Unravelling metabolites conferring intestinal protection in asymptomatic first-degree relatives of patients with celiac disease.

Celiac disease (CeD) is an autoimmune enteropathy; nearly 60-80% of first-degree relatives (FDRs) of CeD patients carry HLA-DQ2/DQ8 haplotypes; however, only 7.5% of them develop enteropathy. This suggests the modulation of biochemical and molecular mechanisms that might help in maintaining intestinal integrity. Thus, the present study investigated the metabolome of FDRs to gain insight into biochemical mechanisms that might help in maintaining intestinal integrity. The metabolome of small intestinal mucosal biopsies, blood plasma and urine of serologically negative first-degree relatives (FDRs, n = 50) was investigated using proton NMR spectroscopy and compared with CeD patients (n = 64) and controls (disease controls, n = 35 or healthy controls, n = 32) using both univariate and multivariate statistical analyses. The metabolic profiles of FDRs of CeD patients differed significantly from both CeD patients and controls. Higher myo-inositol and fumarate in the mucosa of FDRs suggest the role of these metabolites in modulating the immune response and inflammation, which may protect intestinal integrity in FDRs. Elevated formate and tyrosine levels in the intestinal mucosa of FDRs, compared to both CeD patients and controls, suggested alterations in gut microbiota that may support intestinal homeostasis. Furthermore, significant changes in levels of branched-chain amino acids in FDRs compared to CeD patients indicated their increased utilization for enterocytes renewal, upregulation of tight junction proteins and modulating immune response to maintain villous architecture. Our data showed that FDRs exhibit a specific metabolic signature that may represent an adaptive response aimed at maintaining intestinal homeostasis and mucosal integrity despite genetic predisposition.