Ontology highlight
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PROVIDER: PRJNA1305136 | ENA |
REPOSITORIES: ENA
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Project description:Morphine and its pharmacological derivatives are the most prescribed analgesics for moderate to severe pain management. However, chronic use of morphine reduces pathogen clearance and induces bacterial translocation across the gut barrier. The enteric microbiome has been shown to play a critical role in the preservation of the mucosal barrier function and metabolic homeostasis. Here, we show for the first time, using bacterial 16s rDNA sequencing, that chronic morphine treatment significantly alters the gut microbial composition and induces preferential expansion of the gram-positive pathogenic and reduction of bile-deconjugating bacterial strains. A significant reduction in both primary and secondary bile acid levels was seen in the gut, but not in the liver with morphine treatment. Morphine induced microbial dysbiosis and gut barrier disruption was rescued by transplanting placebo-treated microbiota into morphine-treated animals, indicating that microbiome modulation could be exploited as a therapeutic strategy for patients using morphine for pain management. In this study, we establish a link between the two phenomena, namely gut barrier compromise and dysregulated bile acid metabolism. We show for the first time that morphine fosters significant gut microbial dysbiosis and disrupts cholesterol/bile acid metabolism. Changes in the gut microbial composition is strongly correlated to disruption in host inflammatory homeostasis13,14 and in many diseases (e.g. cancer/HIV infection), persistent inflammation is known to aid and promote the progression of the primary morbidity. We show here that chronic morphine, gut microbial dysbiosis, disruption of cholesterol/bile acid metabolism and gut inflammation; have a linear correlation. This opens up the prospect of devising minimally invasive adjunct treatment strategies involving microbiome and bile acid modulation and thus bringing down morphine-mediated inflammation in the host.
2016-06-01 | E-MTAB-3722 | biostudies-arrayexpress
Project description:Morphine causes microbial dysbiosis. In this study we focused on restoration of native microbiota in morphine treated mice and looked at the extent of restoration and immunological consequences of this restoration. Fecal transplant has been successfully used clinically, especially for treating C. difficile infection2528. With our expanding knowledge of the central role of microbiome in maintenance of host immune homeostasis17, fecal transplant is gaining importance as a therapy for indications resulting from microbial dysbiosis. There is a major difference between fecal transplant being used for the treatment of C. difficile infection and the conditions described in our studies. The former strategy is based on the argument that microbial dysbiosis caused by disproportionate overgrowth of a pathobiont can be out-competed by re-introducing the missing flora by way of a normal microbiome transplant. This strategy is independent of host factors and systemic effects on the microbial composition. Here, we show that microbial dysbiosis caused due to morphine can be reversed by transplantation of microbiota from the placebo-treated animals.
2016-06-01 | E-MTAB-3723 | biostudies-arrayexpress
Project description:Burn injury remains a major clinical challenge to both survival and to quality of life. Its progressive, aberrant inflammation underlies the lethal dysfunction of various organs and the pain it induces is excruciating and notoriously difficult to manage. While it is known that burn injury’s complex local and disseminating pathology is orchestrated from the burned tissue, few studies have sought to characterise the local signalling environment. An enhanced understanding of the local and acutely temporally-dynamic processes defining burn injury and its progression is required for the development of novel therapeutic interventions. Microdialysis was used as an interstitial sampling technique, conducted over three hours post-burn. Samples were analysed by metabolomics and a multiplex cytokine immunoassay. Next-Generation sequencing libraries of the burn and control microdialysis sites were prepared to measure transcriptional changes potentially underlying the interstitial profile characterising burn injury.
