IgA deficiency reveals a microbiota-dependent pathway to gluten sensitivity

Selective IgA deficiency (sIgAD) is the most common primary immunodeficiency and increases susceptibility to gluten-related enteropathies, but the underlying mechanisms of pathogenesis are unknown. Utilizing IgA^-/- mice and wild-type controls, we investigated how dietary gluten shapes susceptibility to small intestinal inflammation. We found that IgA^-/- mice developed gluten-induced villus blunting in the ileum and enhanced T_h17 responses. Exposure to a gluten-free diet prevented villus blunting in IgA^-/- mice. Dietary gluten promoted the expansion of Streptococcus and Desulfovibrio species, depletion of members of the order Lactobacillales, and shifts in microbial metabolic pathways related to lipid metabolism. Next, to determine if gluten sensitivity is microbiota-dependent, germ-free colonization experiments were performed using complete microbiota transfers or mono-colonization with a single Streptococcus species (Streptococcus lutetiensis), both of which were sufficient to recapitulate gluten-sensitive enteropathy. Our findings demonstrate that dietary gluten promotes small intestinal inflammation and mucosal remodeling in IgA-deficient mice through microbiota-dependent mechanisms. This work highlights a key role for sIgA in maintaining immune homeostasis at the diet-microbiota interface and reveals a novel microbial pathway underlying gluten sensitivity.