The intestinal mucosa constitutes the first-line defense against dietary or microbial challenges and usually avoids unwarranted inflammatory reactions in response to non-self-antigens by promoting oral tolerance [
1]. The capacity of the mucosal immune system to neutralize harmful luminal challenges, can be subverted by exogenous triggers, such as viruses [
2], or conditions in which still undefined inherited or acquired cell-autonomous factors favor an intestinal pro-inflammatory state. Cystic fibrosis (CF), the most frequent monogenic lethal disease in the Caucasian population [
3], is the quintessential example of a disease in which cell-autonomous triggers favor antigen mishandling by the intestinal mucosa. Indeed, in the CF intestine, two unfavorable events determine an inadequate cellular and humoral immune response to food components, (i) the increased antigenic load due to pancreatic insufficiency and (ii) the constitutive chronic intestinal inflammation due to loss-of function-mutations in the CF transmembrane conductance regulator (CFTR) gene [
4,
5]. Accordingly, CF patients often manifest increased levels of antibodies against alimentary antigens, including anti-gliadin IgA antibodies, increased intestinal permeability, elevated levels of fecal calprotectin, shifts in the intestinal microbiota, and increased intestinal permeability [
5‐
7]. Importantly, CF patients manifest a threefold increase in the prevalence of celiac disease (CD) [
8,
9] a permanent intolerance to gluten/gliadin proteins that occurs in a proportion of susceptible individuals who bear the human leukocyte antigen (HLA) DQ2/DQ8 [
10‐
12]. Of note, a prevalence as high as ~ 4% of positive anti-TG2-IgA autoantibodies, a serological marker of CD, has been reported in several cohorts of CF patients [
5‐
7], even in the absence of villous damage, the hallmark of CD. Thus, there is an epidemiological link between CF and CD.