Association of Exacerbation Phenotype with the Sputum

Association of Exacerbation Phenotype with the Sputum

Yang et al. J Transl Med (2021) 19:121 https://doi.org/10.1186/s12967-021-02788-4 Journal of Translational Medicine RESEARCH Open Access Association of exacerbation phenotype with the sputum microbiome in chronic obstructive pulmonary disease patients during the clinically stable state Chia‑Yu Yang1,2,3 , Shiao‑Wen Li3, Chia‑Yin Chin3, Chia‑Wei Hsu3,4, Chi‑Ching Lee5, Yuan‑Ming Yeh6† and Kuo‑An Wu7,8*† Abstract Background: Chronic obstructive pulmonary disease (COPD) is a progressive, life‑threatening lung disease with increasing prevalence and incidence worldwide. Increasing evidence suggests that lung microbiomes might play a physiological role in acute exacerbations of COPD. The objective of this study was to characterize the association of the microbiota and exacerbation risk or airfow limitation in stable COPD patients. Methods: The sputum microbiota from 78 COPD outpatients during periods of clinical stability was investigated using 16S rRNA V3‑V4 amplicon sequencing. The microbiome profles were compared between patients with difer‑ ent risks of exacerbation, i.e., the low risk exacerbator (LRE) or high risk exacerbator (HRE) groups, and with diferent airfow limitation severity, i.e., mild to moderate (FEV1 50; PFT I) or severe to very severe (FEV1 < 50; PFT II). ≥ Results: The bacterial diversity (Chao1 and observed OTUs) was signifcantly decreased in the HRE group compared to that in the LRE group. The top 3 dominant phyla in sputum were Firmicutes, Actinobacteria, and Proteobacteria, which were similar in the HRE and LRE groups. At the genus level, compared to that in the LRE group (41.24%), the proportion of Streptococcus was slightly decreased in the HRE group (28.68%) (p 0.007). However, the bacterial diver‑ sity and the proportion of dominant bacteria at the phylum and genus levels were= similar between the PFT I and PFT II groups. Furthermore, the relative abundances of Gemella morbillorum, Prevotella histicola, and Streptococcus gordonii were decreased in the HRE group compared to those in the LRE group according to linear discriminant analysis efect size (LEfSe). Microbiome network analysis suggested altered bacterial cooperative regulation in diferent exacerba‑ tion phenotypes. The proportions of Proteobacteria and Neisseria were negatively correlated with the FEV1/FVC value. According to functional prediction of sputum bacterial communities through Phylogenetic Investigation of Commu‑ nities by Reconstruction of Unobserved States (PICRUSt) analysis, genes involved in lipopolysaccharide biosynthesis and energy metabolism were enriched in the HRE group. Conclusion: The present study revealed that the sputum microbiome changed in COPD patients with diferent risks of exacerbation. Additionally, the bacterial cooperative networks were altered in the HRE patients and may contribute *Correspondence: wu5830@ms26.hinet.net †Yuan‑Ming Yeh and Kuo‑An Wu contributed equally to this work 7 Department of Internal Medicine, Taoyuan Armed Forces General Hospital, No. 168, Zhongxing Rd., Longtan District, Taoyuan 32551, Taiwan (R.O.C.) Full list of author information is available at the end of the article © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Yang et al. J Transl Med (2021) 19:121 Page 2 of 14 to disease exacerbation. Our results provide evidence that sputum microbiome community dysbiosis is associated with diferent COPD phenotypes, and we hope that by understanding the lung microbiome, a potentially modifable clinical factor, further targets for improved COPD therapies during the clinically stable state may be elucidated. Keywords: COPD, Sputum microbiome, Stable disease, Exacerbation risk, Lung function, 16S sequencing Background the prevalence of airway bacteria occurring during acute Chronic obstructive pulmonary disease (COPD) is a exacerbations of COPD [10–12]. An increased bacterial common respiratory disease characterized by airfow load has been associated with a decline in lung func- limitation, lung function impairment, and airway infam- tion [13] and increased rates of exacerbations in COPD mation. Te incidence of COPD has increased world- patients [14], suggesting an important role of bacteria in wide, and it will become the third most prevalent