Bile acid modification by the human gut microbiota and its role in pathogenesis of colorectal cancer

The human gut is home to a wide range of bacteria, and every adult harbours around 100 trillion microbial cells in their intestines belonging to hundreds of bacterial species. This population of bacteria is referred to as the gut microbiota, and these bacteria are thought to undertake numerous beneficial activities. However some of the activities undertaken by the gut microbiota may be involved in the development of colorectal cancer (CRC).
Diet, and in particular a high intake of animal fat and red meat, has been identified as a major risk factor for CRC, but it is not yet clear how these dietary factors lead to the development of CRC. It is important for us to understand the causes of diseases like CRC, in order to develop effective treatments or identify ways in which the disease could be prevented altogether.
Recent studies have indicated that the gut microbiota may be an important factor in the influence of diet on CRC risk, and in particular the ability of gut microbes to modify components of bile, called bile acids. Bile acids are naturally produced by our bodies to help us digest the fat contained within the food we eat, and a diet rich in fat results in a increased level of bile acid in the intestine. Bile acids are readily converted to different forms by the gut microbiota, and some of these altered bile acids may be carcinogenic and affect the expression of genes thought to be important in the development of CRC.
The purpose of this study is to investigate the relationship between the modification of bile acids by gut bacteria and development of CRC, to determine how these microbes may cause this disease. By comparing the gut bacteria of individuals with CRC and those who are healthy, we will be able to identify any association between activities of these microbes and risk of disease. Subsequently we will be able to look at the effect of these bacteria on specific human genes known to be associated with CRC, which will allow us to identify the how gut bacteria may trigger development of CRC.

CRC is the third most common malignancy worldwide and it is estimated that more than 100 new cases are diagnosed daily in the UK. The incidence of this disease worldwide has risen from ~500,000 new cases in 1975 to over a million new cases in 2002. Acquisition and pathogenesis of sporadic CRC is complex and multifactorial. While diet has consistently been associated with an increased risk of CRC, the underlying mechanisns which result in genetic damage and carcinogenesis are poorly understood. There is increasing evidence that the indigenous gut microbial population is a significant factor in the pathogenesis of CRC, and that this community mediates the effects of diet on colonic health.
In particular microbial bile acid modification is emerging as a key activity through which the gut microbial population and dietary factors interact to initiate CRC or enhance its progression. The products of microbial bile acid metabolism have been proposed to act as carcinogens and activate pro-inflammatory regulators such as NF-kB and COX-2 which result in the inhibition of apoptosis and the survival of malignant cells. Recent studies have also indicated that the capacity for bile acid modification may vary between the gut microbial populations of different individuals, and if so this could relate to overall risk of CRC acquisition.
The overall aim of this project is to identify any relationship between the capacity for bile acid modification in the human gut microbiota and acquisition of colorectal cancer. The capacity for bile acid metabolism in the gut microbiomes of healthy individuals, and those with CRC and pre-cancerous polyps will be determined and compared. The contribution of microbial bile salt hydrolase (BSH) upon activation of key host encoded genes (NF-kB and COX-2) involved in inflammation, inhibition of apoptosis, and acquisition of CRC will be established. Ultimately this will clarify the relationship between microbial bile acid metabolism and CRC, and elucidate underlying mechanisms of disease.