By exploring mutations involved in inflammatory bowel disease (IBD), researchers have provided insights into the crosstalk between genetics and environmental factors in this condition.
Inflammatory bowel disease
Inflammatory bowel disease (IBD) comprises a group of conditions that are characterised by chronic inflammation. The two main forms of IBD are Crohn’s disease and ulcerative colitis. Researchers have suggested that this inflammation is the result of dysregulated immune responses to intestinal microbiota in genetically susceptible individuals. There has been an abundance of evidence demonstrating that both common and rare variants associated with IBD are involved in host-microbial crosstalk and the regulation of antimicrobial immunity.
One central component of these pathways are Paneth cells, which are secretory intestinal epithelial cells. They reside at the bottom of small intestinal crypts and regulate commensal intestinal microbial composition. Genetic variants, particularly in Paneth cells, have been shown to contribute to IBD. For example, X-linked inhibitor of apoptosis protein (XIAP) alterations are commonly associated with Mendelian IBD. XIAP is a critical component of the NOD1 and NOD2 complex. These are two pattern recognition receptors that are involved in the detection of bacterial motifs. Around 30% of people who harbour this mutation develop IBD. This not only highlights the role of genetics in disease development, but also demonstrates that an individual’s genetic background is not solely at play in this condition. In addition, our current understanding of how XIAP deficiency regulates Paneth cells is still unclear.
Crosstalk between genetics and the environment in IBD
In a recent study, published in Science Immunology, researchers used XIAP knockout mice and organoids to explore how mutations in the XIAP gene alter IBD.
The team observed that loss of XIAP meant that Paneth cells could no longer produce and release antimicrobial molecules to the same extent. As a result, this led to changes in the composition of the microbiota. However, interestingly, the team found that despite these effects, mice did not develop intestinal inflammation. It was only when the researchers introduced pathobionts (organisms that can cause harm under certain conditions) that mice with XIAP defects developed intestinal inflammation reminiscent of IBD.
Professor Sebastian Zeissig, research group leader, explained:
“This could explain why the majority of patients, who have mutations in this gene, do not develop IBD. The genetic condition gives rise to a susceptible environment. But it is the exposure to specific bacteria that ultimately triggers the inflammation.”
The team then decided to test the effects of a possible intervention. Specifically, they re-introduced antimicrobial molecules, similar to those produced by healthy Paneth cells, to mice with the defect. These molecules were subsequently able to prevent intestinal inflammation, even in the presence of pathobionts.
Overall, this data uncovers a critical pathway for host-microbial crosstalk, which is important for intestinal homeostasis and the prevention of inflammation. These results also provide new opportunities for personalised therapies, not just for individuals with XIAP alterations, but for individuals with other IBD-linked genetic defects that disrupt Paneth cells.
Image credit: canva