Single-cell analysis of an adult IBD INCEPTION cohort reveals Galectin-linked disease mechanisms

Abstract

Background and AimsThe molecular pathogenesis of Inflammatory Bowel Disease (IBD) remains unclear. We aimed to establish a high-resolution immune landscape of treatment-naive IBD to identify central drivers of disease onset and early pathogenic signalling. MethodsWe generated a single-cell atlas using intestinal biopsies from a large adult inception cohort of 137 individuals, including treatment-naive Crohns disease (CD), ulcerative colitis (UC), and symptomatic non-IBD controls. We integrated scRNA-seq (1 million cells) with co-varying neighbourhood analysis (CNA) and unbiased tensor decomposition of cell-cell communication (CCC) networks. Findings were validated in vitro macrophage stimulation model and using serum from patients. ResultsThe inception cohort exhibited significantly more homogenous compartmental diversity compared to benchmark reference studies (p < 0.001). Inflammation in both CD and UC was characterized by a marked expansion of inflammatory monocytes. Unbiased CCC analysis identified a dominant disease-specific signalling module centred on the Galectin family (LGALS1 and LGALS9). Galectin-9 expression was specifically enriched in inflammatory monocytes, which exhibited distinct transcriptional programs linked to antigen presentation and microbial sensing. In vitro, Galectin-9 acted as a potent stimulus, driving macrophages toward a pro-inflammatory phenotype. Clinically, serum Galectin-9 levels were significantly elevated in IBD patients and correlated with systemic inflammatory markers and treatment response. ConclusionsOur data identify a galectin-monocyte signalling axis as a unifying inflammatory hallmark of early IBD. Galectin-9 serves as both a functional driver of mucosal inflammation and a dynamic biomarker, offering new opportunities for therapeutic targeting and disease monitoring from diagnosis.