Ontology highlight
ABSTRACT:
PROVIDER: PRJNA328251 | ENA |
REPOSITORIES: ENA
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Project description:Abstract: Many mouse models of neurological disease use the tetracycline transactivator (tTA) system to control transgene expression by oral treatment with the broad-spectrum antibiotic doxycycline. Antibiotic treatment used for transgene control might have undesirable systemic effects, including the potential to affect immune responses in the brain via changes in the gut microbiome. Recent work has shown that an antibiotic cocktail to perturb the gut microbiome can suppress microglial reactivity to brain amyloidosis in transgenic mouse models of Alzheimer's disease based on controlled overexpression of the amyloid precursor protein (APP). Here we assessed the impact of chronic low dose doxycycline on gut microbiome diversity and neuroimmune response to systemic LPS challenge in a tTA-regulated model of Alzheimer's amyloidosis. We show that doxycycline decreased microbiome diversity in both APP transgenic and wild-type mice and that these changes persisted long after drug withdrawal. Despite this change in microbiome composition, dox treatment had minimal effect on transcriptional signatures in the brain, both at baseline and following acute LPS challenge. Our findings suggest that central neuroinflammatory responses may be less affected by dox at doses needed for transgene control than by antibiotic cocktail at doses used for microbiome manipulation.
2024-01-10 | GSE236242 | GEO
Project description:Mammalian species have co-evolved with intestinal microbial communities that can shape development and adapt to environmental changes, including antibiotic perturbation or nutrient flux. In humans, especially children, microbiota disruption is common, yet the dynamic microbiome recovery from early-life antibiotics is still uncharacterized. Using a mouse model mimicking pediatric antibiotic use, we found that therapeutic-dose pulsed antibiotic treatment (PAT) with a beta-lactam or macrolide altered both host and microbiota development. Early-life PAT accelerated total mass and bone growth, and resulted in progressive changes in gut microbiome diversity, population structure, and metagenomic content, with microbiome effects dependent on the number of courses and class of antibiotic. While control microbiota rapidly adapted to a change in diet, PAT slowed the ecological progression, with delays lasting several months in response to the macrolide. This study identifies key markers of disturbance and recovery, which may help provide therapeutic targets for microbiota restoration following antibiotic treatment. C57BL/6J mice received three antibiotic courses: at days 10-15, 28-31, and 37-40 of life, amoxicillin or tylosin.Livers were collected at age 22 weeks, RNA was extracted, and transcriptional differences were measured by microarray analysis.
2015-05-07 | E-GEOD-68603 | biostudies-arrayexpress
Project description:Mammalian species have co-evolved with intestinal microbial communities that can shape development and adapt to environmental changes, including antibiotic perturbation or nutrient flux. In humans, especially children, microbiota disruption is common, yet the dynamic microbiome recovery from early-life antibiotics is still uncharacterized. Using a mouse model mimicking pediatric antibiotic use, we found that therapeutic-dose pulsed antibiotic treatment (PAT) with a beta-lactam or macrolide altered both host and microbiota development. Early-life PAT accelerated total mass and bone growth, and resulted in progressive changes in gut microbiome diversity, population structure, and metagenomic content, with microbiome effects dependent on the number of courses and class of antibiotic. While control microbiota rapidly adapted to a change in diet, PAT slowed the ecological progression, with delays lasting several months in response to the macrolide. This study identifies key markers of disturbance and recovery, which may help provide therapeutic targets for microbiota restoration following antibiotic treatment.
