Scientists at the Francis Crick Institute have untangled a complex pathway that could help explain how interactions between microorganisms and the body’s immune defences lead to gut inflammation and colitis.
Published today in Nature Immunology, their work could lead to the identification of new ways to treat inflammatory bowel disease.
Crohn’s disease and ulcerative colitis are collectively known as inflammatory bowel diseases (IBD). They are incurable conditions that involve excessive inflammation in the gut, leading to symptoms like abdominal pain and diarrhoea.
The intestinal immune response to microorganisms is tightly controlled to limit inflammation, but when factors like genetic susceptibility and environmental triggers come together, this inflammation can progress and cause disease.
Mutations in the cytokine IL-10 or its receptor result in IBD in children, suggesting the pathway is important in controlling intestinal inflammation. The team have previously shown that two other proteins known as transcription factors, c-Maf and Blimp-1, drive the activity of the IL-10 gene in T cells.
In the current study, they deleted c-Maf, Blimp-1, or both proteins in T cells in mice to understand their role in maintaining gut health via IL-10. Removing these proteins was not enough to induce colitis, but when combined with an environmental trigger – infection with the bacteria Helicobacter hepaticus – IL-10 activity in T cells was reduced and inflammation progressed.
The bacteria didn’t cause disease in mice with both proteins present, but when either c-Maf or Blimp-1 were missing, moderate colitis was induced. When both proteins were removed, the mice developed severe colitis.
Sections from the colon 14 days after mice with disruption of important genes in immune cells were infected with H.hepaticus. There was no colitis in control mice (panel 1) and increasing colitis severity as the different genes were disrupted (panel 2-4). Mice with all genes disrupted had severe colitis (4th panel).
The researchers also showed that each protein was protective against inflammation in different ways beyond their action on IL-10, acting additionally through different immune pathways that impact distinct T cell activities.
The team then showed how these pathways could be relevant in human IBD by studying data from colon biopsies of patients with IBD. There were similarities in the genes expressed in humans with IBD and the mice with bacteria-induced inflammation resulting from an absence of either c-Maf or Blimp-1.
Anne O’Garra, head of the Crick’s Immunoregulation and Infection Laboratory, said: “Collectively our findings show that Blimp-1 and c-Maf not only co-operate to regulate IL-10 expression to prevent severe bacteria-induced colitis but reinforce this control by their distinct actions on distinct inflammatory T cell molecules. We hope that these studies will enable further dissection of the roles of key genes and pathways relevant to IBD in humans.”
The team will now continue to investigate how intestinal inflammation develops and progresses to colitis in response to different microorganisms.
