Pathogenesis of Fistulating Crohn's Disease: A Review

Abstract

Sustained, transmural inflammation of the bowel wall may result in the development of a fistula in Crohn's disease (CD). Fistula formation is a recognized complication and cause of morbidity, occurring in 40% of patients with CD. Despite advanced treatment, one-third of patients experience recurrent fistulae. Development of targeting treatment for fistulae will be dependent on a more in depth understanding of its pathogenesis. Presently, pathogenesis of CD-associated fistulae remains poorly defined, in part due to the lack of accepted in vitro tissue models recapitulating the pathogenic cellular lesions linked to fistulae and limited in vivo models. This review provides a synthesis of the existing knowledge of the histopathological, immune, cellular, genetic, and microbial contributions to the pathogenesis of CD-associated fistulae including the widely accredited contribution of epithelial-to-mesenchymal transition, upregulation of matrix metalloproteinases, and overexpression of invasive molecules, resulting in tissue remodeling and subsequent fistula formation. We conclude by exploring how we might utilize advancing technologies to verify and broaden our current understanding while exploring novel causal pathways to provide further inroads to future therapeutic targets.

Keywords: Crohn’s-associated Fistula; Epithelial-to-mesenchymal Transition; Model Systems; Penetrating.

Figure 1

Histopathological image of CD-associated enterocutaneous fistula.A, At low magnification, the central fissure of the fistula tract can be identified (arrows) between the anterior abdominal wall and ileum. On the ileal side of the fistula, the mucosa is destroyed with flattened columnar epithelium due to ischemic/reactive changes in the mucosa. On the cutaneous side of the fistula, features of reactive, narrow squamous epithelium is observed. As observed in the majority of fistulae, erosion of fistula lining is replaced with an inflammatory infiltrate (∗). Chronic fibrosis, which is a histopathological feature of CD-associated fistulae, is characterized here by hypertrophied muscularis propria and fibrotic submucosa within the ileum. Fat wrapping (or creeping fat), which is pathognomonic of ileal CD, is also observed in this specimen (×0.25 original magnification). B, On the ileal side of the fistula, reactive ileal epithelium may be observed. On the cutaneous side, inflammation may be observed within the squamous epithelium leading to ischaemic changes (×5 original magnification). C, A small focus of transitional epithelium is observed lining the fistula at ×5 magnification. In addition, keratinising squamous epithelium and ischaemic columnar mucosa is seen on the cutaneous side and ileal side of the fistula respectively (×5 original magnification). D, Further erosive ischaemic and inflamed changes seen at higher resolution (×10 original magnification) (hematoxylin-eosin).

Figure 2

Schematic of the pathogenesis of CD-associated fistula formation. (1) IECs undergo EMT converting to TC in response to a defect in the epithelial barrier; resultant infiltration of pathogen associated molecular patterns enter the gut mucosa, which elicits an immune response. (2) An upregulation of TNF, a potent inducer of TGF-β, occurs which stimulates a cascade of pro-inflammatory cytokines (IL-13) and cell invasive molecules (β6-integrin) resulting in TCs adopting features of an invasive mesenchymal-like cell. TCs preserve their epithelial origins (CK20/8+); however, they down-regulate expression of epithelial cell adhesion molecules (E-cadherin, β-catenin) and highly express EMT-inducing transcription factors (SNAIL1, SLUG, Ets-1) and cell migratory molecule, DKK-1. In addition, TCs may appear more disordered with a loss of gap junctions and fragmented basement membranes. (3) Chronic inflammation results in reduced epithelial repair and reduced migratory capabilities of CLPFs, which contribute to poor wound healing in fistulating CD; IECs compensate by undergoing EMT in an attempt to restore the epithelial barrier. (4) MMPs (MMP-3, MMP-9) are highly expressed and unopposed (reduced TIMP-1, -2, -3) in fistulating CD tissue, resulting in aberrant breakdown of the extracellular matrix and tissue remodeling. These pathways consequently contribute to fistula formation. (Figure created with BioRender.com and adapted from Siegmund et al. CK, Cytokeratins; PAMP, pathogen-associated molecular pattern.