Control of intestinal macrophage homeostasis by the gut microbiota
Dr Elizabeth Mann
The intestinal immune system is highly specialised to maintain the delicate balance between tolerance towards the trillions of harmless bacteria that line the intestine, and active immune responses against disease-causing pathogens.
Macrophages are crucial components of the intestinal immune system that mediate this balance and usually prevent inappropriate immune responses against the microbiota in healthy individuals. The importance of this pathway is highlighted by the damage caused when this process breaks down, leading to inflammatory bowel disease (IBD).
Inflammatory macrophages accumulate in the inflamed intestine in IBD, producing excess amounts of inflammatory mediators that contribute to the tissue damage and pathology that is characteristic of the disease. Our work focuses on how macrophages become specialised in the intestine to prevent harmful immune responses and, in particular, how their specialised function is shaped by the gut microbiota itself.
The mechanisms by which intestinal macrophages normally become conditioned to promote microbial tolerance are unclear, although strong epidemiological evidence linking disruption of the gut microbiota by antibiotic use to IBD indicates an important role for the gut microbiota in modulating intestinal immunity.
The aims of the lab are to unravel the cellular and molecular pathways by which the gut microbiota controls macrophage function, not only in the intestine but also systemically and at other antigen-rich mucosal sites such as the lung. In particular, we are focusing on antibiotic use to disrupt the intestinal microbiota, which has profound effects on macrophage-mediated control of adaptive immunity, susceptibility to infections and composition of bacterial communities in the intestine.
Another focus of the lab is to investigate the critical windows of development during which macrophage function is shaped by the microbiota and narrowing down bacterial groups, microbiota-associated products and pathways that are involved in this process.
We therefore hope to build a detailed understanding of how intestinal macrophages keep intestinal inflammation under control, to highlight critical pathways that can be targeted to prevent inflammatory disease.