2018-08-31 | GSE102811 | GEO
Project description:Pancreatic cancer is the 3rd most prevalent cause of cancer related deaths in United states alone, with over 55000 patients being diagnosed in 2019 alone and nearly as many succumbing to it. Late detection, lack of effective therapy and poor understanding of pancreatic cancer systemically contributes to its poor survival statistics. Obesity and high caloric intake linked co-morbidities like type 2 diabetes (T2D) have been attributed as being risk factors for a number of cancers including pancreatic cancer. Studies on gut microbiome has shown that lifestyle factors as well as diet has a huge effect on the microbial flora of the gut. Further, modulation of gut microbiome has been seen to contribute to effects of intensive insulin therapy in mice on high fat diet. In another study, abnormal gut microbiota was reported to contribute to development of diabetes in Db/Db mice. Recent studies indicate that microbiome and microbial dysbiosis plays a role in not only the onset of disease but also in its outcome. In colorectal cancer, Fusobacterium has been reported to promote therapy resistance. Certain intra-tumoral bacteria have also been shown to elicit chemo-resistance by metabolizing anti-cancerous agents. In pancreatic cancer, studies on altered gut microbiome have been relatively recent. Microbial dysbiosis has been observed to be associated with pancreatic tumor progression. Modulation of microbiome has been shown to affect response to anti-PD1 therapy in this disease as well. However, most of the studies in pancreatic cancer and microbiome have remained focused om immune modulation. In the current study, we observed that in a T2D mouse model, the microbiome changed significantly as the hyperglycemia developed in these animals. Our results further showed that, tumors implanted in the T2D mice responded poorly to Gemcitabine/Paclitaxel (Gem/Pac) standard of care compared to those in the control group. A metabolomic reconstruction of the WGS of the gut microbiota further revealed that an enrichment of bacterial population involved in drug metabolism in the T2D group.
2020-11-30 | E-MTAB-8739 | biostudies-arrayexpress
Project description:Burn injury induces a systemic hyperinflammatory response with detrimental side effects. Studies have described the biochemical changes induced by severe burns, but the transcriptome response is not well characterized. The goal of this work is to characterize the blood transcriptome after burn injury. Burn patients presenting to a regional center between 2012-2017 were prospectively enrolled. Blood was collected on admission and at predetermined time points (hours 2, 4, 8, 12, 24). RNA was isolated and transcript levels were measured with a gene expression microarray. To identify differentially regulated genes (FDR≤0.1) by burn injury severity, patients were grouped by total body surface area (TBSA) above or below 20% and statistically enriched pathways were identified. Sixty-eight patients were analyzed, most patients were male with a median age of 41 (IQR, 30.5-58.5) years, and TBSA of 20% (11-34%). Thirty-five patients had %TBSA injury ≥20%, and this group experienced greater mortality (26% vs. 3%, p=0.008). Comparative analysis of genes from patients with </≥20% TBSA revealed 1505, 613, 380, 63, 1357, and 954 differentially expressed genes at hours 0, 2, 4, 8, 12 and 24 respectively. Pathway analysis revealed an initial upregulation in several immune/inflammatory pathways within the ≥20% TBSA groups followed by shutdown. Severe burn injury is associated with an early proinflammatory immune response followed by shutdown of these pathways. Examination of the immunoinflammatory response to burn injury through differential gene regulation and associated immune pathways by injury severity may identify mechanistic targets for future intervention.
2021-10-31 | GSE182616 | GEO
Project description:Severe burn injury is a one of the most devastating forms of trauma with over 1.1 million burns each year requiring medical attention in the United States. Deaths from burn injury are commonly caused by immune-related sequelae such as pneumonia, organ failure and other opportunistic bacterial infections. Though there have been numerous studies to assess the immunological dysfunction associated with burn injury, there have yet to be a predictive biomarker, that can be used to assess high risk patients and their outcomes. We hypothesized that circulating extracellular vesicles (EVs) released early after burn injury would promote activate peripheral macrophages and specific cargo could be used as a biomarker to identify at-risk patients. To test this hypothesis, we assessed the immune consequences of adoptive transfer of EVs isolated after burn injury in vitro and used unbiased proteomic on EVs from mouse models and human burn patients from the UNC Jaycee Burn Center. Findings here suggest EVs serve as mediators of immune dysfunction and potential biomarkers.
2022-02-16 | PXD028515 | Pride
Project description:Opioid analgesics are frequently prescribed in the United States and worldwide. However, serious side effects such as addiction, immunosuppression and gastrointestinal symptoms limit long term use. In the current study using a chronic morphine-murine model a longitudinal approach was undertaken to investigate the role of morphine modulation of gut microbiome as a mechanism contributing to the negative consequences associated with opioids use. The results revealed a significant shift in the gut microbiome and metabolome within 24 hours following morphine treatment when compared to placebo. Morphine induced gut microbial dysbiosis exhibited distinct characteristic signatures profiles including significant increase in communities associated with pathogenic function, decrease in communities associated with stress tolerance. Collectively, these results reveal opioids-induced distinct alteration of gut microbiome, may contribute to opioids-induced pathogenesis. Therapeutics directed at these targets may prolong the efficacy long term opioid use with fewer side effects.
