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P089 Stimulation of the ω-3 docosahexaenoic acid metabolism via MFSD2A as a novel therapy for inflammatory bowel disease.

F. Ungaro*1, 2, C. Correale1, P. Corsetto3, L. Massimino4, P. Fonteyne1, C. Tacconi1, K. R. Maddipati5, A. Rizzo3, S. D’Alessio1, 2, S. Danese1

1Humanitas Research Institute, Laboratory of Immunology in Gastroenterology, Milan, Italy, 2University of Milan, Department of Biotechnology and Translational Medicine, Milan, Italy, 3University of Milan, Department of Pharmacology and Biomolecular Science, Milan, Italy, 4San Raffaele Research Institute, Division of Neuroscience, Milan, Italy, 5Wayne State University, Department of Pathology, Detroit, Michigan, United States


Endothelial cells play a key role in the pathogenesis of inflammatory bowel disease (IBD) by governing immune cell migration. However, novel evidence suggested that endothelial cells are also crucially involved in regulating the resolution of inflammation (RoI). RoI is regulated by lipid mediators, such as those derived from the ω-3 docosahexaenoic acid (DHA), whose endothelial specific transporter is the major facilitator superfamily domain containing 2A (MFSD2A). The involvement of MFSD2A-dependent DHA metabolism in IBD has never been explored. Here we show how MFSD2A promotes RoI by modulating the DHA metabolism of intestinal endothelial cells, thus shedding new light on novel pathways that regulate intestinal inflammation.


Lipidomic analysis was performed by liquid chromatography–mass spectrometry (LC-MS) on both mucosal biopsies and primary human intestinal microvascular endothelial cells (HIMEC) isolated from surgical specimens of actively inflamed and resolving IBD subjects. MFSD2A expression was evaluated by qRT-polymerase chain reaction (PCR), Western blot, and immunofluorescence analysis on both mucosal biopsies and HIMEC. Moreover, HIMEC were transduced by lentivirus carrying MFSD2A or GFP encoding sequences and subjected to quantification of proliferation, in-vitro capillary formation, and pro-resolving molecule expression.


LC-MS analysis revealed a higher percentage of ω-3 DHA-derived metabolites in the resolving IBD mucosa, when compared with samples from inflamed tissues (1.40% ± 0.09 vs 0.85% ± 0.15 over total fatty acids; p < 0.05). MFSD2A protein was up regulated in mucosal biopsies from drug-induced resolving IBD patients in comparison with actively inflamed tissue (2 ± 0.3 vs 1 ± 0.1 absolute protein units; p < 0.01), particularly on intestinal microvessels, thus suggesting a direct correlation between MFSD2A expression and pro-resolving lipid production. Lentiviral induction of MFSD2A conferred anti-angiogenic properties to HIMEC, reducing in-vitro capillary formation and proliferation, and significantly inhibited TNFα-triggered pro-inflammatory machinery of NF-κB signalling (p < 0.005), via PPARγ activation. Moreover, lipidomic analysis confirmed that the lentiviral induction of MFSD2A significantly increased the production of pro-resolving DHA-derived metabolites in HIMEC, when compared with GFP control (20% ± 2.5 vs 11% ± 0.05 over total fatty acids; p < 0.05).


Our results show that MFSD2A may act as a new player in the resolution of intestinal inflammation, likely promoting endothelial production of DHA-derived pro-resolving mediators. Stimulating MFSD2A activity in intestinal endothelial cells could be a novel and powerful therapeutic approach to treat IBD.