Single-cell analysis of an adult IBD INCEPTION cohort reveals Galectin-linked disease mechanisms
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Background and Aims
The molecular pathogenesis of Inflammatory Bowel Disease (IBD) remains unclear. We aimed to establish a high-resolution immune landscape of treatment-naïve 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-naïve 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.
