Fibroblast Heterogeneity in Inflammatory Bowel Disease

Abstract

Intestinal fibroblasts are pivotal players in maintaining tissue homeostasis and orchestrating responses to injury and inflammation within the gastrointestinal (GI) tract. Fibroblasts contribute significantly to the pathogenesis of inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis (UC), by secreting pro-inflammatory cytokines, modulating immune cell activity, and promoting fibrosis. In addition, fibroblasts play crucial roles in tissue repair and regeneration following acute injury or chronic inflammation. The dysregulation of fibroblast functions can lead to fibrotic complications, such as intestinal strictures and obstruction, which are common in advanced stages of IBD. Understanding the complex interplay between fibroblasts and other cell types in the intestine is essential to elucidate the underlying mechanisms of intestinal diseases and identify novel therapeutic targets. Future research aimed at deciphering the heterogeneity of intestinal fibroblasts and their dynamic roles in disease progression holds promise for the development of precision therapies to mitigate fibrosis and inflammation in intestinal disorders.

Keywords: fibroblast heterogeneity; fibroblast–immune interaction; inflammatory bowel disease.

Figure 1

Potential sources of pathogenic fibroblasts and pro-fibrotic signalling pathways in Crohn’s disease are multifaceted and stem from a complex interplay of factors. These fibroblasts can originate from various cellular populations, including resident fibroblasts, fibrocytes, and even EMT or EndoMT processes within the intestinal epithelium. In the context of Crohn’s disease, inflammatory cytokines such as TNFα and IL-1β play a crucial role in activating these fibroblasts, promoting their proliferation and the secretion of ECM components. Additionally, signalling pathways, including TGF-β and Wnt/β-catenin, are implicated in the transition of these fibroblasts into myofibroblasts, which further contribute to tissue fibrosis and the characteristic scarring observed in affected individuals. Activated fibroblasts can also exacerbate inflammation and fibrosis by releasing various chemokines and cytokines, which attract additional immune and non-immune cells to the site.