Kazuhiro Yatera,1,* Zhang Wang,2,* Yoko Shibata,3 Nobuhisa Ishikawa,4 Tetsuya Homma,5 Kiyoyasu Fukushima,6 Osamu Hataji,7 Yoshikazu Inoue,8,9 Hiroki Kawabata,1 Keisuke Miki,10 Kazuhiro Sato,11 Kazunori Tobino,12 Makoto Yoshida,13 Takeo Ishii,14 Risako Ito,14 Tamami Kobayashi,14 Shinya Kawamatsu,14 Chris H Compton,15 Paul W Jones15 

1University of Occupational and Environmental Health Japan, Fukuoka, Japan; 2Institute of Ecological Sciences, School of Life Sciences, South China Normal University, Guangzhou, People’s Republic of China; 3Fukushima Medical University, Fukushima, Japan; 4Hiroshima Prefectural Hospital, Hiroshima, Japan; 5Showa University School of Medicine, Tokyo, Japan; 6Japanese Red Cross, Nagasaki Genbaku Isahaya Hospital, Nagasaki, Japan; 7Matsusaka Municipal Hospital, Mie, Japan; 8Osaka Anti-tuberculosis Association, Osaka Fukujuji Hospital, Osaka, Japan; 9NHO Kinki Chuo Chest Medical Center, Osaka, Japan; 10NHO Osaka Toneyama Medical Center, Osaka, Japan; 11Nagaoka Red Cross Hospital, Niigata, Japan; 12Iizuka Hospital, Fukuoka, Japan; 13NHO Fukuoka National Hospital, Fukuoka, Japan; 14GSK K.K., Tokyo, Japan; 15GSK, R&D Global Medical, Brentford, Middlesex, UK

*These authors contributed equally to this work

Correspondence: Zhang Wang, Institute of Ecological Sciences, School of Life Sciences, South China Normal University, Guangzhou, People’s Republic of China, Tel +86-20-85211372, Fax +86-20-85211850, Email wangz@m.scnu.edu.cn

Background: In Western studies, lung microbiome changes are reported in patients with chronic obstructive pulmonary disease (COPD) and are associated with poorer outcomes, but similar studies in Asian patients or those with less severe COPD are limited.
Methods: The Acute Exacerbation and Respiratory InfectionS in COPD Japan (AERIS-J; jRCT1080224632/NCT03957577) was a prospective, non-interventional study to evaluate sputum microbiome diversity at baseline and after 12 months (V2; exploratory analysis), in patients aged 40– 80 years with stable COPD (June 2019–June 2022). Baseline sputum potentially pathogenic organisms (PPOs) were identified. Blood cell counts and COPD Assessment Test (CAT) scores were collected at baseline and COPD symptoms measured over 12 months using the Evaluating Respiratory Symptoms in COPD and EXAcerbations of Chronic pulmonary disease Tool, collected by eDiary.
Results: Patients (N=63) had a mean age of 72.8 years, and percent predicted post-bronchodilator forced expiratory volume in 1 second was 58.3%; 92% were male. Across 62 baseline sputum samples, microbiome composition was similar between 16S rRNA/metagenomic datasets. Patients graded Global Initiative for Chronic Obstructive Lung Disease (GOLD) III versus GOLD I/II had minimal differences in their microbial taxonomic profile and no differences in microbial diversity (Wilcoxon P=0.71). Alpha diversity (Shannon index) positively correlated with blood basophils (rho=0.41; P=0.0019) and negatively correlated with CAT score (rho=0.36; P=0.0069). Alpha diversity and sputum (rho: − 0.0637; P=0.7836) or blood (rho: 0.1739; P=0.2043) eosinophils were not correlated. No difference in alpha (P=0.5) or beta (P=0.3) diversity or Operational Taxonomic Unit (Anosim R=− 0.024; P=0.892) was observed between PPO-positive or -negative sputum.
Conclusion: A less diverse microbiome correlated with poorer health status and lower blood basophils in patients with COPD and moderate airflow limitation. There was no relationship between PPO presence and microbiome diversity.
Plain Language Summary: Chronic obstructive pulmonary disease (COPD) is a progressive lung condition resulting in breathing difficulties. Research has shown that patients with COPD experience changes in the diversity of bacteria in their lungs, leading to a worsening of symptoms. The lung microbiome includes different types of bacteria, and is involved in important roles, such as regulating the immune system and protecting the lung from invading pathogens. Many studies on the microbiome have been based in western countries, and there are few studies among Asian patients and populations with moderate COPD.
The aim of this year-long study was to assess the diversity of the lung microbiome in Japanese patients with COPD and moderate airflow limitation, and how it affects patients’ immunity and disease severity. Patients’ sputum and blood samples were obtained at the start of the study and the different types of bacteria in the sputum and the number of immune cells in the blood were measured. Patients’ symptoms were also assessed at study start. Results showed that a less diverse lung microbiome was associated with lower levels of blood immune cells and worse COPD symptoms.
These results improve our knowledge of the lung microbiome in an Asian population with COPD, providing insights into how lower bacterial diversity may worsen patient immunity and COPD severity.

Keywords: 16S rRNA, Asia, basophil, COPD assessment test, sputum, metagenomic