Excessive poly(ADP)-ribosylation in the inflamed mucosa of pediatric celiac disease points to a novel inflammatory mechanism and therapeutic target

Background: Celiac disease (CD) is an immune-mediated enteropathy triggered by gluten exposure in genetically susceptible individuals, characterized by chronic intestinal inflammation, epithelial damage, and immune dysregulation. Several programmed cell death pathways have been implicated in CD pathogenesis, including apoptosis and pro-inflammatory pathways of programmed cell death, such as pyroptosis and necroptosis. Hypothesis: Parthanatos - a caspase-independent, inflammatory cell death pathway mediated by poly(ADP-ribose) polymerases (PARP-1/2) and excessive poly(ADP)-ribosylation (PARylation), also contributes to epithelial cell death in CD. Methods: Duodenal and bulb biopsies from 15 pediatric patients with biopsy-confirmed CD and 15 non-CD controls were analyzed using immunofluorescence staining for poly(ADP-ribose) (PARylation) and CD3+ T cell infiltration. Results: CD biopsies from duodenum and duodenal bulb demonstrated pathological hyperPARylation (p<0.001) and CD3+ T cell infiltration (p<0.001) compared to non-CD controls. HyperPARylation was evident both in epithelial and subepithelial compartments of the inflamed mucosa and was positively correlated with Marsh scoring criteria. Conclusions: Our findings identify mucosal hyperPARylation as a novel feature of the inflamed mucosa in pediatric CD, supporting a potential role for Parthanatos in mucosal injury and amplification of inflammatory responses. This opens new avenues for therapeutic exploration, including PARP inhibition, particularly in refractory CD.