The Exosomal miR-130b-5p Derived From Crohn's Disease-Associated Mesenteric Adipose Tissue Promotes Ileocolonic Anastomotic Fibrosis via the Smad Signaling Pathway.

Mesenteric tissue in Crohn's disease is associated with the severity of intestinal fibrosis. However, the role of hypertrophic mesenteric adipose tissue in the pathogenesis of CD, especially in the progression of postoperative anastomotic recurrence, remains unknown. Exosomes were isolated from hypertrophic mesenteric adipose tissue from diseased bowel (HtMAT) and macroscopically normal mesenteric adipose tissue from surgical margins (nMAT) of patients with CD. Using a surgical model in IL10 knockout mice, a series of in vitro and in vivo experiments were conducted to study the effects of exosomes on ileocolonic anastomotic fibrosis and fibroblast activation. A microRNA microarray analysis was performed. Western blot, luciferase assay, and immunofluorescence were performed to further detect the underlying mechanisms. The results indicated that HtMAT-Exos (Ht-exos) promoted intestinal fibrosis by activating fibroblasts in a dose-dependent manner. Further analysis indicated that exosomal miR-130b-5p was enriched in Ht-Exos and participated in exosome-mediated fibroblast activation. TGFBR3 was identified as a target gene of miR-130b-5p. Mechanistically, HtMAT released exosomal miR-130b-5p and promoted fibroblast activation by targeting TGFBR3 and promoting Smad2/3 phosphorylation. We also found that the expression of miR-130b-5p was positively associated with the degree of ileocolonic anastomosis fibrosis in CD. Our findings show that exosomal miR-130b-5p from HtMAT promotes ileocolonic anastomosis fibrosis by activating fibroblasts via the Smad signaling pathway, suggesting that HtMAT significantly contributes to anastomotic fibrosis in CD.