Inflammatory bowel disease (IBD) is a severe, chronic pathology presenting with progressive intestinal inflammation and fibrosis, whose exact causes and key pathways remain poorly defined. Stromal–immune cell interactions have recently gained momentum in conceptualizing tissue homeostasis and our lab offered solid evidence establishing fibroblast heterogeneity and dominant roles in intestinal pathophysiology. Our recent preliminary evidence, indicated diverse spatial distribution of subsets of activated fibroblasts and revealed synergistic interplays of important inflammatory pathways driving pathogenicity. Detailed insights into such contextual complexities remain obscure. Here, we propose a novel unifying hypothesis that progressive IBD is orchestrated by specific subsets of fibroblasts, becoming causal to pathogenesis, depending on contextual information dictated by origin, topology, and cross-talks with immune or stromal cell types. We propose to use single-cell spatiotemporal phenotyping to deconvolute fibroblast subset-specific functions in disease-staged, fibrotic and non-fibrotic animal models of IBD. We aim to: (1) Map dynamic chromatin and gene expression programs that define cellular heterogeneity and infer cell interactions to build an ‘IBD connectome’ atlas (2) Analyse the origin, spatial distribution, plasticity and lineage trajectories of intestinal fibroblasts and reveal potential functions of pathogenic subsets (3) Perform discovery screens and functional validations on known (TNF, IFNγ, TGFb and interleukins) and novel fibroblast-subset-specific pathways focusing on potential synergistic interplays (4) Employ clinical material to validate involvement of the most prominent new pathways in human. The proposed research should help tackle the complexities of chronic inflammatory and fibrotic disorders in the intestine and beyond, advance mechanistic concepts in immune disease pathophysiology and promote fibroblast-targeting therapeutic discovery.