Title: Identifying the influence of the microbiome and metabolome on the normal and malignant murine intestinal stem cell
Funder: World Cancer Research Fund

Abstract: Background: In 2011 the World Cancer Research Fund upgraded the evidence for a protective effect of dietary fibre on colorectal cancer (CRC) from 'probable' to 'convincing'. One reason suggested for this effect is that the fibre is known to promote the growth of certain types of bacteria commonly found in the intestine. These bacteria digest the fibre and produce chemicals which interact with the cells that line the intestine. These types of bacteria are often referred to as probiotics and have been shown to suppress immune inflammatory responses. Inflammation of the intestine is linked to the onset of CRC, as it can cause damage to the DNA of intestinal stem cells, which maintain the surface of the intestine. In contrast, other types of bacteria produce chemicals which are known to mutate DNA and could potentially cause the DNA mutations in the stem cells that initiate and drive CRC. Thus the interactions between the diet, bacteria, immune system and the intestinal stem cells that promote or prevent CRC is highly complex. Our limited understanding of this effect is currently a significant barrier to the obvious potential for identifying possible treatments for CRC, the fourth most commonly diagnosed cancer in the world. Aims and Objectives: Our overall aim is to identify if certain bacteria that live in the intestine can affect the behaviour of a normal and/or cancerous intestinal stem cell and establish how they do it. We will determine this in two ways. Firstly by extracting normal and cancerous stem cells and growing them in the laboratory in the presence of different bacteria or the chemicals that they produce. Secondly by introducing different types of bacteria to the intestine in which we can create cancerous stem cells in a controlled fashion. This will allow us to directly investigate the effect that each bacteria has on the stem cells in the absence or presence of normal bacteria and immune responses. How It Will Be Done: We will perform this work using state of the art experimental models of CRC in which the intestinal stem cells have been labelled. This label allows us to identify them and isolate them for growth in the laboratory. We can use these stem cells to grow the normal structures of the lining of the intestine. We can also take these stem cells and in a controlled fashion mutate a gene called Apc. Mutation of the Apc gene is the earliest and most common event in CRC patients. After mutation, the stem cells then grow to form structures similar to the tumours observed in CRC patients. We will grow these stem cells together with different bacteria that have been associated with pro- or anti- CRC effects. Using this method we will screen for bacteria that have an effect on the normal and/or cancerous stem cells. Any bacteria we identify will then be introduced to the intestine in which we can also replicate cancer by deleting the Apc gene. Using these tools, we propose to grow normal and cancerous stem cells in the presence of different bacterial species, to identify which types alter their behaviour and which chemicals are responsible for the effect. Potential Impact: At the end of this study, we will have identified types of bacteria which affect the behaviour of the normal and cancerous intestinal stem cell and which chemicals they produce are responsible. The project could have two key impacts. It will create an explanation of how diet via the bacteria in our intestine can have a negative or positive impact on CRC, thereby helping to promote the benefits of a good diet. Secondly our increased understanding of the relationships between bacteria and the normal or cancerous stem cell may identify new treatments for CRC and/or it may deliver a set of bacterial markers that will permit a much better risk assessment for patients with CRC or identify patients who are susceptible to CRC.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;INFECTION