Background: Celiac disease (CeD) is an autoimmune disease featuring a small intestinal enteropathy triggered by dietary gluten. The clinical presentation and response to a gluten-free diet (GFD), the only effective treatment, vary widely, underscoring the need to better understand disease heterogeneity and its molecular determinants.
Methods: We assembled 323 high-quality duodenal transcriptomes from 290 individuals, including 143 non-celiac controls, 89 patients with active CeD (ACD), and 91 patients on a GFD, spanning 2–73 years of age. We systematically investigated interindividual variation in immune activation, epithelial and metabolic programs, tissue damage, and regeneration according to sex and age, and developed a statistical framework to identify transcriptomic signatures associated with mucosal deterioration. Using the GFD group we defined a plasticity score to identify molecular pathways reverting on not during disease remission.
Results: Sex- and age-associated molecular programs revealed substantial heterogeneity in CeD pathophysiology. Women exhibited stronger adaptive immune activation during ACD, whereas men showed broader epithelial and metabolic remodeling, including enhanced regenerative programs and reduced nutrient-absorption pathways. Age further shaped immune responses, with pediatric patients showing stronger T-cell programs and greater reversal of immune activation following gluten withdrawal, together with sustained tissue-renewal signals. Although sex and age significantly influenced immune activation, they accounted for only a limited proportion of interindividual variation. We identified a CeD-specific 101-gene signature derived from interindividual expression variability, whose expression collectively captured interindividual variation in active disease independently of sex and age.
Conclusions: These findings provide a comprehensive molecular framework for interindividual variation in CeD, linking immune activation, epithelial regeneration, metabolic remodeling, and mucosal damage. They establish molecular stratification of CeD beyond the conventional active-versus-remission classification and provide a transcriptomic framework for understanding disease heterogeneity.