Potential Treatment Targets for C2 Microbiome-Driven Asthma Phenotype

Findings from a research letter published in the European Respiratory Journal describe the identification of several potential treatment targets for a microbiome-driven asthma phenotype by the Unbiased Biomarkers in Prediction of Respiratory Disease Outcomes (U-BIOPRED) study.

The researchers wrote that previous reports have identified an association between airway bacterial imbalance and neutrophilic asthma, suggesting an involvement of airway microbiota composition and the neutrophilic phenotype. In the study, the investigators assessed the underlying molecular mechanisms of microbiome-driven phenotypes, with a focus on differences in proteomics, transcriptomics, and sputum eicosanoids to identify possible targets for diagnosis and management of asthma.

Patients with the microbiome-driven cluster 2 (C2) were compared with patients with the cluster 1 (C1) phenotype by sputum transcriptomics and proteomics. According to the researchers, the C2 phenotype demonstrates worse asthma outcomes and microbial imbalance compared with C1. Also included in the study were patients with mild-to-moderate asthma as well as healthy controls, all of whom were compared with the C2 group.

Sputum 11-dehdro-TXB2 and PGE2 were significantly increased in the C2 group compared with the C1 patients (q <.05), with the researchers suggesting that this was “consistent with sputum PTGS2 gene upregulation in C2.” Levels of 15-HETE, LTE4, and PGD2 were also higher in C2 compared with the mild-to-moderate asthma and/or healthy control groups. The investigators explained that these findings were significantly associated with a reduced Shannon alpha-diversity in C2 compared with the other groups (P <.001), which was “consistent with the increase in the inflammatory signal with the increased severity level in the groups.”

The investigators found 2578 differentially expressed genes that were different between the C2 and C1 groups. A total of 194 of these genes had at least a twofold change. Additionally, the investigators found several up-regulated differentially expressed genes that were associated with immune regulation and inflammation, including tumor necrosis factor (TNF)α and related regulatory genes (eg, TNFAIP-6, TNFAIP3, TNFSF10, TNFRSF10, and TNFSF14), interleukins (IL) and related regulatory genes (eg, IL18R1, IL18RAP, IL1R1, IL1R2, IL1B, IRAK2, IRAK3, IL6, and IL6R), Toll-like receptors (eg, TLR2, TLR4, and TLR10), and inflammasomes (eg, NLRP3, NLRP12, and NLRC5) in C2 compared with C1.

Down-regulated pathways identified in the study were oxidative phosphorylation (OXPHOS), reactive oxygen species (ROS), DNA-repair, cell cycle, proliferation and growth, peroxisome, and metabolism. The researchers noted that similar up-regulated and down-regulated pathways were significant in participants with the C2 phenotype compared with patients with mild-to-moderate asthma and the healthy control group.

According to the researchers, varying “biological pathways and mediators involved in these patients suggest that pharmacotherapies targeting multiple mechanisms might be required.” They added that the findings also suggest that “neutrophilic asthma is not a single phenotype and underlying mechanisms should be considered to optimize treatment.”

Disclosure: Multiple authors declared affiliations with the pharmaceutical industry. Please refer to the original article for a full list of disclosures.

Reference

Abdel-Aziz MI, Vijverberg SJH, Neerincx AH, et al; U-BIOPRED Study Group. A multi-omics approach to delineate sputum microbiome-associated asthma inflammatory phenotypes. Eur Respir J. Published online November 25, 2021. doi:10.1183/13993003.02603-2021