A full-thickness spatial transcriptomics atlas of medically refractory ulcerative colitis identifies niche signatures associated with biologic non-response

BACKGROUND: Ulcerative colitis (UC) is a chronic mucosal immune disorder in which 30-50% of patients fail biologic therapy, yet the full-thickness immune architecture of medically refractory disease and reliable tissue-level markers of treatment response remain undefined.

METHODS: Using 10x Visium HD spatial transcriptomics (16-µm bins; 615,274 bins), we generated a full-thickness spatial atlas of surgically resected colon from patients with medically refractory UC (n=3) and controls (n=3), integrating niche-stratified differential expression, spatial cell-cell communication, SCENIC regulon inference and single-sample GSEA with immunofluorescence and DSS-colitis flow cytometry.

RESULTS: We resolved 18 spatial immune-stromal niches across five tissue modules. At the mucosal frontline, epithelial barrier collapse was accompanied by a 20-fold expansion of ulcer-bed stroma (p=0.030) that co-localised with an Acute Neutrophil Niche and was associated with neutrophil recruitment via CXCL12-CXCR4 signalling, forming a spatially integrated ulcerogenic unit. In the submucosa, a humoral immune programme was associated with tertiary lymphoid structures (TLS) and plasma-cell survival-related signalling (MIF-CD74 and LTB-CD40). This niche architecture was immunologically informative: an Acute Neutrophil Niche signature was enriched in biologic non-responders across six adult cohorts (AUC 0.67-0.99) and in non-remission patients of the paediatric PROTECT cohort, and a five-niche model showed discriminative performance in adult cohorts across independent datasets and drug classes (anti-TNF and anti-integrin; cross-cohort AUC 0.68-0.97), although this performance did not transfer to the paediatric cohort (AUC ≈ 0.51-0.62). Expansion of TNFAIP2+ TLS-resident B cells was confirmed at the protein level in a DSS colitis mouse model by immunofluorescence and flow cytometry (p=0.0079).

CONCLUSION: Together, this full-thickness atlas defines the spatial immune ecosystem of refractory UC - neutrophil niches, TLS and plasma-cell survival programmes - and yields cellular-niche signatures reproducibly associated with treatment outcome across drug classes, providing an immunologically grounded framework that may inform biologic selection, pending prospective validation.