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Abstract or Project Description

In 1848, a German philosopher, Ludwig Feuerbach, first used the phrase “We are what we eat.” This famous statement is particularly true in Inflammatory Bowel Disease (IBD) where a western diet lacking in plant derived components is a well-recognised risk factor. However, we still do not understand how the food we eat can contribute to IBD. It is clear that diet alone does not cause IBD. Instead, people also need to carry genetic risk factors. Unfortunately, nobody knows how genetics and diet interact to cause IBD. 

Crucially, there is a gene, called AHR, that is both an important sensor of dietary compounds and an IBD risk factor. This provides a unique chance to study how diet and genes interact in IBD. We have found that AHR probably contributes to IBD through effects in an important immune cell, called macrophages. However, exactly what AHR does in macrophages is unknown. Our proposal brings together two labs at the Francis Crick Institute, one that specifically works on AHR and one that specifically works on IBD genetics in immune cells. Together, we will investigate what AHR is doing in macrophages, and intend to figure out how this goes wrong in IBD.

Abstract or Project Description

The bacteria in the human colon can influence gastrointestinal lining cells [intestinal epithelial cells (IECs)] and immune cells within the intestines and throughout the body. One way that bacteria do this is through their metabolites, the chemicals they produce. By influencing IECs and immune cells, gut bacterial metabolites affect resistance and susceptibility to Inflammatory Bowel Disease (IBD), as bacterial metabolites can positively or negatively affect intestinal inflammation and IEC function. Using the methods employed in most human IBD metabolite stool studies, 99% of bacterial metabolites remain unidentified. We have developed a workflow to determine which of these molecules are potentially important for IBD, which are bacterially derived, and which are active or act on immune cells and IECs. In this proposal, we will focus on determining the activity of a class of bacterial molecules called fatty acid amides. We will investigate if they change the activity of IECs and an important immune cell type called dendritic cells. A subset of the fatty acid amide compounds that we find act on IECs and/or dendritic cells will be tested in two models of colonic injury and inflammation.