# Tissue-layer-resolved proteome landscape of Crohn’s disease strictures highlights potential drivers of fibrosis progression

## TL;DR

This study maps the proteome of intestinal layers in Crohn’s disease strictures, identifying tissue-specific changes that may drive fibrosis and inform new therapies.

## Contribution

The study provides the first tissue-layer-resolved proteome analysis of Crohn’s disease strictures, revealing potential drivers of fibrosis.

## Key findings

- Strictured submucosa shows reduced vascular and lipid metabolism proteins and increased immune and ECM-related proteins.
- Muscularis propria in strictures exhibits increased ECM and immune proteins with decreased muscle and metabolic functions.
- Proteomic trends near strictures suggest progressive fibrotic remodeling and muscle expansion.

## Abstract

The chronic inflammation of Crohn’s disease frequently leads to fibrosis and muscular hypertrophy of the intestinal wall. This often culminates in strictures, a serious condition lacking directed therapy. Severe pathological changes occur in the submucosa and muscularis propria intestinal wall layers of strictures, yet stricture-associated proteome changes in these layers is unexplored. We perform unbiased proteomics on submucosa and muscularis propria microdissected from transmural sections of strictured and nonstrictured ileum. Proteome changes in strictured submucosa reflected a transition from homeostasis to tissue remodeling, inflammation, and smooth muscle changes. Top submucosal features included reduced vascular components and lipid metabolism proteins accompanied by increased proteins with immune-, ECM-, or stress-related functions, including CTHRC1, TNC, IL-16, MZB1, and TXNDC5. In parallel, predominant changes in strictured muscularis propria included increased ECM (POSTN) and immune (mast cell CPA3) proteins alongside decreased proteins with lipid metabolic, mitochondrial, or key muscle functions. Finally, trends of differentially expressed proteins along nonstrictured submucosa suggest progressive profibrotic tissue remodeling and muscle expansion as proximity to strictures increases. The comprehensive proteome map presented here offers tissue-layer-resolved insight into the stricture microenvironment and potential drivers of fibrotic disease, providing a valuable resource to fuel biomarker and therapeutic target research.

Proteome landscape of Crohn’s disease intestinal strictures reveals tissue layer-specific changes, offering insight into potential drivers of fibrosis to fuel research on biomarkers and therapeutic targets.