2018-04-16 | E-MTAB-5550 | biostudies-arrayexpress
Project description:Full thickness and deep partial thickness burn injuries heal by scarring. There are several mechanisms thought to be essential for the development of burn scars, but a challenge to studying the skin response to burn injury is that there are few animal models of burn scarring that are either clinically similar to human burn scars or are practical for most investigators to use. The purpose of this study was to examine the changes in RNA expression in human skin to burn injury. This was done by comparing pre-injury tissue from otherwise healthy adults undergoing aesthetic scarification created by branding with a hot metal object to serial samples of untreated wounds in the same subjects.
2014-01-22 | E-MTAB-1323 | biostudies-arrayexpress
Project description:A dysregulated immune response after severe burn injury is associated with detrimental short and long-term clinical outcomes. Key changes to gene expression within the first 24 h after burn injury have been identified, but longitudinal data is lacking. Therefore, this study aims to characterize gene expression during the first 3 weeks after burn injury and identify specific genes and pathways associated with distinct clinical outcomes. Patients presenting within 4 h of injury had blood RNA isolated for microarray gene expression at admission and set timepoints to 21 days. Inter- and intra-group comparisons were performed between 4 groups (G1 died within 7 days; G2 died after 7 days; G3 discharged after 7 days; and G4 discharged within 7 days). A total of 17 289 transcripts were quantified from 116 patients. At admission, there were 110, 80, and 31 differentially expressed genes in G1, G2, and G3, respectively, compared to G4, and were largely nonoverlapping. Longitudinal intra-group analyses also showed distinct group- and time-dependent patterns. Upregulation of genes and pathways related to the innate immune response and unfolded protein response predominated during early time points, while persistent upregulation of coagulation pathways and downregulation of immune-related pathways were identified days to weeks following injury. Overall, burn injury induces widespread transcriptomic responses, with larger and more sustained changes observed in patients with worse clinical outcomes. These gene expression signatures reveal underlying molecular mechanisms that occur immediately following injury and may have prognostic and diagnostic utility in the care of burn-injured patients.
2025-05-28 | GSE269523 | GEO
Project description:Introduction Severe injury, including burn trauma, leads to profound immune dysfunction, yet the mechanisms driving these changes remain incompletely defined. This lack of understanding has hindered efforts to modulate the immune response effectively. Additionally, a clear biomarker profile to guide clinicians in identifying burn patients at high risk for poor clinical outcomes is lacking. Extracellular vesicles (EVs) have emerged as novel mediators of immune dysfunction in various pathologies. Prior studies in mouse models have demonstrated that plasma EVs increase following burn injury and contribute to immune dysfunction. Furthermore, EVs have potential as biomarkers for predicting extended hospital stays in burn patients. This study hypothesizes that human EVs, purified early and late after burn injury, will exhibit immune reprogramming effects similar to those observed in mice and that specific EV protein cargo may serve as biomarkers of immune and physiological responses to burn injury. Methods EVs were isolated from the plasma of burn-injury patients at early (<72h) and late (≥14 days) time points post-injury. Using unbiased immune transcriptome and bioinformatic causal network analyses, the immunomodulatory effects of these EVs were assessed in human THP-1 macrophages. Mass spectrometry-based quantitative proteomics and pathway analyses were conducted to characterize the protein cargo of EVs from both human and mouse models at different post-burn phases. Results Early post-burn human EVs induced significant immune reprogramming in macrophages, increasing pro-inflammatory signaling while suppressing anti-inflammatory pathways. In contrast, late post-burn EVs exhibited an immunosuppressive profile, with downregulation of pro-inflammatory pathways and upregulation of anti-inflammatory signaling. Proteomic analyses revealed that human and mouse EVs contained unique and overlapping protein cargo across different time points. At day 7 post-burn, mouse EVs were enriched in circulation/complement and neuronal proteins, whereas by day 14, reductions in membrane and metabolism-associated proteins were observed. Similarly, in human EVs at 14 days post-burn, increased levels of circulation/complement, immune, and transport proteins were detected. Conclusions EVs from burn-injury patients at distinct time points differentially modulate immune responses in macrophages, mirroring the temporal immune phenotypes observed in clinical settings. These findings suggest that EV-macrophage interactions play a crucial role in burn-induced immune dysfunction and highlight the potential of EV protein cargo as biomarkers for immune status and patient outcomes following burn injury.
2025-05-21 | PXD062615 | Pride