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Histopathologic Evaluation and Single-cell Spatial Transcriptomics of the Colon Reveal Cellular and Molecular
Andrea D Olivas1, Paul Chak Mou Ngai2, Emily Schahrer3
1Department of Pathology, University of Chicago Medical Center, Chicago, Illinois.
Background & Aims:
Total abdominal colectomy (TAC) with a staged ileal pouch-anal anastomosis (IPAA) is a common surgical treatment for ulcerative colitis (UC). However, a significant percentage of patients experience pouch failure, leading to morbidity. This retrospective case-control study identified histopathologic features of the TAC specimen associated with pouch failure and investigated the molecular mechanisms of this susceptibility using single-cell spatial transcriptomics.
Methods:
We analyzed a cohort of 417 patients who underwent IPAA between 2000 and 2010 at the University of Chicago Medical Center for up to 18 years. Histologic examination of TAC specimens focused on disease activity, depth of inflammation, and specific features, including granulomas and deep ulcers. A subset of patients was profiled using single-cell spatial transcriptomics to map gene expression and immune cell interactions in relation to the risk of pouch failure.
Results:
The 18-year pouch failure risk was 23%, with post-procedure clinical features of Crohn's disease as a major risk factor (hazard ratio [HR], 4.3; 95% confidence interval [CI], 2.3-8.1) as well as high-risk histologic features, including deep chronic inflammation (HR, 21; 95% CI, 11-41) and severe disease activity (HR, 14; 95% CI, 5.7-32) in TAC specimens. Spatial transcriptomics showed immune infiltration of T and myeloid cells, reduced myocyte-glial interactions, and cytokine signaling pathways such as interleukin (IL)-10, IL-1β, and type I/II interferons, associated with an increased risk of pouch failure. CD68 immunohistochemistry confirmed that deep CD68+ macrophage infiltration is associated with increased risk of future pouch failure.
Conclusion:
Histologic features including CD68 immunohistochemisty and spatial molecular profiling are predictive of IPAA failure. These findings support the use of histologic evaluation and targeted molecular analysis of the TAC specimen to identify high-risk patients and improve IPAA outcomes.
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