Juan Francisco Guerra^1,2, Denver Lough¹, Joseph Abdo¹, Cal Matsumoto¹, Michael Zasloff¹, Thomas Fishbein¹

¹Transplant Institute, Georgetown University Hospital, Washington, DC, United States; ²Departamento Cirugia Digestiva, Pontificia Universidad Catolica de Chile, Santiago, Chile

Introduction: NOD2 encodes for an antimicrobial sensor associated with innate intestinal immunity and is associated with Crohn's Disease. Intestinal failure (IF) represents a wider spectrum of diseases resulting from disruption of intestinal homeostasis. We previously demonstrated a high incidence of NOD2 mutations among IF patients, and an association with immunologic failure after intestinal transplants. Here, our aim was to evaluate the prevalence of NOD2 mutations in a more extensive population with IF and to evaluate possible NOD2 associations with the different specific disease states leading to IF.

Methods: We prospectively genotyped 192 consecutive patients meeting the diagnosis of irreversible IF and 103 healthy controls for the three most common NOD2 polymorphisms. Allele and haplotype frequencies were determined. NOD2 genotypes were compared between the groups and were related to the entities causing IF.

Results: A surprisingly high percentage (26%) of patients with IF had at least one of the three most common NOD2 polymorphisms, while only a 4.8% of healthy controls had a mutant genotype (consistent with multiple healthy population studies). If we consider patients with any cause of intestinal failure other than Crohn's disease the incidence remains as high as 18.8%. We evaluated specific diseases including gastroschisis, atresia, NEC, volvulus and could not establish a specific association between a NOD2 mutant genotype with any clinical condition other than Crohn's disease. Additional disease types, categorized as developmental, ischemic or acquired degenerative disease also failed to demostrate specific polymorphism associations.

Conclusions: NOD2 polymorphisms are present with a high frequent in a large population of patients with IF. We could not establish an association with other specific clinical conditions. Our findings suggest that NOD2 signalling may play a role in development of IF via maintainence of intestinal immune homeostasis which, when disrupted, may lead to loss of potential for intestinal recovery during an insult.