Defining microbial and metabolite markers for exacerbation in chronic obstructive pulmonary disease (COPD)

Abstract

Chronic Obstructive Pulmonary Disease (COPD) is a common, yet preventable and treatable disease. COPD is characterised by emphysema, chronic bronchitis, and by a constant airflow limitation. Even with treatment, in 2016 COPD was the cause of more than 3 million deaths. It is the third disease in terms of mortality, and it has been associated with a significant health and economic burdens through hospital admissions and absenteeism from work. Cigarette smoking is one of the main risk factors to develop the disease. Exacerbation periods are associated with the worsening of symptoms and is linked with inflammatory responses and microbial infections, with a decrease of lung function and quality of life. However, greater understanding is needed into COPD to provide insight into the underlying disease and to provide biomarkers for diagnosis and treatment. In this study the use of microbiomic and metabolomic technologies were explored to assess patients with COPD, and to correlate the disease with its severity status, exacerbation periods, antibiotics and corticosteroids treatments, smoking status and different time points of collection. Firstly, flow infusion electrospray ionization mass spectrometry (FIE-MS) was tested if it could reveal biologically meaningful data using biopsies of lung squamous cell carcinoma (SSC) samples paired with histologically normal adjacent tissues. Lung SSC represented a well-characterised tissue and there is an increased risk of lung cancer in COPD patient. A total of 8 paired biopsies samples (tumour tissue and matched histologically normal tissue) were collected from patients with lung SCC and assessed using FIE-MS. These analyses showed the established metabolomic changes in SCC but revealed some novel aspects, particularly in vitamin metabolism. Having validated the metabolomic approach, the sputum metabolomes of 17 patients with COPD collected in four different time points, over the period of 18 months were assessed. The saliva of 22 patients was also examined and collected at four different time points over 18 months, using metabolomics approaches as FIE-MS. Sputum metabolomics suggested mitochondrial dysfunction associated with disease severity. Putrescine was shown to be associated with oxidative stress during exacerbation periods and found fatty acids changes associated with antibiotics treatment was seen. The saliva metabolome showed that oxidative stress has an important facet of disease severity and that ammonia recycling might be linked to amino acid metabolism due to muscle wastage in severe and very severe patients. Alterations in energy metabolism pathways and mitochondrial function were also observed. The microbiome of 14 patients using paired saliva and sputum samples was also investigated. Samples were collected in four different time points over 18 months and assessed by 16S rRNA amplicon sequencing. The results demonstrated that Firmicutes was the most abundant phylum in COPD oral cavity and lower respiratory tract. It was also found that the oral cavity microbial population may linked to the lower respiratory tract. Antibiotics and corticosteroids affected the microbiome of patients, proving an environment for other commensal pathogens to grow. The findings also showed that Firmicutes and Proteobacteria were associated with exacerbation periods in sputum and saliva samples. In summary, metabolomic aspects were identified in saliva and sputum that characterise changes in the energy metabolism, mitochondrial function and oxidative stress which could have systemic effects, especially on skeletal muscle. The microbiome showed that oral cavity microbial population may have an impacted in the lower respiratory tract

Date of Award	2020
Original language	English
Awarding Institution	Aberystwyth University
Supervisor	Luis Mur (Supervisor) & Sharon Huws (Supervisor)