Inflammatory bowel disease (IBD) is a group of disorders where people have recurring inflammation in their gastrointestinal tract. There is no cure for IBD, and it’s remained unknown what is causing these overactive inflammatory responses. New research from scientists at the Technical University of Munich suggests one cause of IBD is the bacteria living in the gut microbiome.
The gut microbiome is host to trillions of microorganisms. Some ‘good’ bacteria are essential players in digestion and regulating the immune system. However, the gut microbiome is a balancing act — the gut bacteria target harmful bacteria while avoiding useful bacteria. Disrupting this imbalance dysregulates the immune response.
Mutations on the XIAP gene can cause the rare disease XLP2 and trigger chronic inflammation of the bowels 30% of the time. However, until this current study, the mechanism behind chronic inflammation in disease remained unknown, making it difficult to find effective anti-inflammatory treatments.
“The innate immune system overreacts to microbes in the gut,” said Dr. Monica Yabal, a research group leader at the Institute of Molecular Immunology in a statement. The immune system in healthy people eliminates bacteria that causes illness and then returns to its resting state. But in some XLP2 patients, a fatal chain reaction begins:
Toll-like receptors (TLR) are part of the innate immune system, the one that responds immediately to a potential threat. They use molecules in the cell wall to identify pathogens. When TLRs identify harmful microbes, they bind to the molecule triggering activation of TNF and its TNFR1 and TNFR2 receptors to induce inflammation and eliminate the pathogen.
But for people with the XLP2 genetic mutation, the binding of TNF to the TNFR1 receptor on Paneth cells causes them to die. Paneth cells in the gut mucus layer are necessary for creating antimicrobial substances and maintaining the bacterial balance in the intestines. The result is a vicious cycle where TNF mistakes beneficial bacteria as dangerous, attacks and eliminates them, activates the immune system where other good bacteria are targeted again.
The findings could help create new drugs to lower high inflammation as dysregulated Paneth cells have been seen in many patients with IBD. “We believe that this principle might also be applicable to other inflammatory bowel diseases and not only in XLP2 patients,” said Percy Knolle, the Director of the Institute for Molecular Immunology at TUM in the press release.
Patients with chronic bowel inflammation are typically given drugs inhibiting the TNF receptors. However, these are non-specific molecules and could end up deactivating TNFR1 and TNFR2. The study suggests a specific inhibitor for the TNFR1 receptor could be potentially efficacious.
The research study is available in Science Immunology.