Meta-omics profiling of the gut-lung axis illuminates metabolic networks and host-microbial interactions associated with elevated lung elastance in a murine model of obese allergic asthma.

Autor: Heinrich VA; Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.; Medical Scientist Training Program, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States., Uvalle C; Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA, United States., Manni ML; Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States., Li K; Center for Medicine and the Microbiome, University of Pittsburgh, Pittsburgh, PA, United States., Mullett SJ; Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.; Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA, United States., Donepudi SR; Integrative Systems Biology Program, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States., Clader J; Center for Medicine and the Microbiome, University of Pittsburgh, Pittsburgh, PA, United States., Fitch A; Center for Medicine and the Microbiome, University of Pittsburgh, Pittsburgh, PA, United States., Ellgass M; Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA, United States., Cechova V; Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States., Qin S; Center for Medicine and the Microbiome, University of Pittsburgh, Pittsburgh, PA, United States.; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States., Holguin F; Division of Pulmonary Sciences and Critical Care, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States., Freeman BA; Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States., Methé BA; Center for Medicine and the Microbiome, University of Pittsburgh, Pittsburgh, PA, United States.; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States., Morris A; Center for Medicine and the Microbiome, University of Pittsburgh, Pittsburgh, PA, United States.; Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.; Department of Clinical and Translational Science, University of Pittsburgh, Pittsburgh, PA, United States., Gelhaus SL; Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States.; Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, PA, United States.; Department of Clinical and Translational Science, University of Pittsburgh, Pittsburgh, PA, United States.
Jazyk: angličtina
Zdroj: Frontiers in microbiomes [Front Microbiomes] 2023; Vol. 2. Date of Electronic Publication: 2023 May 05.
DOI: 10.3389/frmbi.2023.1153691
Abstrakt: Obesity and associated changes to the gut microbiome worsen airway inflammation and hyperresponsiveness in asthma. Obesogenic host-microbial metabolomes have altered production of metabolites that may influence lung function and inflammatory responses in asthma. To understand the interplay of the gut microbiome, metabolism, and host inflammation in obesity-associated asthma, we used a multi-omics approach to profile the gut-lung axis in the setting of allergic airway disease and diet-induced obesity. We evaluated an immunomodulator, nitro-oleic acid (NO 2 -OA), as a host- and microbial-targeted treatment intervention for obesity-associated allergic asthma. Allergic airway disease was induced using house dust mite and cholera toxin adjuvant in C57BL6/J mice with diet-induced obesity to model obesity-associated asthma. Lung function was measured by flexiVent following a week of NO 2 -OA treatment and allergen challenge. 16S rRNA gene (from DNA, taxa presence) and 16S rRNA (from RNA, taxa activity) sequencing, metabolomics, and host gene expression were paired with a Treatment-Measured-Response model as a data integration framework for identifying latent/hidden relationships with linear regression among variables identified from high-dimensional meta-omics datasets. Targeting both the host and gut microbiota, NO 2 -OA attenuated airway inflammation, improved lung elastance, and modified the gut microbiome. Meta-omics data integration and modeling determined that gut-associated inflammation, metabolites, and functionally active gut microbiota were linked to lung function outcomes. Using Treatment-Measured-Response modeling and meta-omics profiling of the gut-lung axis, we uncovered a previously hidden network of interactions between gut levels of amino acid metabolites involved in elastin and collagen synthesis, gut microbiota, NO 2 -OA, and lung elastance. Further targeted metabolomics analyses revealed that obese mice with allergic airway disease had higher levels of proline and hydroxyproline in the lungs. NO 2 -OA treatment reduced proline biosynthesis by downregulation of pyrroline-5-carboxylate reductase 1 (PYCR1) expression. These findings are relevant to human disease: adults with mild-moderate asthma and BMI ≥ 25 had higher plasma hydroxyproline levels. Our results suggest that changes to structural proteins in the lung airways and parenchyma may contribute to heightened lung elastance and serve as a potential therapeutic target for obese allergic asthma.
Competing Interests: Conflict of interest BF acknowledges an interest in Creegh Pharmaceuticals, Inc. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Databáze: MEDLINE
Externí odkaz: