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

Background and Aims: The 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. Methods: We generated a single-cell atlas using intestinal biopsies from a large adult inception cohort of 137 individuals, including treatment-naive Crohn's 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. Results: The 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. Conclusions: Our 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. Keywords: Inflammatory Bowel Disease; Crohn's Disease; Ulcerative Colitis; Single-cell RNA sequencing; Galectin-9; Inflammatory monocytes.