Impaired resolution of blood transcriptomes through tuberculosis treatment with diabetes comorbidity
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PROVIDER: PRJNA798677 | ENA |
REPOSITORIES: ENA
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Project description:People with diabetes are more likely to develop tuberculosis (TB) and to have poor TB treatment outcomes than those without. We previously showed that blood transcriptomes in people with TB-diabetes (TB-DM) co-morbidity have excessive inflammatory and reduced interferon responses at TB diagnosis. It is unknown whether this persists through treatment, potentially underlying adverse outcomes. Methods Pulmonary TB patients were recruited in South Africa, Indonesia and Romania, and classified as having TB-DM, TB with prediabetes, TB-related hyperglycaemia or uncomplicated TB, based on glycated haemoglobin (HbA1c) concentration at TB diagnosis and after 6 months of TB treatment. Gene expression in blood samples collected at diagnosis and at regular intervals throughout treatment was measured by unbiased RNA-Seq and targeted Multiplex Ligation-dependent Probe Amplification. Results Gene expression was modulated by TB treatment in all groups but to different extents, such that differences remained in people with TB-DM relative to TB-only throughout, including genes involved in innate responses, anti-microbial immunity and the inflammasome. People with prediabetes or with TB-related hyperglycaemia had gene expression more similar to people with TB-DM than TB-only throughout treatment. The overall pattern of change was similar across clinical groups irrespective of glycaemic index, permitting models predictive of TB treatment to be developed. Conclusions The exacerbated transcriptome changes seen in TB-DM take longer to resolve during TB treatment, indicating that prolonged treatment or host-directed therapy may be needed to improve TB treatment outcomes. Development of transcriptome-based biomarker signatures of TB-treatment response should include people with diabetes to be useful across populations.
2023-09-05 | GSE193978 | GEO
Project description:Type 2 diabetes (DM2) is a disease that hinders tuberculosis (TB) control strategies worldwide. TB infection, progression, morbidity, treatment success, adverse effects, relapse, and mortality are worse in these susceptible populations. Therefore, expanding the partially known molecular mechanisms leading to TB-DM2 comorbidity may be essential to face both epidemics. Consequently, a transcriptomic study was conducted on TB-DM2 comorbidity, associated with patients with DM2 who have poor glycaemic control (PDM2), since they have a higher risk of getting TB. Human blood samples from healthy controls (CTRL, HbA1c < 6.5%), TB ( HbA1c < 6.5%), TB-DM2, DM2 (HbA1c < 8.9%), and PDM2 (HbA1c > 10%) groups (n=4 each) were analyzed using high-density human GE 4X44K v2 differential expression microarrays.
2024-06-04 | GSE249102 | GEO
Project description:BackgroundPeople with diabetes are more likely to develop tuberculosis (TB) and to have poor TB-treatment outcomes than those without. We previously showed that blood transcriptomes in people with TB-diabetes (TB-DM) co-morbidity have excessive inflammatory and reduced interferon responses at diagnosis. It is unknown whether this persists through treatment and contributes to the adverse outcomes.MethodsPulmonary TB patients recruited in South Africa, Indonesia and Romania were classified as having TB-DM, TB with prediabetes, TB-related hyperglycaemia or TB-only, based on glycated haemoglobin concentration at TB diagnosis and after 6 months of TB treatment. Gene expression in blood at diagnosis and intervals throughout treatment was measured by unbiased RNA-Seq and targeted Multiplex Ligation-dependent Probe Amplification. Transcriptomic data were analysed by longitudinal mixed-model regression to identify whether genes were differentially expressed between clinical groups through time. Predictive models of TB-treatment response across groups were developed and cross-tested.ResultsGene expression differed between TB and TB-DM patients at diagnosis and was modulated by TB treatment in all clinical groups but to different extents, such that differences remained in TB-DM relative to TB-only throughout. Expression of some genes increased through TB treatment, whereas others decreased: some were persistently more highly expressed in TB-DM and others in TB-only patients. Genes involved in innate immune responses, anti-microbial immunity and inflammation were significantly upregulated in people with TB-DM throughout treatment. The overall pattern of change was similar across clinical groups irrespective of diabetes status, permitting models predictive of TB treatment to be developed.ConclusionsExacerbated transcriptome changes in TB-DM take longer to resolve during TB treatment, meaning they remain different from those in uncomplicated TB after treatment completion. This may indicate a prolonged inflammatory response in TB-DM, requiring prolonged treatment or host-directed therapy for complete cure. Development of transcriptome-based biomarker signatures of TB-treatment response should include people with diabetes for use across populations.
| S-EPMC10468587 | biostudies-literature
Project description:Whole RNA profiling of Tuberculosis-diabetes comorbidity linked to diabetes with poor glycemic control
| PRJNA1047166 | ENA
Project description:Neutrophil extracellular traps (NETs) promote inflammation and atherosclerosis progression. In diabetes they are increased and impair wound healing, during which inflammation normally resolves. Atherosclerosis regression, a process resembling wound healing, is also impaired in diabetes. Thus, we hypothesized that NETs impede atherosclerosis regression in diabetes through unresolved inflammation. Objective: To investigate in diabetes the effect of NETs on plaque macrophage inflammation and whether NETs reduction improves atherosclerosis regression. Findings: Transcriptomic profiling of plaque macrophages from NET positive and negative areas in Ldlr-/- mice revealed inflammasome and glycolysis pathway upregulation, indicating a pro-inflammatory phenotype. During atherosclerosis regression in non-diabetic mice, plaque NET content decreased. In contrast, in diabetic mouse plaques NETs were enriched and persisted after lipid-lowering. DNase1 treatment (to degrade NETs) of diabetic mice reduced plaque NETs and macrophage inflammation and improved atherosclerosis regression after lipid-lowering. Conclusions: NETs decline during atherosclerosis regression in non-diabetic mice, but persist in diabetes and impair regression by exacerbating macrophage inflammation. DNase1 reduced diabetic plaque NETs and macrophage inflammation, and restored atherosclerosis resolution after lipid-lowering, despite ongoing hyperglycemia. Given that humans with diabetes also exhibit impaired atherosclerosis resolution with lipid-lowering, these data suggest that NETs contribute to the increased CVD risk in this population.
