髓系细胞流入结肠上皮与溃疡性结肠炎患者的疾病严重程度和抗肿瘤坏死因子治疗无应答相关

Ulcerative colitis (UC) is an idiopathic chronic inflammatory disease of the colon with sharply rising global prevalence. Dysfunctional epithelial compartment (EC) dynamics are implicated in UC pathogenesis although EC-specific studies are sparse. Applying orthogonal high-dimensional EC profiling to a Primary Cohort (PC; n=222), we detail major epithelial and immune cell perturbations in active UC.

Prominently, reduced frequencies of mature BEST4 + OTOP2 + absorptive and BEST2 + WFDC2 + secretory epithelial enterocytes were associated with the replacement of homeostatic, resident TRDC + KLRD1 + HOPX + γδ + T cells with RORA + CCL20 + S100A4 + T H17 cells and the influx of inflammatory myeloid cells. The EC transcriptome (exemplified by S100A8, HIF1A, TREM1, CXCR1 ) correlated with clinical, endoscopic, and histological severity of UC in an independent validation cohort (n=649).

Furthermore, therapeutic relevance of the observed cellular and transcriptomic changes was investigated in 3 additional published UC cohorts (n=23, 48 and 204 respectively) to reveal that non-response to anti-Tumor Necrosis Factor (anti-TNF) therapy was associated with EC related myeloid cell perturbations. Altogether, these data provide high resolution mapping of the EC to facilitate therapeutic decision-making and personalization of therapy in patients with UC.