Modulation of Orosomucoid-like Protein 3 Activity in the Management of Inflammatory Bowel Disease

Author(s): Ugljesa Malicevic, Vikrant Rai, Ranko Skrbic, Devendra K Agrawal

Inflammatory bowel disease (IBD), encompassing Crohn's disease and ulcerative colitis, is a chronic and relapsing condition characterized by persistent inflammation of the gastrointestinal tract. The complex pathogenesis of IBD involves a combination of genetic, environmental, and immune factors, which complicates the achievement of long-term remission. Lower abdominal pain, stomach cramps, blood in stool, chronic diarrhea, fatigue, and unexpected weight loss are common presenting symptoms. Despite the range of therapies and medications, including anti-inflammatory and anti-diarrheal drugs, immunosuppressants, antibiotics, and analgesics aimed at managing symptoms and controlling inflammation, a definitive cure for IBD remains elusive. Current therapy targets inflammation, mainly cytokines, inflammatory receptors, and immune cells, however, there is a need for novel targets to improve clinical outcomes. To identify novel targets and interactions among various factors, we performed a network analysis using various cytokines, TLRs, and NLRP3 inflammasome as inputs. This analysis revealed orosomucoid-like protein 3/ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) as a central hub gene interacting with multiple factors. While the role of ORMDL3 in IBD pathogenesis is not well-established, our findings and existing literature suggest that ORMDL3 plays a role in inflammation, impaired mitochondrial function, and disrupted autophagy, all contributing to the disease progression. Given its central role in these pathogenic processes, targeting ORMDL3 presents a promising therapeutic target. Modulating ORMDL3 activity could alleviate inflammation, restore mitochondrial function, and enhance autophagy, potentially leading to more effective treatments and improved outcomes for IBD patients.