Previous studies in mice showed that induction of H2O2-generating dual oxidase 2 (Duox2) in barrier epithelia constitutes a sentinel response to mucosal dysbiosis. In addition, Duox2-deficiency in mice alters mutualistic host-microbiota interactions that are fundamental in maintaining healthy gut immune homeostasis. Rare loss-of-function DUOX2 variants are commonly found in the general human population. We present evidence linking DUOX2 mutational burden with susceptibility to mucosal dysbiosis and associated phenotypes.