2020-05-12 | GSE145200 | GEO
Project description:RFX6 haploinsufficiency predisposes to diabetes through impaired beta cell function
| PRJNA980693 | ENA
Project description:People living with diabetes have an increased risk of developing active tuberculosis. The effects of diabetes (HbA1c ≥6.5%) and intermediate hyperglycaemia (HbA1c 5.7-6.5%), on this transcriptomic signature were investigated by RNA-seq, to enhance understanding of immunological susceptibility in diabetes-tuberculosis comorbidity.Diabetes increased the magnitude of gene expression change in the host transcriptome in tuberculosis, characterised by an increase in innate, and decrease in adaptive immune responses. Strikingly, patients with intermediate hyperglycaemia and tuberculosis exhibited blood transcriptomes much more similar to diabetes-tuberculosis patients than to uncomplicated tuberculosis patients. Aberrant transcriptomes unveil a susceptibility mechanism of DM patients to TB of enhanced inflammation and reduced interferon responses.
2020-07-16 | GSE114192 | GEO
Project description:Diabetes is a risk factor for the development of cardiovascular diseases that are associated with impaired angiogenesis or increased endothelial cell apoptosis. Here is it shown that angiogenic repair of ischemic hind limbs was impaired in Lepr db/db mice, a leptin receptor deficient model of diabetes, compared to wild-type C57BL/6 (WT) mice as evaluated by laser Doppler flow and capillary density analyses. To identify molecular targets associated with this disease process, hind limb cDNA expression profiles were created from adductor muscle of Lepr db/db and WT mice before and after hind limb ischemia using Affymetrix GeneChip® Mouse Expression Set microarrays. The expression patterns of numerous angiogenesis related proteins were altered in Lepr db/db versus WT mice following ischemic injury. These transcripts included neuropilin-1, VEGF-A, placental growth factor, elastin and matrix metalloproteinases that are implicated in blood vessel growth and maintenance of vessel wall integrity. These data illustrate that impaired ischemia-induced neovascularization in type 2 diabetes is associated with the dysregulation of a complex angiogenesis-regulatory network. Keywords: Diabetes, ischemia, angiogenesis, microarrays
2014-06-30 | GSE3313 | GEO
Project description:Circulating miRNAs constitute a novel class of disease biomarkers, which are altered in diabetes but the effect of diabetes associated inflammation as seen in chronic wounds is unknown. We here compared the miRNA pattern in diabetic patients in presence or absence of chronic wound with PAD. The clinical plasma samples were obtained from Heart and Diabetes centre, NRW and compared for plasma miRNA levels in 2 pools of 17 T2DM+PAD+Wound patients vs 2 pools from 20 T2DM controls
2015-06-09 | E-GEOD-49885 | biostudies-arrayexpress
Project description:<p>Pulmonary tuberculosis (PTB) and diabetes mellitus (DM) are common chronic diseases that threaten human health. Patients with DM are susceptible to PTB, an important factor that aggravates the complications of diabetes. However, the molecular regulatory mechanism underlying the susceptibility of patients with DM to PTB infection remains unknown. Healthy subjects, patients with primary PTB and patients with primary PTB complicated by DM were recruited according to inclusion and exclusion criteria. Peripheral whole blood was collected, and alteration profiles and potential molecular mechanisms were further analyzed using integrated bioinformatics analysis of metabolomics and transcriptomics. In this study, transcriptional data revealed that lipocalin 2 (LCN2), defensin alpha 1 (DEFA1), peptidoglycan recognition protein 1 (PGLYRP1) and integrin subunit alpha 2b (ITGA2B) were significantly upregulated, while chloride intracellular channel 3 (CLIC3) significantly down-regulated in PTB-DM by contrast to HC group. Additionally, the IL-17, PI3K-AKT and PPAR signaling pathways are important for PTB infection and regulation of PTB-complicated diabetes. Metabolomic data showed that glycerophospholipid metabolism, carbon metabolism and fat digestion and absorption processes were enriched in the differential metabolic analysis. Finally, integrated analysis of both metabolomic and transcriptomic data indicated that the NOTCH1/JAK/STAT signaling pathway is important in PTB complicated by DM. In conclusion, PTB infection altered the transcriptional and metabolic profiles of patients with DM. Metabolomic and transcriptomic changes were highly correlated in PTB-infected patients with DM. Peripheral metabolite levels may be used as biomarkers for PTB management in patients with DM.</p><p><strong>IMPORTANCE:</strong> The comorbidity of diabetes mellitus (DM) significantly increases the risk of tuberculosis infection and adverse tuberculosis treatment outcomes. Most previous studies have focused on the relationship between the effect of blood glucose control and the outcome of anti-tuberculosis treatment in pulmonary tuberculosis (PTB)-DM; however, early prediction and the underlying molecular mechanism of susceptibility to PTB infection in patients with DM remain unclear. Here, transcriptome sequencing and untargeted metabolomics were performed to elucidatethe key molecules and signaling pathways involved in PTB infection and the susceptibility of patients with diabetes to PTB. Our findings contribute to the development of vital diagnostic biomarkers for PTB or PTB-DM and provide acomprehensive understanding of molecular regulation during disease progression.</p>
2023-07-26 | MTBLS7623 | MetaboLights