Low vitamin D status in pregnancy was proposed as a risk factor of preeclampsia.
We assessed the effect of vitamin D supplementation (4,400 vs. 400 IU/day), initiated early in pregnancy (10-18 ...weeks), on the development of preeclampsia. The effects of serum vitamin D (25-hydroxyvitamin D 25OHD) levels on preeclampsia incidence at trial entry and in the third trimester (32-38 weeks) were studied. We also conducted a nested case-control study of 157 women to investigate peripheral blood vitamin D-associated gene expression profiles at 10 to 18 weeks in 47 participants who developed preeclampsia.
Of 881 women randomized, outcome data were available for 816, with 67 (8.2%) developing preeclampsia. There was no significant difference between treatment (N = 408) or control (N = 408) groups in the incidence of preeclampsia (8.08% vs. 8.33%, respectively; relative risk: 0.97; 95% CI, 0.61-1.53). However, in a cohort analysis and after adjustment for confounders, a significant effect of sufficient vitamin D status (25OHD ≥30 ng/ml) was observed in both early and late pregnancy compared with insufficient levels (25OHD <30 ng/ml) (adjusted odds ratio, 0.28; 95% CI, 0.10-0.96). Differential expression of 348 vitamin D-associated genes (158 upregulated) was found in peripheral blood of women who developed preeclampsia (FDR <0.05 in the Vitamin D Antenatal Asthma Reduction Trial VDAART; P < 0.05 in a replication cohort). Functional enrichment and network analyses of this vitamin D-associated gene set suggests several highly functional modules related to systematic inflammatory and immune responses, including some nodes with a high degree of connectivity.
Vitamin D supplementation initiated in weeks 10-18 of pregnancy did not reduce preeclampsia incidence in the intention-to-treat paradigm. However, vitamin D levels of 30 ng/ml or higher at trial entry and in late pregnancy were associated with a lower risk of preeclampsia. Differentially expressed vitamin D-associated transcriptomes implicated the emergence of an early pregnancy, distinctive immune response in women who went on to develop preeclampsia.
ClinicalTrials.gov NCT00920621.
Quebec Breast Cancer Foundation and Genome Canada Innovation Network. This trial was funded by the National Heart, Lung, and Blood Institute. For details see Acknowledgments.
Universality of human microbial dynamics Bashan, Amir; Gibson, Travis E; Friedman, Jonathan ...
Nature (London),
06/2016, Letnik:
534, Številka:
7606
Journal Article
Recenzirano
Odprti dostop
Human-associated microbial communities have a crucial role in determining our health and well-being, and this has led to the continuing development of microbiome-based therapies such as faecal ...microbiota transplantation. These microbial communities are very complex, dynamic and highly personalized ecosystems, exhibiting a high degree of inter-individual variability in both species assemblages and abundance profiles. It is not known whether the underlying ecological dynamics of these communities, which can be parameterized by growth rates, and intra- and inter-species interactions in population dynamics models, are largely host-independent (that is, universal) or host-specific. If the inter-individual variability reflects host-specific dynamics due to differences in host lifestyle, physiology or genetics, then generic microbiome manipulations may have unintended consequences, rendering them ineffective or even detrimental. Alternatively, microbial ecosystems of different subjects may exhibit universal dynamics, with the inter-individual variability mainly originating from differences in the sets of colonizing species. Here we develop a new computational method to characterize human microbial dynamics. By applying this method to cross-sectional data from two large-scale metagenomic studies--the Human Microbiome Project and the Student Microbiome Project--we show that gut and mouth microbiomes display pronounced universal dynamics, whereas communities associated with certain skin sites are probably shaped by differences in the host environment. Notably, the universality of gut microbial dynamics is not observed in subjects with recurrent Clostridium difficile infection but is observed in the same set of subjects after faecal microbiota transplantation. These results fundamentally improve our understanding of the processes that shape human microbial ecosystems, and pave the way to designing general microbiome-based therapies.
Abstract
The versatility of cellular response arises from the communication, or crosstalk, of signaling pathways in a complex network of signaling and transcriptional regulatory interactions. ...Understanding the various mechanisms underlying crosstalk on a global scale requires untargeted computational approaches. We present a network-based statistical approach, MuXTalk, that uses high-dimensional edges called multilinks to model the unique ways in which signaling and regulatory interactions can interface. We demonstrate that the signaling-regulatory interface is located primarily in the intermediary region between signaling pathways where crosstalk occurs, and that multilinks can differentiate between distinct signaling-transcriptional mechanisms. Using statistically over-represented multilinks as proxies of crosstalk, we infer crosstalk among 60 signaling pathways, expanding currently available crosstalk databases by more than five-fold. MuXTalk surpasses existing methods in terms of model performance metrics, identifies additions to manual curation efforts, and pinpoints potential mediators of crosstalk. Moreover, it accommodates the inherent context-dependence of crosstalk, allowing future applications to cell type- and disease-specific crosstalk.
