TMEM219 inhibition shows promise in restoring intestinal health in IBD

An international study led by Paolo Fiorina from Boston Children's Hospital and in collaboration with researchers from University of Milan highlights the beneficial effect of inhibiting the death receptor TMEM219 to restore mucosal healing in inflammatory bowel diseases. Findings were published today in the Journal of Clinical Investigation.

Fiorina and colleagues demonstrated that the pharmacological blockade of TMEM219 signal through a recombinant protein based on the extracellular portion of the TMEM219 receptor is able to preserve self-renewal ability of intestinal stem cells in inflammatory bowel disease, protect intestinal stem cells from cell death induced by TMEM219 activation, and prevent colitis development in mouse models. These results were confirmed by the selective genetic inhibition of TMEM219 on intestinal stem cells LGR5 in vivo which allowed for the preservation of mucosal regeneration and healing in inflammatory bowel disease. This may thus represent a new mechanism of disease in which TMEM219 overactivation induces intestinal stem cell death and prevents mucosal renewal during inflammation.

This new signaling is able to control the fate of intestinal stem cells and modulate their survival. The study shows how this new mechanism of disease, which is overactive in the intestine during inflammation, is able to control mucosal self-renewal, particularly in inflammatory bowel disease. The dysregulation of this axis in patients with IBD and non-responding to therapy or with active disease suggests that TMEM219 signaling may prevent mucosal healing and therefore exerts a detrimental effect that aggravates the disease condition." 

Paolo Fiorina, Associate Scientist at Boston Children's Hospital Nephrology Division and Lecturer at Harvard Medical School

Previous studies conducted by the same group of researchers had highlighted the importance of the IGFBP3 / TMEM219 signaling in the context of diabetes, particularly on insulin-producing beta cells. This study goes further and identifies the TMEM219 signals as a novel mechanism of disease in colitis.

"The possibility of re-establishing self-renewal abilities of intestinal stem cells and promote mucosal healing during colitis is of extraordinary importance for patients with inflammatory bowel disease, especially in those not responding to current therapy in whom the disease is relapsing frequently, and surgery is at the end required," says Fiorina.