Gastrointestinal Research Group
Principal Investigators: Professor Emad El-Omar and Dr Georgina Hold
The main research thrust of this group is to understand the role of chronic inflammation in GI malignancy. The common theme is the link between microbial-induced gastrointestinal inflammation and risk of malignant transformation. The main expertise is in molecular microbiology and molecular genetic research.
A major strength of the group is the total support and active involvement of the clinical GI staff within the hospital, creating unprecedented access to valuable clinical material. Collaborations are strong with the Pathology group, Genetics, Immunology, Microbiology and the Rowett Research Institute. There are also strong collaborations with US, European and Japanese groups. Three novel research programmes have been set up around gastric cancer, colorectal cancer and inflammatory bowel disease.
Gastric Cancer Research
Gastric cancer (GC) remains a global health problem being the second commonest cancer killer. The most importnat aetiological agent for this cancer is Helicobacter pylori infection and its associated chronic gastritis. Understanding the mechanisms by which the infection induces cancer offers the only hope of eradicating this disease. It also provides insight into novel strategies for preventing and treating the precancerous stages of the disease. We have previously shown that host genetic polymorphisms in adaptive and innate immune response genes increase the risk of GC and its precursors substantially. We have also shown that the initial handling of H. pylori LPS and CagA is crucial to subsequent events and risk of GC. The specific aims of our programme are to (1) examine the role of some of the newer polymorphisms in relevant genes of the innate and adaptive immune responses in GC, (2) study the molecular mechanisms by which some of the identified polymorphisms increase the risk of GC and its precursors and (3) study the interaction between host genetic factors and bacterial virulence.
Photograph taken at endoscopy of a gastric cancer.
NF-kB (p65) staining of monocytes obtained from TLR4 Asp299Gly wild type and variant subjects. The figure depicts NF-kB staining in red and nuclear staining (DAPI) in blue following E. coli LPS stimulation for 30 min. It can be seen that NF-kB staining remains within the cytoplasm in carriers of the variant TLR4 Asp299Gly allele, whilst in the wild type NF-kB staining has co-localised with the nuclear stain indicating translocation has occurred.
Colorectal Cancer Research
Colorectal cancer (CRC) is the second most common cause of cancer death in the UK. It is estimated that upwards of 50 people die of CRC per day in the UK, and is therefore a major burden to our society and to NHS resources. However, the pathogenesis of CRC remains poorly understood despite major advances in understanding the genetic basis of the disease. Most colorectal cancers arise from small adenomatous polyps that progress through several histologically distinct stages comprising the so-called “adenoma to carcinoma sequence”. These steps are characterised by genetic mutations that occur consequentially but it is not clear what initiates these mutations and what drives their progression. Furthermore, it is not clear why some polyps progress to cancer while the majority do not. The main aims of our CRC research programme are:
- To assess the role of the colonic microbiota in CRC progression
- To study different aspects of the expression of inflammation within the CRC disease process
- Correlate inflammatory changes with known genetic alterations that occur during the course of CRC
Left - Photograph taken during colonoscopy of healthy colonic mucosa.
Right - Photograph taken during colonscopy of a colorectal cancer
Left - Denaturing gradient gel electrophoresis profiles of microbial diversity obtained from colonic polyps and their adjacent normal mucosa indicating that microbial diversity can be dramatically different within a distance of ~ 2cm.
Inflammatory Bowel Disease Research
Ulcerative colitis and Crohn's disease are conditions in which there is chronic inflammation of the digestive tract. Together they are referred to as 'inflammatory bowel disease' (IBD), which affects up to 6% of the population, with approximately 8,500 new cases each year. North East Scotland has a higher than average incidence for both conditions. The pathogenesis of IBD remains poorly understood, although an infectious agent is suspected and several clinical observations support a role for enteric bacteria in IBD. However, no bacterial infection has been consistently linked to the pathogenesis of IBD. The identification of specific gene defects in IBD that are involved in bacterial recognition (e.g. NOD2/CARD15 mutations) strengthens the role of the microbiota in this disease.
Left - Photograph taken during colonoscopy of Crohn’s disease
Right - Photograph taken during colonoscopy of ulcerative colitis
Left - Photograph taken during colonoscopy of normal colonic mucosa
Right - Fluorescent in-situ hybridisation image of Helicobacter within a colonic crypt
The two main areas of research we are currently exploring include the assessment of non-pylori Helicobacter in ulcerative colitis. Within this project we have established fluorescent in-situ hybridisation techniques, which allowus to detect non-pylori Helicobacter within archival and fresh UC tissue specimens. We are also developing proteomics approaches to comparing Helicobacter species that are isolated from colonic tissue.
The second area of IBD research focusses on the role of the colonic microbiota and their metabolic products. The complexity of the colonic microbiota, the relationship of the bacteria to the mucosal surface and the effects of the metabolites, principally the short chain fatty acids, remain poorly understood and require further investigation to increase our knowledge of the bacteria, bacterial metabolite and host responses in the development of inflammatory bowel disease.