Uninflamed colonic tissue harbors humoral activity linked to anti-TNF therapy non-response in ulcerative colitis

Anti-TNF therapy is central for treating ulcerative colitis, yet ∼40% are primary non-responders. To find pre-treatment signatures distinguishing anti-TNF non-responders from responders, we did serum cytokine profiling and laser microdissection transcriptomics on paired uninflamed and inflamed colonic epithelium and lamina propria from patients matched at baseline but differing in endoscopic outcome. Although inflammation drove more epithelial changes, the signatures separating non-responders from responders were found in uninflamed lamina propria, with elevated cell-cycle genes and a co-expression network enriched for humoral immune genes consistently higher expressed in non-responders. Cellular deconvolution localized this network to IgA plasma cells, confirmed by tissue staining, and the association was validated by pseudobulk analysis of an independent single-cell atlas. Baseline epithelial signatures or serum cytokines did not differ significantly between groups. These findings point to TNF-independent humoral activity already present in uninflamed mucosa as a candidate contributor to non-response, with implications for prediction and alternative therapies.