- Title
- Understanding the molecular mechanisms of chronic respiratory diseases through multiomics approaches
- Creator
- Rehman, Saima Firdous
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2022
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Background: Chronic obstructive pulmonary disease (COPD) is the third top cause of deaths worldwide. Currently, there are limited therapeutic approaches available that predominantly relieve symptoms, but they do not stop disease progression. The gut microbiome and metabolome, the impact of host and microbial metabolites, including lipid mediators, is poorly understood, as is the role of dietary PUFAs in influencing disease progression in COPD. Hypothesis and Aims: Therefore, I hypothesised and aimed that COPD patients have altered microbiome composition and metabolism associated with disease development and progression. In a murine model of experimental COPD, cigarette smoke exposure alters lipid mediator profiles, and modification of these profiles through dietary MUFA (monounsaturated diet), LA (linoleic acid) or ALA (alpha-linolenic acid diet) or pharmacological intervention (soluble epoxide hydrolase: sEH inhibition) will affect COPD pathogenesis. Integrative multi-omics approaches will assist in elucidating these microbiome, metabolome and lipid mediator changes in COPD pathogenesis. Methods: Microbiome analysis and metabolomics were applied to define and characterize the microbiome and metabolome composition changes in human COPD patients and healthy controls. Female C57BL/6 mice were exposed to nose-only cigarette smoke exposure for 12 weeks to profile oxylipins using ultra-high-performance lipid chromatography-tandem mass spectrometry (UPLC-MS/MS). In addition, the hallmark features of COPD (airway inflammation, histology, and lung function) were assessed. Female C57BL/6 mice were fed a normal control diet, or three different high-fat diets composed of predominantly oleic acid MUFA, linoleic acid (LA) omega-6 PUFA, or α-linolenic acid (ALA) omega-3 PUFA diets. TPPU, an sEH inhibitor, was also administered in drinking water and mice exposed to cigarette smoke to induce experimental COPD. Results: Streptococcus species and Lachnospiraceae family members were identified as key separators of COPD patients from healthy controls.12-week cigarette smoke exposure induced the hallmark features of COPD in mice. LTE4 and 19,20-DiHDoHE were negatively correlated with inflammation and lung function. All high-fat diets reduced cigarette smoke-induced lung inflammation but did not improve emphysema or lung function compared to the control diet. Compared to the MUFA diet, both PUFA-dominant high-fat diets increased inflammation, and the LA diet improved lung function. sEH treatment reduced inflammation in acute (2 weeks) and chronic (12 weeks) cigarette smoke exposure, irrespective of diet composition. Conclusions: A distinct disease-associated gut microbiome and metabolome exist in COPD patients and healthy controls. Key lipid mediators associated with inflammation and lung function decline in experimental COPD were identified. LTE4 and 19,20-DiHDPA and other significant lipids could be further explored for their potential role in disease and as therapeutic targets, especially in COPD disease progression. Both amount and composition of dietary fats impact disease features in COPD, with airway inflammation and lung function both affected. Inhibition of sEH reduced airway inflammation and may prove useful as a therapeutic strategy. The conclusions of this thesis will provide valuable knowledge of the biomarkers, bacterial species, and lipid mediators and their role in COPD pathogenesis.
- Subject
- COPD; gut microbiome; metabolome; dietary interventions; experimental COPD; multiomics
- Identifier
- http://hdl.handle.net/1959.13/1508073
- Identifier
- uon:56081
- Rights
- Copyright 2022 Saima Firdous Rehman
- Language
- eng
- Full Text
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|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 6 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 375 KB | Adobe Acrobat PDF | View Details Download |