PubMed · 466304
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J W Paulley. 1979-07-14. Saving asthmatics.. https://doi.org/10.1136/bmj.2.6182.130-c
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The field of asthma microbiome research has shifted rapidly in recent years. Advances in sequencing technology have led to an increased ability to characterize multikingdom microbial species and integration with host -omics profiling to enhance future translational applications. Traditional bacteria-centric, cross-sectional studies are giving way to mechanistic frameworks that incorporate fungi, viruses, and host-immune interactions. In this state-of-the-art review of emerging concepts in microbiome asthma research, we first propose a structured framework to consider microbiome studies across 5 major domains-microbial kingdom, site of sampling, integration with host -omics, clinical outcome domain, and translational relevance-in order to synthesize recent high-impact human microbiome studies in asthma. We highlight emerging evidence that fungal and viral communities contribute independently to asthma risk and that human microbial communities are linked to distinct inflammatory and immune pathways shaped by host genetic susceptibility.
BACKGROUND: Asthma is a heterogeneous chronic inflammatory syndrome, with the T2-high endotype defined by robust type 2 immune responses and skewed T helper polarization. Although H3K9 acetylation (H3K9ac) is a key activating histone mark in T helper differentiation, its genome-wide promoter landscape in circulating immune cells of T2-high asthma remains uncharacterized. METHODS: Integrated ChIP-seq and RNA-seq profiling was performed on peripheral blood mononuclear cells (PBMCs) from ten T2-high asthma patients and ten healthy controls. Differential H3K9ac enrichment and gene expression were analyzed, followed by concordance and Spearman correlation analyses to identify genes under H3K9ac-linked transcriptional regulation. Findings were contextualized using publicly available H3K27ac ChIP-seq datasets from asthmatic airway tissue and glucocorticoid-treated airway epithelial cells. RESULTS: We identified 2340 differential enrichment regions (DERs), 95.9% mapping to promoters, with nearly all showing H3K9ac loss and enrichment in T cell receptor signaling and Th1/Th2/Th17 differentiation pathways. Genes encoding histone-modifying enzymes, including HATs, HDACs, and HMTs, were overrepresented, suggesting a self-reinforcing epigenetic feedback loop. Integrated analysis identified 979 genes with concordant H3K9ac and expression changes: downregulated genes were enriched in lymphocyte activation and TNF signaling, whereas upregulated genes were enriched in AKT and MAPK pathways. Locus-specific analyses showed H3K9ac loss at Th1/Th17 genes (TBX21, IFNG, CCR6) and gain at Th2 genes (IL4, TSLP). Targeted RT-qPCR provided independent experimental support for reduced expression of Th1-associated genes, with significant decreases in STAT1 and STAT4 in T2-high asthma patients. Correlation analysis identified six genes with significant H3K9ac-expression associations. CONCLUSIONS: Promoter H3K9ac remodeling is a defining epigenetic feature of T2-high asthma, reflecting coordinated alterations at T helper lineage-defining loci and inflammatory pathways.
As a consequence of climate change and land-use policies, there has been a historic rise in wildfire smoke across the United States and the world. Although the deleterious effects of wildfire smoke and associated air pollution on asthma outcomes are established epidemiologically, genetic risks and molecular mechanisms of how wildfire smoke affects asthma are unknown. This knowledge gap hinders the identification of high-risk individuals and the creation of targeted therapies or recommendations to protect these individuals. We identified 52 genetic risk variants that colocalized with genomic responses to woodsmoke particles (WSPs), a model of wildfire particulate matter, and associated with asthma in the GERA (Genetic Epidemiology Research on Adult Health and Aging) cohort. We used additional filters to prioritize variants for direct testing of allele-dependent transcriptional regulatory function in plasmid reporters. We found that the rs3861144 variant (odds ratioasthma, 1.036) changes SPRY2 responses to WSPs in airway epithelial cells, which are involved in IL-8 secretion, ERK (extracellular signal-related kinase) activation, and mechanical scratch repair in cell culture. These findings provide insights into the molecular pathways through which WSPs may influence asthma risk and propose genetic candidates that warrant further study for their potential as clinical tools for asthma.