An international study led by scientists at The Roslin Institute highlights gut macrophage dysregulation as a key process leading to Inflammatory Bowel Disease.
Over 200 different regions of the genome have been associated with IBD susceptibility. Most studies to date have implicated overactivation of T- cells, aberrant protein and organelle recycling and abnormal immune responses to certain bacteria in the development of the disease. However, the role of intestinal macrophages, key regulators of the inflammatory response in the gut, is not clearly understood.
Dr Kenneth Baillie and Professor David Hume at The Roslin Institute, together with colleagues from the international FANTOM Consortium, have examined the differentiation of monocytes to macrophages in the presence of the growth factor macrophage colony-stimulating factor (CSF1) and their response to the bacterial-associated molecule lipopolysaccharide (LPS), which mirrors the adaptation of monocytes to the gut environment.
Using the transcriptional profiling data generated within FANTOM5, the authors were able to dissect the complex sequence of gene expression events that takes place in macrophages as they differentiate to adapt to the gut wall. They found that many of the genomic regions previously associated with IBD contain promoters that were strongly and specifically involved in the responses to CSF1 and LPS. Based upon these findings, the authors identified novel candidate genes within known IBD loci and identified a further 134 candidate genomic regions associated with IBD susceptibility.
This study published in PLoS Genetics highlights the importance of gene promoters and enhancers in the modulation of macrophage response to bacterial stimuli in the gut and how defects in this process are likely to lead to the development of IBD.
The study was led by Professor Hume of The Roslin Institute.
“This study represents a paradigm shift in the analysis of genome-wide. Instead of approaching the question hypothesis-free, we used genetic data from humans to test clear prior hypothesis and found that it was strongly supported by the data. The results suggest potential therapeutic approaches, in that we now know that monocyte differentiation is the key process that goes wrong in IBD patients”.
Professor David Hume,The Roslin Institute