Mesenteric Adipose Tissue Contributes to Intestinal Fibrosis in Crohn’s Disease Through the ATX–LPA Axis

Abstract

Abstract Background and Aims Intestinal fibrostenosis is an important cause of surgical intervention in patients with Crohn’s disease [CD]. Hypertrophic mesenteric adipose tissue [MAT] is associated with the disease process of CD. The purpose of this study was to investigate the contribution of MAT to intestinal fibrosis. Methods MAT from surgical specimens of fibrostenotic CD patients and controls was collected for measurement of the levels of autotaxin [ATX] and lysophosphatidic acid [LPA]. ATX was inhibited in vivo in DNBS [dinitrobenzene sulfonic acid]-induced colitis mice, which were evaluated for colonic inflammation and fibrosis. 3T3-L1 cells and primary colonic fibroblasts were used in vitro to investigate the interaction between MAT and intestinal fibrosis, as well as the molecular mechanism underlying this interaction. Results MAT adjacent to the fibrostenotic intestine in CD patients showed an activated ATX–LPA axis. An in vivo study indicated that inhibition of ATX was associated with the improvement of morphology and function of diseased MAT, which was combined with ameliorated intestinal inflammation and fibrosis in DNBS-instilled mice. In vitro studies showed that hypoxia stimulated adipocyte ATX expression and that LPA stabilized adipocyte HIF-1α protein, forming an ATX–LPA–HIF-1α amplification loop and aggravating adipocyte dysfunction. LPA secreted by adipocytes bound to LPA1 on the surface of fibroblasts, promoted their proliferation and differentiation, and increased the expression of fibrosis-related factors. Conclusions The ATX–LPA axis regulated intestinal fibrosis by influencing the proliferation and differentiation of intestinal fibroblasts. Inhibiting this axis may be a therapeutic target for intestinal fibrosis in CD.