3 Key Takeaways
Plain English Summary- 01Core Finding
We investigated the role of TG2 in intestinal fibrosis (tissue scarring).
- 02Study Evidence
Tested in a observational cohort study at the real-world cohort stage.
- 03Practical Meaning
Observational cohort findings reveal real-world links, though lifestyle or unmeasured factors cannot be fully ruled out without an RCT.
What This Means for You
TG2 may be involved in inflammation-independent progression of intestinal fibrosis (tissue scarring).
The Discovery
Excessive accumulation of extracellular matrix (ECM) derived from human intestinal myofibroblasts (HIMFs) drives the significant clinical problem of intestinal fibrosis (tissue scarring). Fibrosis is believed to progress even in the absence of intestinal inflammation. The ECM-bound transglutaminase 2 (TG2) enzyme may exert direct profibrotic effects. We investigated the role of TG2 in intestinal fibrosis. TG2 expression and activity in human intestinal tissue and HIMFs from patients with strictured Crohn's disease and control subjects were measured. ECM accumulation by HIMF in the presence or absence of TG2 inhibitors was determined. Putative TG2 signaling pathways discovered in HIMF using bulk RNA sequencing and single-cell RNA sequencing were functionally validated. Role of TG2 in vivo was confirmed using inducible global knockout of TGM2 (encoding TG2) in 2 experimental fibrosis models. Transglutaminase (TG) activity was increased in strictured Crohn's disease compared with controls, with up to 100% activity attributable to TG2. TG activity correlated with the degree of histopathologic tissue fibrosis. HIMFs were the major source of TG2, with ≥95% of HIMF TG activity being derived from TG2. Tissue distribution of TG2 in myofibroblasts was confirmed by single-cell RNA sequencing. Selective inhibition of TG2 activity reduced fibronectin and collagen I, III, and VI accumulation by HIMFs. Novel TG2 signaling pathways revealed by bulk RNA sequencing were functionally validated. Inducible TGM2 knockout prevented experimental fibrosis without affecting the degree of intestinal inflammation.
How It Works, Simply
This gastroenterology research focuses on inflammation · Enzyme. Researchers evaluated it using an observational cohort study at the real-world cohort stage of medical research.
3 Key Takeaways
Clinical Takeaways- 01Core Finding
We investigated the role of TG2 in intestinal fibrosis.
- 02Study Evidence
Tested in a observational cohort study at the real-world cohort stage.
- 03Practical Meaning
Observational cohort findings reveal real-world links, though lifestyle or unmeasured factors cannot be fully ruled out without an RCT.
Biological Mechanism & Study Design
Study Design & Cohort
Observational cohort study
Observational cohort study · Real-World Cohort
Biological Pathway & Modality
Inflammation · Enzyme
Intervention: Myofibroblast-Derived Transglutaminase 2 Activity is Upregulated in Stricturing
Experimental Findings & Endpoints
Excessive accumulation of extracellular matrix (ECM) derived from human intestinal myofibroblasts (HIMFs) drives the significant clinical problem of intestinal fibrosis.
Fibrosis is believed to progress even in the absence of intestinal inflammation. The ECM-bound transglutaminase 2 (TG2) enzyme may exert direct profibrotic effects.
We investigated the role of TG2 in intestinal fibrosis. TG2 expression and activity in human intestinal tissue and HIMFs from patients with strictured Crohn's disease and control subjects were measured.
ECM accumulation by HIMF in the presence or absence of TG2 inhibitors was determined. Putative TG2 signaling pathways discovered in HIMF using bulk RNA sequencing and single-cell RNA sequencing were functionally validated.
Role of TG2 in vivo was confirmed using inducible global knockout of TGM2 (encoding TG2) in 2 experimental fibrosis models. Transglutaminase (TG) activity was increased in strictured Crohn's disease compared with controls, with up to 100% activity attributable to TG2.
TG activity correlated with the degree of histopathologic tissue fibrosis. HIMFs were the major source of TG2, with ≥95% of HIMF TG activity being derived from TG2.
Tissue distribution of TG2 in myofibroblasts was confirmed by single-cell RNA sequencing. Selective inhibition of TG2 activity reduced fibronectin and collagen I, III, and VI accumulation by HIMFs.
Novel TG2 signaling pathways revealed by bulk RNA sequencing were functionally validated. Inducible TGM2 knockout prevented experimental fibrosis without affecting the degree of intestinal inflammation.
Clinical Translation & Practice Context
TG2 may be involved in inflammation-independent progression of intestinal fibrosis.
The Bottom Line · Clinical Pearl
“TG2 may be involved in inflammation-independent progression of intestinal fibrosis.”
Published in Gastroenterology · Current Stage: Real-World Cohort
