A new study has revealed that a crucial gene in the immune system may play a role in the reason why some people are more likely to develop inflammatory bowel disease (IBD) than others.
Mater Researchers Professor David Hume AO and Professor Kim Summers, in collaboration with experts from the University of Canberra, Canberra Hospital and the Australian National University, suggest that IBD susceptibility is linked to issues with how certain immune cells—called monocytes—adapt to the environment in the gut.
IBD, which includes Crohn’s disease and ulcerative colitis, has a strong genetic component with more than 300 regions of the human genome linked to IBD. However, the exact mechanisms behind disease development remain unclear. Unlike genetic diseases caused by single mutations, IBD results from complex interactions between multiple genes and environmental triggers.
Prof Hume, leader of the Macrophage Biology Research Group said that traditional theories have centred on an overactive immune response, where monocytes and macrophages react too strongly to bacteria.
“Our research, however, indicates that the problem may lie in the immune system's inability to turn off inflammation once it has started,” Prof Hume said.
“This could explain why IBD persists as a chronic condition rather than resolving like a typical infection.”
One of the study’s key focuses is ETS2, a gene located on chromosome 21 that plays a crucial role in the immune system. ETS2 is a transcription factor that helps regulate the activity of other genes and is particularly active in monocytes, which develop into macrophages—immune cells that control inflammation in the gut.
In a healthy gut, macrophages remain tolerant to harmless bacteria and food, preventing unnecessary inflammation. However, in some people with IBD this balance is disrupted, leading to an immune response that damages the intestines.
The research team reanalysed the function of a genetic variant called rs2836882 near the ETS2 gene that is associated with IBD risk in European populations.
While other research groups have recently analysed this association and considered ETS2 as a pro-inflammatory gene and a potential drug target, Prof Hume’s research team have offered an alternative viewpoint - that ETS2 is involved in the pathway of macrophage development that restrains and resolves inflammation.
This pathway is driven by a critical regulator called macrophage colony-stimulating factor (known as CSF1), associating ETS2 with a broad class of genes they call inflammation suppressor genes which includes many other genes linked to IBD susceptibility.
The current study follows their recent joint research on IBD families published in Human Genetics which highlighted extreme inter-individual variation in the response of monocytes and macrophages to CSF1 and microbial challenge that could underlie chronic inflammation.
Prof Hume said that the difference in interpretation of the role of ETS2 is critical.
“In our view, inhibition of pathways leading to ETS2 has the potential to exacerbate or prolong disease,” Prof Hume said.
While current IBD treatments primarily focus on suppressing inflammation, the research team is focussed on the potential of CSF1 as a treatment to promote resolution and repair of IBD and other inflammatory diseases.
The full paper, titled “The relationship between CSF1R signaling, monocyte-macrophage differentiation and susceptibility to inflammatory bowel disease” was published in Cellular and Molecular Gastroenterology and Hepatology in March 2025. The research was done as a collaboration between Mater Research, University of Canberra, The Australian National University and Canberra Hospital.
