It remains unknown what causes inflammatory bowel disease (IBD), including signaling networks perpetuating chronic
gastrointestinal inflammation in Crohn’s disease (CD) and ulcerative colitis (UC), in humans. According to an analysis of up to
500 patients with IBD and 100 controls, we report that key transcripts of the IL-7 receptor (IL-7R) pathway are accumulated in
inflamed colon tissues of severe CD and UC patients not responding to either immunosuppressive/corticosteroid, anti-TNF,
or anti-a4ß7 therapies. High expression of both IL7R and IL-7R signaling signature in the colon before treatment is strongly
associated with nonresponsiveness to anti-TNF therapy. While in mice IL-7 is known to play a role in systemic inflammation,
we found that in humans IL-7 also controlled a4ß7 integrin expression and imprinted gut-homing specificity on T cells. IL-7R
blockade reduced human T cell homing to the gut and colonic inflammation in vivo in humanized mouse models, and altered
effector T cells in colon explants from UC patients grown ex vivo. Our findings show that failure of current treatments for
CD and UC is strongly associated with an overexpressed IL-7R signaling pathway and point to IL-7R as a relevant therapeutic
target and potential biomarker to fill an unmet need in clinical IBD detection and treatment.