cause the pathogenesis of COPD. Advances in next-generation of death by 2030 [1]. Te Epidemiology and Impact of sequencing platforms for 16S rRNA gene sequencing COPD (EPIC) Asia survey concluded that there was a have provided opportunities to study the lung microbi- high prevalence of COPD and a substantial socioeco- omes in COPD patients, and the results have suggested nomic burden of the disease in nine Asia–Pacifc regions that changes in the lung microbiota may be associated [2]. Airway obstruction, which is confrmed by spirom- with enhanced airway infammation and disease pro- etry, leads to air trapping and shortness of breath in gression [15]. In patients with COPD, two large studies response to physical exertion, and the poorly irreversible (AERIS study and COPDMAP study) have recently inves- airway obstruction that characterizes COPD is progres- tigated the value of respiratory microbiome research to sive. In 2007, the grading of COPD severity proposed by understand the association of microbiome changes and the Global Initiative for Chronic Obstructive Lung Dis- COPD exacerbations [16, 17]. Interestingly, both studies ease (GOLD) was based on forced expiratory volume in also identifed alteration in the taxonomic composition of 1 s (FEV1) only. Tis classifcation could not adequately the lung microbiome related to the frequency of exacer- predict clinical outcomes [3, 4]. Exacerbations of COPD bation. Pragman et al. reported that even during periods are important events in the disease course, and in par- of clinical stability, the frequent exacerbation phenotype ticular, mortality in the year after an exacerbation requir- is associated with decreased alpha diversity, beta diver- ing hospital admission is estimated to be as high as 21% sity clustering, and changes in taxonomic abundance [5]. Te Evaluation of COPD Longitudinally to Identify [18]. Predictive Surrogate End-points (ECLIPSE) study sug- Most patients with COPD are stable outpatients, and gested that individuals with two or more exacerbations an important clinical challenge is to provide COPD out- in a given year represent a distinct frequent exacerbation patients appropriate education and prescribe appropriate phenotype [6]. However, exacerbations can occur across therapy to prevent exacerbations. Te current param- all stages of airfow limitation measured by FEV1, which eters for evaluating the severity of COPD patients are emphasizes the need to identify other predictors of high airfow limitation, symptoms, and exacerbation risks. exacerbation risk [6]. Te GOLD 2011 revision presented Terefore, we undertook the present study to determine an ABCD classifcation that combined respiratory symp- if the lung microbiome is associated with COPD clinical toms, risks of exacerbations, and airfow limitations as assessment parameters. Our hypothesis is that the lung indicated by FEV1 [7]. In 2017, Te Global Initiative for microbiota alteration is important factor of exacerbation Chronic Obstructive Lung Disease (GOLD) guide to risk or airfow limitation in COPD outpatients during COPD diagnosis and management used a threshold of periods of clinical stability. We hope that by understand- two or more acute exacerbations in the previous year or ing the lung microbiome, a potentially modifable clinical at least one hospital admission related to an acute exacer- factor, further targets for improved COPD therapies may bation to identify individuals at high risk of future events be elucidated. (groups C and D) and separated spirometric grades from the “ABCD” groupings [8]. Methods Recent data have suggested that COPD is a complex Study subjects and study design and heterogeneous disease resulting from a number of Seventy-eight subjects with COPD were enrolled in diferent pathological processes, including infections this study. Te study was approved by the Institutional [9]. Bacterial pathogens are commonly identifed in the Review Board of the Tri-Service General Hospital Tai- respiratory tracts of patients both in the stable state and wan, and all subjects were enrolled from April 2015 to during acute exacerbations, with signifcant changes in April 2016 and provided written informed consent. Te Yang et al. J Transl Med (2021) 19:121 Page 3 of 14 patients were included if they were aged

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