2015-05-07 | GSE68603 | GEO
Project description:Opioids such as morphine have many beneficial properties as analgesics, however, opioids may induce multiple adverse gastrointestinal symptoms. We have recently demonstrated that morphine treatment results in significant disruption in gut barrier function leading to increased translocation of gut commensal bacteria. However, it is unclear how opioids modulate the gut homeostasis. By using a mouse model of morphine treatment, we studied effects of morphine treatment on gut microbiome. We characterized phylogenetic profiles of gut microbes, and found a significant shift in the gut microbiome and increase of pathogenic bacteria following morphine treatment when compared to placebo. In the present study, wild type mice (C57BL/6J) were implanted with placebo, morphine pellets subcutaneously. Fecal matter were taken for bacterial 16s rDNA sequencing analysis at day 3 post treatment. A scatter plot based on an unweighted UniFrac distance matrics obtained from the sequences at OTU level with 97% similarity showed a distinct clustering of the community composition between the morphine and placebo treated groups. By using the chao1 index to evaluate alpha diversity (that is diversity within a group) and using unweighted UniFrac distance to evaluate beta diversity (that is diversity between groups, comparing microbial community based on compositional structures), we found that morphine treatment results in a significant decrease in alpha diversity and shift in fecal microbiome at day 3 post treatment compared to placebo treatment. Taxonomical analysis showed that morphine treatment results in a significant increase of potential pathogenic bacteria. Our study shed light on effects of morphine on the gut microbiome, and its role in the gut homeostasis.
2018-04-16 | E-MTAB-5546 | biostudies-arrayexpress
Project description:Epithelial Ovarian Cancer (EOC) is the leading cause of gynecologic cancer death. Despite many patients achieving remission with first-line therapy, up to 80% of patients will recur and require additional treatment. Retrospective clinical analysis of OC patients indicates antibiotic use during chemotherapy treatment is associated with poor overall survival. We assessed whether antibiotic (ABX) therapy would impact growth of EOC and sensitivity to cisplatin in murine models. Immune competent or compromised mice were given control or ABX containing water (metronidazole, ampicillin, vancomycin, and neomycin) before being intraperitoneally injected with murine EOC cells. Stool was collected to confirm microbiome disruption and tumors were monitored, and cisplatin therapy was administered weekly until endpoint. EOC tumor-bearing mice demonstrate accelerated tumor growth and resistance to cisplatin therapy in ABX treated compared with nonABX treatment. Stool analysis indicated most gut microbial species were disrupted by ABX treatment except for ABX resistant bacteria. To test for role of the gut microbiome, cecal microbiome transplants (CMTs) of microbiota derived from ABX or nonABX treated mice were used to recolonize the microbiome of ABX treated mice. nonABX cecal microbiome was sufficient to ameliorate the chemoresistance and survival of ABX treated mice indicative of a gut derived tumor suppressor. Mechanistically, tumors from ABX treated compared to nonABX treated mice contained a high frequency of cancer stem cells that were augmented by cisplatin. These studies indicate an intact microbiome provides a gut derived tumor suppressor and maintains chemosensitivity that is disrupted by ABX treatment.
2022-11-01 | GSE200025 | GEO
Project description:Hepatocellular carcinoma (HCC) is the fourth most frequent cause of cancer-related mortality worldwide. While ablation, resection and orthotopic liver transplantation are indicated at an early stage of the disease, Sorafenib (Sfb) is the current most administrated first-line treatment for advanced HCC, even thought its therapeutic benefit is limited as a consequence of the appearance of resistances. Deep knowledge on the molecular consequences of Sfb-treatment is essentially required for optimizing novel therapeutic strategies to improve the outcomes for patients with advanced HCC. In this study, we analysed differential gene expression changes in two well characterized HCC cell lines upon a Sfb-treatment, demonstrating that both lines responded similarly to the treatment. Our results provide valuable information on the molecular action of Sfb on diverse cellular fundamental processes such as DNA repair, translation and proteostasis and identify rationalization issues that could give a different therapeutic perspective to Sfb.
2022-02-24 | GSE186280 | 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. 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:We report that adhesion of microbes to intestinal epithelial cells is a critical cue for Th17 induction. SFB colonized in the intestine of mice can adhere to mouse small intestinal epithelial cells and induce intestinal Th17 cells. However, SFB colonized in rats cannot adhere to mouse intestinal epithelial cells and induce Th17 cells. Likewise, Citrobacter rodentium (WT) can adhere to mouse colonic epithelial cells and induce Th17 cells, but non-adherent mutant of C. rodentium (Δeae) cannot induce Th17 cells. To examine the influence of adherent bacteria on intestinal epithelial cells, we performed RNA seq. Germ free mice were orally inoculated with M-SFB or R-SFB and total RNA was isolated from small intestinal epithelial cells 1 week after inoculation. Alternatively, germ free mice were orally inoculated with C. rodentium WT or eae mutant and total RNA was isolated from colonic epithelial cells 5 days after inoculation. The gene expression of small intestinal epithelial cells isolated from small intestine of germ free mice (2 mice), mice monocolonized with M-SFB (2 mice) or R-SFB (3 mice), and colon of germ free mice (3 mice), mice monocolonized C. rodentium WT (3 mice) or eae mutant (3 mice).
2015-09-24 | E-GEOD-71734 | biostudies-arrayexpress
Project description:Innate lymphoid cells (ILCs) play a critical role in maintaining intestinal health in homeostatic and diseased conditions. During C. difficile infection (CDI), IL-33 activates ILC2 to protect from colonic damage and mortality. The function of IL-33 and ILC is tightly regulated by the intestinal microbiota. We set out to determine the impact of antibiotic-induced disruption of the microbiome on ILC function. Our goal was to understand antibiotic-induced changes in ILC function on susceptibility to C. difficile colitis in a mouse model. We utilized high-throughput single-cell RNAseq to investigate the phenotypic features of colonic ILC at baseline, after antibiotic administration with or without IL-33 treatment. We identified a heterogeneous landscape of colonic ILCs with gene signatures of inflammatory, anti-inflammatory, migratory, progenitor, plastic, and antigen-presenting ILC. Antibiotic treatment decreased ILC2 while coordinately increasing ILC1 and ILC3 phenotypes. Notably, Ifng+, Ccl5+, and Il23r+ ILC increased after antibiotics. IL-33 treatment counteracted the antibiotic effect by downregulating ILC1 and ILC3 and activating ILC2. In addition, IL-33 treatment markedly induced the expression of type 2 genes, including Areg and Il5. Finally, we identified amphiregulin, produced by ILC2, as protective duringC. difficileinfection. Together, our data expand our understanding of how antibiotics induce susceptibility to C. difficile colitis through their impact on ILC subsets and function.
2024-02-04 | GSE254628 | GEO
Project description:Vertebrates typically harbor a rich gastrointestinal microbiota, which has co-evolved with the host over millennia and is essential for several of its physiological functions, in particular maturation of the immune system. Recent studies have highlighted the importance of a single bacterial species, segmented filamentous bacteria (SFB), in inducing a robust T helper (Th)17 population in the small intestinal lamina propria (SI-LP) of the mouse gut. Consequently, SFB can promote IL-17-dependent immune and autoimmune responses, gut-associated as well as systemic, including inflammatory arthritis and experimental autoimmune encephalomyelitis. Here, we exploit the incomplete penetrance of SFB colonization of NOD mice in our animal facility to explore its impact on the incidence and course of type-1 diabetes in this prototypical, spontaneous model. There was a strong co-segregation of SFB-positivity and diabetes protection in females, but not in males, which remained relatively disease-free regardless of the SFB status. In contrast, insulitis did not depend on SFB colonization. SFB-positive, but not SFB-negative, females had a substantial population of Th17 cells in the SI-LP, which was the only significant, repeatable difference in the examined T cell compartments of the gut, pancreas or systemic lymphoid tissues. Th17 signature transcripts dominated the very limited SFB-induced molecular changes detected in SI-LP CD4+ T cells. Thus, a single bacterium, and the gut immune system alterations associated with it, can either promote or protect from autoimmunity in predisposed mouse models, likely reflecting their variable dependence on different Th subsets.
2011-06-09 | GSE29806 | GEO