Background: Fibrosis in IBD has significant clinical consequences yet advances in anti-fibrotic therapies are lagging, in part due to a lack of consensus definition on fibrosis clinical trial endpoints. A reliable biomarker of fibrosis is needed to assess emerging anti-fibrotic therapies in IBD. Moreover, elucidating the temporal and spatial relationship between inflammation and fibrosis across bowel wall layers would further opportunities in therapeutic targets. We utilized a method to annotate, quantify, and characterize collagen directly from H&E WSIs to better understand the nuances of fibrosis in IBD.
Methods: IBDExploreTM, 1 (PathAI, Boston), a model previously trained to quantify tissue features (e.g., epithelium) and cells (e.g., neutrophils), and a collagen quantification model, inferred quantitative multimodal anisotropic imaging (iQMAI1, PathAI, Boston) were deployed on a clinical cohort of 116 digitized H&E-stained specimens from control, ulcerative colitis (UC) and Crohn Disease (CD). The difference in iQMAI feature values between IBD and control was assessed using Cohen’s D. Correlations between IBDExplore and iQMAI features were assessed using Pearson Correlation.
Results: Mucosal collagen intensity, fiber area, width, tortuosity and density were all significantly greater in UC and CD compared to control (Fig 1). In UC, the submucosa contained fibers that were significantly longer (Cohen’s D 0.74; p-value 0.018) and straighter (-1.08; 0.001) compared to the control group. In CD, fiber tortuosity in the submucosa was also significantly lower compared with the control group (-1.33; < 0.001), though significant changes in fiber length were not observed. IBDExplore was used to quantify inflammation in the mucosa. Submucosa fiber tortuosity was negatively correlated with mucosal epithelial neutrophil infiltration (Pearson r= -0.36 for UC, -0.46 for CD).
Conclusions: Combined insights from quantitative collagen fiber and histological feature characterization highlight distinct fibroinflammatory niches at mucosal and submucosal levels of IBD. Decreased fiber tortuosity emerged as an important differentiator between IBD and control samples, imparting a rigid appearance at the microscopic level (Fig 2). These findings raise the possibility that fiber tortuosity may be a surrogate marker for clinical features such as fibrotic stricture in CD. The negative correlation of acute inflammation in the mucosa with fiber tortuosity in the submucosa raises the possibility of gathering information about deeper bowel wall layers from a more easily acquired mucosal biopsy. Additional investigations with external cohorts will be required to determine whether the correlation of mucosal acute inflammation with abnormal submucosal fiber features are reflective of unique patient populations of IBD.
1For Research Use Only. Not for use in diagnostic procedures.
Authors
- Tauber et al.