Crohn’s disease (CD) is a chronic inflammatory intestinal disease, with frequent aberrant healing and stricturing complications. Crosstalk between activated myeloid and stromal cells is critical in pathogenicity1,2 with increases in intravasating monocytes correlated to anti-TNF treatment non-response3. The highest effect risk alleles are loss-of-function NOD24,5 mutations, which increase risk for stricturing6. However, mechanisms underlying NOD2-pathogenicity and salvage pathways in anti-TNF refractory patients remain largely uncharacterized. Here we show that NOD2 loss leads to dysregulated activated fibroblast and macrophage homeostasis by direct ex vivo analyses of patients carrying NOD2 risk alleles. CD14+PBMCs from NOD2 carriers produce collagen-high expressing cells, and elevation of conserved signatures is observed in nod2-deficient zebrafish models of intestinal injury. Enrichment of STAT3 regulation and gp130-ligands in activated fibroblasts and macrophages led us to reason that gp130 blockade might rescue the activated program. We correlate post-treatment induction of this pathway in anti-TNF non-responders and demonstrate in vivo amelioration of the activated myeloid-stromal niche, using a specific gp130 inhibitor, bazedoxifene. Our results demonstrate novel biological insights into NOD2-driven fibrosis in CD; gp130 blockade may benefit selected CD patients, potentially complementing anti-TNF therapy.