Fibrostenosing Crohn's Disease: Pathogenetic Mechanisms and New Therapeutic Horizons

Abstract

Bowel strictures are well recognized as one of the most severe complications in Crohn's disease, with variable impacts on the prognosis and often needing surgical or endoscopic treatment. Distinguishing inflammatory strictures from fibrotic ones is of primary importance due to the different therapeutic approaches required. Indeed, to better understand the pathogenesis of fibrosis, it is crucial to investigate molecular processes involving genetic factors, cytokines, alteration of the intestinal barrier, and epithelial and endothelial damage, leading to an increase in extracellular matrix synthesis, which ultimately ends in fibrosis. In such a complex mechanism, the gut microbiota also seems to play a role. A better comprehension of molecular processes underlying bowel fibrosis, in addition to radiological and histopathological findings, has led to the identification of high-risk patients for personalized follow-up and testing of new therapies, primarily in preclinical models, targeting specific pathways involving Transforming Growth Factor-β, interleukins, extracellular matrix balance, and gut microbiota. Our review aims to summarize current evidence about molecular factors involved in intestinal fibrosis' pathogenesis, paving the way for potential diagnostic biomarkers or anti-fibrotic treatments for stricturing Crohn's disease.

Keywords: Crohn’s disease; anti-fibrotic treatments; intestinal fibrosis.

Figure 1

Therapeutic algorithm for bowel obstruction in CD. A multidisciplinary approach is crucial to choose the best therapeutic option. The role of pharmacological therapy is limited to bowel strictures with an inflammatory component, while surgery is required both in emergent complicated situations and in cases of stenoses showing a prevalent fibrostenotic pattern.

Figure 2

Pathogenetic factors influencing intestinal fibrosis development in fibrostenosing CD. Abbreviations: NOD2: nucleotide-binding oligomerization domain-containing gene 2; IL-23R: interleukin-23 receptor; ATG16L1: autophagy-related 16-like 1 gene; CX3CR1: C-X3-C Motif Chemokine Receptor 1; TGFβ1: transforming growth factor beta 1; miRNA: micro-ribonucleic acid; DNA: deoxyribonucleic acid; MDP: muramyl dipeptide; NF-kB: nuclear factor kappa-light-chain-enhancer of activated B cells; TIMPs: tissue inhibitors of metalloproteinases; MMPs: matrix metalloproteinases; Th: T-helper cells.

Figure 3

Genetic factors influencing the pathogenesis of stenoses in CD and their corresponding molecular pathways. Abbreviations: ATG16L1: autophagy-related 16-like 1 gene; CX3CR1: C-X3-C Motif Chemokine Receptor 1; DAMPs: damage-associated molecular patterns; DNA: deoxyribonucleic acid; ER: endoplasmic reticulum; IL: interleukin; IL-R: interleukin receptor; IKK: IkappaB kinase; IFN-γ: interferon gamma; IRF3: interferon regulatory factor 3; JAK2: Janus Kinase 2; MDP: muramyl dipeptide; NOD2: nucleotide-binding oligomerization domain-containing gene 2; NF-kB: nuclear factor kappa-light-chain-enhancer of activated B cells; P: phosphate group; RIP2: receptor-interacting protein kinase 2; STAT3: signal transducer and activator of transcription 3; TGFβ1: transforming growth factor beta 1; TLR4: Toll-like receptor 4; TNF α: tumor necrosis factor alpha; TRAF6: tumor necrosis factor receptor associated factor 6; UPR: unfolded protein response.