Fecal microbiota samples of NIK-deficient and control wild-type mice Raw sequence reads. Fecal microbiota samples of NIK-deficient and control wild-type mice

Microfold cells (M-cells) are specialized cells of the intestine that sample luminal microbiota and dietary antigens to educate the immune cells of the intestinal lymphoid follicles. The role of M-cells in local and systemic inflammatory responses are unknown. Here we demonstrate that epithelial non-canonical NFkB signaling mediated by NFkB inducing kinase (NIK) is highly active in intestinal lymphoid follicles and is required for M-cell maintenance. Intestinal NIK signaling acts as a critical molecular regulator of Mcell differentiation and also elicits a local and systemic IL17A and IgA production. Importantly, intestinal NIK signaling is chronically active in mouse models of colitis and IBD patients. Constitutive NIK signaling increases the susceptibility to inflammatory injury through ectopic M-cell differentiation and a chronic increase in IL17A. This work highlights a novel role of non-canonical NFkB and M-cells in immune homeostasis, inflammation and polymicrobial sepsis.