REG3A and IL22 have opposite effects on fat accumulation in the liver in a high-fat diet.

IL22 is a cytokine with many immunoregulatory effects. It also promotes mucus production, cell proliferation and wound healing, making it a key component of intestinal health. An increasing body of studies highlight the potential of IL22 as a therapeutic drug against NAFLD through the induction of antimicrobial peptides, especially of the Reg3 lectins family, and the regulation of gut microbiota. However, adverse reactions to this molecule in long term administration are little-studied. In this study, we gave daily doses of recombinant L. lactis delivering DNA vaccine for REG3A and IL-22 production to mice fed with a butter-based high fat diet (milk-fat diet or MFD). We aim to compare the effects of REG3A and IL-22 expression by the epithelial cells on the development of obesity-related conditions and the composition of the microbiota. We show that they have opposite effects on fat accumulation in the liver and insulin resistance development despite inducing a similar shift in fecal microbiota composition. Here, we provide evidence that daily long term administration of IL22 can aggravate NAFLD by mechanisms independent from gut microbiota.