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A full-thickness spatial transcriptomics atlas of medically refractory ulcerative colitis identifies niche signatures
Qingquan Bai1,2, Runyang Li3, Zhengjin Liu4
1Department of Hepatobiliary and Pancreatic Surgery, Ningbo Medical Centre Lihuili Hospital, Affiliated Lihuili Hospital of Ningbo University, Ningbo, China.
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.