Barrett's oesophagus (BO) arises from chronic gastro-oesophageal reflux disease(GORD). Patients have an increased risk of adenocarcinoma (ADC), which is the sixth most common cause of cancer mortality in the UK. All ADC develop from BO, and over the last twenty years there has been a marked increase in both conditions. The reasons for this are not known, however, as with some forms of gastric cancer, it is possible that there may be a bacterial aetiology. This study employed both culturebased and molecular techniques to characterise microbial communities colonising the distal oesophageal mucosae in individuals with GORD, BO and ADC, together with healthy controls. Furthermore, in vitro models were designed to create an oral microbiota, from which an oesophageal community could develop. Microbial analysis identified a shift in oesophageal population composition with disease progression, with an incremental increase in total eubacterial scores related to the metaplasia-dysplasia sequence. Additionally, an increased proportion of Gram negative species and potentially pathogenic organisms, such as Peptostreptococcus were identified. Campylobacter spp. were isolated from 75%, 50% and 60% of GORD, BO and ADC patients, respectively, compared with 20% of controls. Helicobacter pylori, which has been proposed to be protective in oesophageal disease, was significantly reduced in disease, especially in ADC patients. In vitro models were successful, with a simple oral microbiota leading to the development of unique, varied oesophageal populations representative of those found in vivo. Additionally, after exposure of this community to bile acid, population dynamics were altered, with an increase in Gram negative species, associated with a rise in haemolytic and mucinolytic activities. Exposure of oesophageal cell lines to these stressed biofilms resulted in increased cell death, and in some cases, amplified expression of p53 and COX-2. In conclusion, this research proved an association between bacterial composition and oesophageal disease. With progression to adenocarcinoma, the community becomes increasingly diversified and Gram negative in character, and therefore, is proposed to be more pathogenic. Further research is required to investigate causal relationships, through which mechanisms for disease initiation and/or maintenance can be understood.
|Date of Award||2010|
|Sponsors||Royal Society of Edinburgh|
|Supervisor||George Macfarlane (Supervisor) & John Dillon (Supervisor)|
- Oesophageal adenocarcinoma
- Barrett's oesophagus
- Oesophageal bacteria
- In vitro models