TOPLINE:

Creeping fat — the abnormal expansion of mesenteric adipose tissue around the intestines — is an active driver of intestinal scarring in Crohn’s disease (CD), highlighting a potential new therapeutic avenue for CD strictures, new research shows. 

METHODOLOGY:

• Researchers used tissue samples from over 400 patients with and without CD to create a detailed map of fibroblast activity in the bowel and surrounding fat.
• They used spatial transcriptomics and ultrastructural analysis to localize fibrotic activity in human CD strictures
• They developed a mouse model to mimic the creeping fat and intestinal scarring seen in human CD.
• Gene-editing techniques were used to turn off a key signaling pathway (YAP/TAZ) in creeping fat-derived fibroblasts and examine the effects on scar formation. 

TAKEAWAY:

• Creeping fat contains fibroblasts that express CTHRC1 (collagen triple helix repeat containing 1), a secreted protein involved in various physiological processes including tissue remodeling.
• These fibroblasts migrate into fibrotic niches at the border between the creeping fat and bowel wall interface where they produce large amounts of collagen and promote scar formation via the YAP/TAZ signaling pathway.
• In a mouse model, blocking the activity of these fibroblasts significantly reduced the amount of intestinal scarring and fat wrapping.
• Inhibition of YAP/TAZ signaling via conditional knockout or pharmacologic targeting in creeping fat-derived fibroblasts decreased extracellular matrix deposition, fibroblast migration, and stricture formation. 

IN PRACTICE:

“Our findings identify creeping fat as a key source of pro-fibrotic fibroblasts and raise the possibility of improving future clinical management of stricture progression by targeting

not only the bowel but also creeping fat,” the authors wrote. 

SOURCE:

The study, with first author Khristian E. Bauer-Rowe, MD/PhD student, Stanford University School of Medicine, California, was published online in Cell. 

LIMITATIONS:

Most of the CD data relied on mucosal biopsies, limiting insight into submucosal fibrosis. The mouse model lacked chronic inflammation, and the study did not evaluate microbiome contributions or fully explore other mechano-signaling pathways.

DISCLOSURES:

The study was supported by grants from the National Institutes of Health, the Scleroderma Research Foundation, and several foundations. The authors have filed a provisional patent on YAP inhibition for intestinal fibrosis.