The upper-airway microbiome as a biomarker of asthma exacerbations despite inhaled corticosteroid treatment

Javier Perez-Garcia; Mario González-Carracedo; Antonio Espuela-Ortiz; José M Hernández-Pérez; Ruperto González-Pérez; Olaia Sardón-Prado; Elena Martin-Gonzalez; Elena Mederos-Luis; Paloma Poza-Guedes; Paula Corcuera-Elosegui; Ariel Callero; Inmaculada Sánchez-Machín; Javier Korta-Murua; José A Pérez-Pérez; Jesús Villar; Maria Pino-Yanes; Fabian Lorenzo-Diaz

doi:10.1016/j.jaci.2022.09.041

The upper-airway microbiome as a biomarker of asthma exacerbations despite inhaled corticosteroid treatment

J Allergy Clin Immunol. 2023 Mar;151(3):706-715. doi: 10.1016/j.jaci.2022.09.041. Epub 2022 Nov 4.

Authors

Javier Perez-Garcia¹, Mario González-Carracedo², Antonio Espuela-Ortiz¹, José M Hernández-Pérez³, Ruperto González-Pérez⁴, Olaia Sardón-Prado⁵, Elena Martin-Gonzalez¹, Elena Mederos-Luis⁶, Paloma Poza-Guedes⁴, Paula Corcuera-Elosegui⁷, Ariel Callero⁸, Inmaculada Sánchez-Machín⁶, Javier Korta-Murua⁵, José A Pérez-Pérez², Jesús Villar⁹, Maria Pino-Yanes¹⁰, Fabian Lorenzo-Diaz¹¹

Affiliations

¹ Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), La Laguna, Tenerife, Spain.
² Department of Biochemistry, Microbiology, Cell Biology and Genetics, ULL, La Laguna, Tenerife, Spain; Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias (IUETSPC), ULL, La Laguna, Tenerife, Spain.
³ Pulmonary Medicine Service, Hospital Universitario de NS de Candelaria, La Laguna, Tenerife, Spain; Pulmonary Medicine Section, Hospital Universitario de La Palma, La Palma, Spain.
⁴ Severe Asthma Unit, Allergy Department, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain.
⁵ Division of Pediatric Respiratory Medicine, Hospital Universitario Donostia, San Sebastián, Spain; Department of Pediatrics, University of the Basque Country (UPV/EHU), San Sebastián, Spain.
⁶ Allergy Department, Hospital Universitario de Canarias, La Laguna, Tenerife, Spain.
⁷ Division of Pediatric Respiratory Medicine, Hospital Universitario Donostia, San Sebastián, Spain.
⁸ Allergy Service, Hospital Universitario NS de Candelaria, La Laguna, Tenerife, Spain.
⁹ CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; Multidisciplinary Organ Dysfunction Evaluation Research Network (MODERN), Research Unit, Hospital Universitario Dr Negrín, Las Palmas de Gran Canaria, Spain; Li Ka Shing Knowledge Institute at the St Michael's Hospital, Toronto, Ontario, Canada.
¹⁰ Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), La Laguna, Tenerife, Spain; CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain; Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna, La Laguna, Tenerife, Spain. Electronic address: mdelpino@ull.edu.es.
¹¹ Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna (ULL), La Laguna, Tenerife, Spain; Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias (IUETSPC), ULL, La Laguna, Tenerife, Spain. Electronic address: florenzo@ull.edu.es.

PMID: 36343772
DOI: 10.1016/j.jaci.2022.09.041

Abstract

Background: The response to inhaled corticosteroids (ICS) in asthma is affected by the interplay of several factors. Among these, the role of the upper-airway microbiome has been scarcely investigated. We aimed to evaluate the association between the salivary, pharyngeal, and nasal microbiome with asthma exacerbations despite receipt of ICS.

Methods: Samples from 250 asthma patients from the Genomics and Metagenomics of Asthma Severity (GEMAS) study treated with ICS were analyzed. Control/case subjects were defined by the absence/presence of asthma exacerbations in the past 6 months despite being treated with ICS. The bacterial microbiota was profiled by sequencing the V3-V4 region of the 16S rRNA gene. Differences between groups were assessed by PERMANOVA and regression models adjusted for potential confounders. A false discovery rate (FDR) of 5% was used to correct for multiple comparisons. Classification models of asthma exacerbations despite ICS treatment were built with machine learning approaches based on clinical, genetic, and microbiome data.

Results: In nasal and saliva samples, case subjects had lower bacterial diversity (Richness, Shannon, and Faith indices) than control subjects (.007 ≤ P ≤ .037). Asthma exacerbations accounted for 8% to 9% of the interindividual variation of the salivary and nasal microbiomes (.003 ≤ P ≤ .046). Three, 4, and 11 bacterial genera from the salivary, pharyngeal, and nasal microbiomes were differentially abundant between groups (4.09 × 10^-12 ≤ FDR ≤ 0.047). Integrating clinical, genetic, and microbiome data showed good discrimination for the development of asthma exacerbations despite receipt of ICS (AUC_training: 0.82 and AUC_validation: 0.77).

Conclusion: The diversity and composition of the upper-airway microbiome are associated with asthma exacerbations despite ICS treatment. The salivary microbiome has a potential application as a biomarker of asthma exacerbations despite receipt of ICS.

Keywords: 16S rRNA; asthma; biomarker; exacerbations; inhaled corticosteroids; microbiota; nasal; pharyngeal; precision medicine; saliva.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Administration, Inhalation
Adrenal Cortex Hormones / therapeutic use
Anti-Asthmatic Agents* / therapeutic use
Asthma* / drug therapy
Biomarkers
Humans
Microbiota*
RNA, Ribosomal, 16S

Substances

Anti-Asthmatic Agents
RNA, Ribosomal, 16S
Adrenal Cortex Hormones
Biomarkers