Graphical Abstract
Graphical Abstract
Inhaled corticosteroids (ICS) are key treatments for controlling asthma and preventing asthma attacks. However, the responsiveness to ICS varies among individuals. MicroRNAs (miRNAs) have been lauded ...for their prognostic utility.
We hypothesized that circulating miRNAs obtained at baseline/prerandomization in the Childhood Asthma Management Program (CAMP) could serve as biomarkers and biologic mediators of ICS clinical response over the 4-year clinical trial period.
We selected baseline serum samples from 462 CAMP subjects subsequently randomized to either ICS (budesonide) or placebo. Samples underwent small RNA sequencing, and read counts were normalized and filtered by depth and coverage. Linear regression was used to associate miRNAs with change in FEV
% (prebronchodilator FEV
as a percent predicted) over the 4-year treatment period in both main effects and interaction models. We validated the function of the top associated miRNAs by luciferase reporter assays of glucocorticoid-mediated transrepression and predicted response to ICS through logistic regression models.
We identified 7 miRNAs significantly associated with FEV
% change (
≤ 0.05) and 15 miRNAs with significant interaction (
≤ 0.05) to ICS versus placebo treatments. We selected three miRNAs for functional validation, of which hsa-miR-155-5p and hsa-miR-532-5p were significantly associated with changes in dexamethasone-induced transrepression of NF-κB. Combined, these two miRNAs were predictive of ICS response over the course of the clinical trial, with an area under the receiver operating characteristic curve of 0.86.
We identified two functional circulating miRNAs predictive of asthma ICS treatment response over time.
Biomarkers are needed to inform the choice of biologic therapy in patients with asthma given the increasing number of biologics. We aimed to identify proteins associated with response to omalizumab ...and mepolizumab.
Aptamer-based proteomic profiling (SomaScan) was used to assess 1437 proteins from 51 patients with moderate to severe asthma who received omalizumab (n = 29) or mepolizumab (n = 22). Response was defined as the change in asthma-related exacerbations in the 12 months following therapy initiation. All models were adjusted for age, sex, and pre-treatment exacerbation rate. Additionally, body mass index was included in the omalizumab model and eosinophil count in the mepolizumab model. We evaluated the association between molecular signatures and response using negative binomial regression correcting for the false discovery rate (FDR) and gene set enrichment analyses (GSEA) to identify associated pathways.
Over two-thirds of patients were female. The average age for omalizumab patients was 42 years and 57 years for mepolizumab. At baseline, the average exacerbation rate was 1.5/year for omalizumab and 2.4/year for mepolizumab. Lower levels of LOXL2 (unadjusted p: 1.93 × 10E-05, FDR-corrected: 0.028) and myostatin (unadjusted: 3.87 × 10E-05, FDR-corrected: 0.028) were associated with better response to mepolizumab. Higher levels of CD9 antigen (unadjusted: 5.30 × 10E-07, FDR-corrected: 0.0006) and MUC1 (unadjusted: 1.15 × 10E-06, FDR-corrected: 0.0006) were associated with better response to omalizumab, and LTB4R (unadjusted: 1.12 × 10E-06, FDR-corrected: 0.0006) with worse response. Protein-protein interaction network modeling showed an enrichment of the TNF- and NF-kB signaling pathways for patients treated with mepolizumab and multiple pathways involving MAPK, including the FcER1 pathway, for patients treated with omalizumab.
This study provides novel fundamental data on proteins associated with response to mepolizumab or omalizumab in severe asthma and warrants further validation as potential biomarkers for therapy selection.
Accurate species identification and abundance estimation are critical for the interpretation of whole metagenome sequencing (WMS) data. Yet, existing metagenomic profilers suffer from false-positive ...identifications, which can account for more than 90% of total identified species. Here, by leveraging species-specific Type IIB restriction endonuclease digestion sites as reference instead of universal markers or whole microbial genomes, we present a metagenomic profiler, MAP2B (MetAgenomic Profiler based on type IIB restriction sites), to resolve those issues. We first illustrate the pitfalls of using relative abundance as the only feature in determining false positives. We then propose a feature set to distinguish false positives from true positives, and using simulated metagenomes from CAMI2, we establish a false-positive recognition model. By benchmarking the performance in metagenomic profiling using a simulation dataset with varying sequencing depth and species richness, we illustrate the superior performance of MAP2B over existing metagenomic profilers in species identification. We further test the performance of MAP2B using real WMS data from an ATCC mock community, confirming its superior precision against sequencing depth. Finally, by leveraging WMS data from an IBD cohort, we demonstrate the taxonomic features generated by MAP2B can better discriminate IBD and predict metabolomic profiles.
Patients with severe or difficult-to-treat asthma are an understudied population but account for considerable asthma morbidity, mortality, and costs. The Epidemiology and Natural History of Asthma: ...Outcomes and Treatment Regimens (TENOR) study was a large, 3-year, multicenter, observational cohort study of 4756 patients (n = 3489 adults ≥18 years of age, n = 497 adolescents 13-17 years of age, and n = 770 children 6-12 years of age) with severe or difficult-to-treat asthma. TENOR's primary objective was to characterize the natural history of disease in this cohort. Data assessed semiannually and annually included demographics, medical history, comorbidities, asthma control, asthma-related health care use, medication use, lung function, IgE levels, self-reported asthma triggers, and asthma-related quality of life. We highlight the key findings and clinical implications from more than 25 peer-reviewed TENOR publications. Regardless of age, patients with severe or difficult-to-treat asthma demonstrated high rates of health care use and substantial asthma burden despite receiving multiple long-term controller medications. Recent exacerbation history was the strongest predictor of future asthma exacerbations. Uncontrolled asthma, as defined by the 2007 National Heart, Lung, and Blood Institute guidelines' impairment domain, was highly prevalent and predictive of future asthma exacerbations; this assessment can be used to identify high-risk patients. IgE and allergen sensitization played a role in the majority of severe or difficult-to-treat asthmatic patients.
Rejuvenating the human gut microbiome Ke, Shanlin; Weiss, Scott T; Liu, Yang-Yu
Trends in molecular medicine,
08/2022, Letnik:
28, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Industrial advances have caused significant loss of diversity in our gut microbiome, potentially increasing our susceptibility to many diseases. Recently, rewilding the human gut microbiome - that ...is, bringing it back to an ancestral or preindustrial state (e.g., by transplanting stool material from donors in nonindustrial societies) - has been hotly debated from medical, ethical, and evolutionary perspectives. Here we propose an alternative solution: rejuvenating the human gut microbiome by stool banking and autologous fecal microbiota transplantation, that is, collecting the hosts' stool samples at a younger age when they are at optimal health, and cryopreserving the samples in a stool bank for the hosts' own future use. In this article we discuss the motivation, applications, feasibility, and challenges of this solution.
Asthma is a chronic inflammatory respiratory disease that affects over 300 million people worldwide. Glucocorticoids are a mainstay therapy for asthma because they exert anti-inflammatory effects in ...multiple lung tissues, including the airway smooth muscle (ASM). However, the mechanism by which glucocorticoids suppress inflammation in ASM remains poorly understood. Using RNA-Seq, a high-throughput sequencing method, we characterized transcriptomic changes in four primary human ASM cell lines that were treated with dexamethasone--a potent synthetic glucocorticoid (1 µM for 18 hours). Based on a Benjamini-Hochberg corrected p-value <0.05, we identified 316 differentially expressed genes, including both well known (DUSP1, KLF15, PER1, TSC22D3) and less investigated (C7, CCDC69, CRISPLD2) glucocorticoid-responsive genes. CRISPLD2, which encodes a secreted protein previously implicated in lung development and endotoxin regulation, was found to have SNPs that were moderately associated with inhaled corticosteroid resistance and bronchodilator response among asthma patients in two previously conducted genome-wide association studies. Quantitative RT-PCR and Western blotting showed that dexamethasone treatment significantly increased CRISPLD2 mRNA and protein expression in ASM cells. CRISPLD2 expression was also induced by the inflammatory cytokine IL1β, and small interfering RNA-mediated knockdown of CRISPLD2 further increased IL1β-induced expression of IL6 and IL8. Our findings offer a comprehensive view of the effect of a glucocorticoid on the ASM transcriptome and identify CRISPLD2 as an asthma pharmacogenetics candidate gene that regulates anti-inflammatory effects of glucocorticoids in the ASM.
...the identification of novel therapeutic strategies represents an important unmet need for underserved Black and Hispanic children living in urban areas.4 Biologic therapies (ie, treatments created ...from living animals, plants, or cells5) provide a compelling option. Jackson and colleagues based their analyses on a set of previously defined nasal gene networks that have been linked to risk for asthma exacerbations; however, these networks were derived in only 208 children.8 Furthermore, the networks were based on nasal airway samples rather than biosamples more proximal to the relevant lower airways. ...additional validation of these networks and further interrogation of the gene-expression data are warranted before definitive conclusions can be drawn on the basis of these omic data. ...while advocating for novel therapies for all in whom they are indicated, we must not forget the importance of addressing the underlying environmental causes of asthma morbidity among disadvantaged populations and of the benefits of continuing to focus on education and health promotion to encourage adherence to existing therapies.
PDF
