- Title
- Utilisation of diet and microbial products as novel therapies for COPD
- Creator
- Budden, Kurtis Francis
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2020
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous respiratory condition caused primarily by cigarette smoke. It is the third leading cause of death globally, in part because current treatments/interventions (including smoking cessation) cannot halt or reverse progression. The gastrointestinal microbiome has been implicated in the pathogenesis of chronic respiratory diseases through the gut-lung axis, and both host and the microbial metabolism of dietary components can regulate immune responses that contribute to COPD pathogenesis. Hypothesis and Aims: We hypothesised cigarette smoke-induced changes in host and microbial metabolism would contribute to the development and progression of disease in a murine model of experimental COPD, and that these changes might be targeted by dietary or pharmacological interventions to alleviate disease symptoms. Thus, the aims of this project were to characterise changes in metabolite profiles of the lung, plasma and caecum contents in experimental COPD, and assess the impact of microbial metabolites (short chain fatty acids; SCFAs), dietary (resistant starch; RS, omega-3 polyunsaturated fatty acids or linoleic acid; LA) or pharmacological interventions (probiotic administration or inhibition of soluble epoxide hydrolase; sEH) on host and microbial metabolism and disease pathogenesis. Methods: Female c57BL/6 mice were fed experimental diets (control, high RS, high omega-3, LA diets), were treated with probiotic Bifidobacterium longum by gavage, or were administered SCFAs or soluble epoxide-hydrolase (sEH) in drinking water. GPR43-deficient (GPR43-/-) mice were also used in experiments with the high RS diet and SCFAs. Mice were exposed to cigarette smoke or room air for up to 12 weeks, with treatments maintained for the duration of the experiment. Hallmark features of COPD assessed by airway inflammation in bronchoalveolar lavage fluid (BALF), parenchymal inflammation, alveolar destruction and collagen deposition in lung histology, and lung function analysis. The abundance of metabolites in lung tissue, plasma, caecum contents and BALF supernatant were analysed by ultra high performance liquid chromatography-tandem mass spectrometry or gas chromatography, and factors associated with immune regulation assessed by qPCR (for mRNA) or ELISA (for protein). Results: Cigarette smoke exposure for 12 weeks induced hallmark features of COPD and altered the metabolite profiles of lung tissue, plasma and caecum contents, with the greatest effect in lung tissue. Amino acid, bile acid and microbial metabolism (e.g. short chain fatty acid) pathways were altered in lung tissue, plasma and caecum contents, and additional changes were observed in individual tissue types. Cigarette smoke-exposure for 8 weeks also reduced caecal, but not plasma SCFAs. A high RS diet prevented cigarette smoke-induced SCFA depletion and alleviated inflammation and alveolar destruction after 8 weeks of cigarette smoke exposure, and inflammation, collagen deposition and lung obstruction after 12 weeks of cigarette smoke exposure. These effects were preserved in GPR43-/- mice and were associated with reduced lung IL-33 protein and colon Tlr4 expression, but increased lung chemokine expression (Ccl4, Ccl12, Cxcl9). Administration of SCFAs (acetate, propionate or butyrate) replicated most effects of the high RS diet, although there were differences between individual SCFAs. Whilst probiotic administration increased caecal butyrate and alleviated cigarette smoke-induced inflammation, the use of repeated gavage was not suitable use in the current model. Finally, the omega-3 diet had little impact on hallmark features of COPD, but increased BAL supernatant concentrations of lipid-derived immune mediators (oxylipins)produced from metabolism of omega-3 polyunsaturated fatty acids. The LA diet increased the number of macrophages in BALF, and increased the abundance of LA-derived oxylipins including sEH-derived DiHOMEs in both room air- and cigarette smoke-exposed mice. Inhibition of sEH alleviated LA-induced airway inflammation which was associated with reduced 12(13)-DiHOME, Inhibition of sEH also alleviated cigarette smoke-induced alveolar destruction and improved lung function. Cigarette smoke exposure had little influence on oxylipin profiles in mice fed the control diet, but altered the abundance of omega--3 and LA-derived oxylipins in the respective diets. Conclusion: Cigarette smoke exposure altered the abundance of host and microbial metabolites in the lung, as well as in plasma and caecum contents. Cigarette smoke-induced depletion of SCFAs contributed to the pathogenesis of experimental COPD, and high LA intake increased airway inflammation, potentially due to increased production of 12(13)-DiHOME. These findings provide further evidence for the role of diet and host/microbial metabolism in COPD pathogenesis, and suggest that a high RS or low LA diet, SCFA supplementation or sEH inhibition may be novel therapeutic strategies for COPD patients, either alone or in combination with existing treatments. These findings provide important initial data which will help to develop future studies in animal models and human COPD patients to further refine these interventions and improve outcomes for COPD patients.
- Subject
- COPD; microbiome; linoleic acid; fibre; metabolites; metabolomics; diet; SCFA; propionate; cigarette smoke; omega-3; omega-6
- Identifier
- http://hdl.handle.net/1959.13/1412409
- Identifier
- uon:36481
- Rights
- Copyright 2020 Kurtis Francis Budden
- Language
- eng
- Full Text
- Hits: 4586
- Visitors: 5152
- Downloads: 671
| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 7 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 321 KB | Adobe Acrobat PDF | View Details Download |