhancement appears to be independent of SCFA production in males, while female XX-dependent responses relied on SCFAs. FCG mice have been used to assess sex hormones and sex chromosome complements influences on various sexually dimorphic traits. The current study indicates that the gut microbiome impacts humoral responses in an XX-dependent manner, suggesting that the collaborative influence of gut bacteria and other sex-specific factors should be considered when interpreting data aimed at delineating the mechanisms that promote sexual dimorphisms.
2023-12-06 | GSE244866 | GEO
Project description:Early life exposure to antibiotics alters the gut microbiome. These alterations lead to changes in metabolic homeostasis and an increase in host adiposity. We used microarrays to identify metabolic genes that may be up- or down-regulated secondary to antibiotic exposure. Low dose antibiotics have been widely used as growth promoters in the agricultural industry since the 1950’s, yet the mechanisms for this effect are unclear. Because antimicrobial agents of different classes and varying activity are effective across several vertebrate species, we hypothesized that such subtherapeutic administration alters the population structure of the gut microbiome as well as its metabolic capabilities. We generated a model of adiposity by giving subtherapeutic antibiotic therapy (STAT) to young mice and evaluated changes in the composition and capabilities of the gut microbiome. STAT administration increased adiposity in young mice and altered hormones related to metabolism. We observed substantial taxonomic changes in the microbiome, changes in copies of key genes involved in the metabolism of carbohydrates to short-chain fatty acids (SCFA), increases in colonic SCFA levels, and alterations in the regulation of hepatic metabolism of lipids and cholesterol. In this model, we demonstrate the alteration of early life murine metabolic homeostasis through antibiotic manipulation.
2012-07-01 | GSE38880 | GEO
Project description:Alterations in the composition of the gut microbiome have an emerging role in brain function and behaviour. We have porposed that short chain fatty acids (SCFA) including propionate and butyrate which are present in the diet and are fermantation products of many gastrointestinal bacteria are contributing environmental factors in autism spectrum disorders (ASD). Here we used the microarray technology to compare global changes in gene expression profiles following exposure of PC12 cells to structurally related SCFA propionate and butyrate each in two different concentrations. Large number of affected genes, common for both SCFA were identified, including genetic networks and GO processes implicated in ASD.
2014-06-02 | GSE56516 | GEO
Project description:Increasing the consumption of dietary fibre has been proposed to alleviate the progression of non-communicable diseases such as obesity, type 2 diabetes and cardiovascular disease, yet the effect of dietary fibre on host physiology remains unclear. In this study, we performed a multiple diet feeding study in C57BL/6J mice to compare high fat and high fat modified with dietary fibre diets on host physiology and gut homeostasis by combining proteomic, metagenomic, metabolomic and glycomic techniques with correlation network analysis. We observed significant changes in physiology, liver proteome, gut microbiota and SCFA production in response to high fat diet. Dietary fibre modification did not reverse these changes but was associated with specific changes in the gut microbiota, liver proteome, SCFA production and colonic mucin glycosylation. Furthermore, correlation network analysis identified gut bacterial-glycan associations.
2021-09-08 | PXD014132 | Pride
Project description:Aging is associated with declining immunity and inflammation as well as alterations in the gut microbiome with a decrease of beneficial microbes and increase in pathogenic ones. The aim of this study was to investigate aging associated gut microbiome in relation to immunologic and metabolic profile in a non-human primate (NHP) model. 12 old (age>18 years) and 4 young (age 3-6 years) Rhesus macaques were included in this study. Immune cell subsets were characterized in PBMC by flow cytometry and plasma cytokines levels were determined by bead based multiplex cytokine analysis. Stool samples were collected by ileal loop and investigated for microbiome analysis by shotgun metagenomics. Serum, gut microbial lysate and microbe-free fecal extract were subjected to metabolomic analysis by mass-spectrometry. Our results showed that the old animals exhibited higher inflammatory biomarkers in plasma and lower CD4 T cells with altered distribution of naïve and memory T cell maturation subsets. The gut microbiome in old animals had higher abundance of Archaeal and Proteobacterial species and lower Firmicutes than the young. Significant enrichment of metabolites that contribute to inflammatory and cytotoxic pathways was observed in serum and feces of old animals compared to the young. We conclude that aging NHP undergo immunosenescence and age associated alterations in the gut microbiome that has a distinct metabolic profile.
2022-02-01 | E-MTAB-10160 | biostudies-arrayexpress