title: Eicosapentaenoic acid free fatty acid prevents and suppresses colonic neoplasia in colitis-associated colorectal cancer acting on Notch signaling and gut microbiota.
abstract: Inflammatory bowel diseases are associated with increased risk of developing colitis-associated colorectal cancer (CAC). Epidemiological data show that the consumption of ω-3 polyunsaturated fatty acids (ω-3 PUFAs) decreases the risk of sporadic colorectal cancer (CRC). Importantly, recent data have shown that eicosapentaenoic acid-free fatty acid (EPA-FFA) reduces polyp formation and growth in models of familial adenomatous polyposis. However, the effects of dietary EPA-FFA are unknown in CAC. We tested the effectiveness of substituting EPA-FFA, for other dietary fats, in preventing inflammation and cancer in the AOM-DSS model of CAC. The AOM-DSS protocols were designed to evaluate the effect of EPA-FFA on both initiation and promotion of carcinogenesis. We found that EPA-FFA diet strongly decreased tumor multiplicity, incidence and maximum tumor size in the promotion and initiation arms. Moreover EPA-FFA, in particular in the initiation arm, led to reduced cell proliferation and nuclear β-catenin expression, whilst it increased apoptosis. In both arms, EPA-FFA treatment led to increased membrane switch from ω-6 to ω-3 PUFAs and a concomitant reduction in PGE2 production. We observed no significant changes in intestinal inflammation between EPA-FFA treated arms and AOM-DSS controls. Importantly, we found that EPA-FFA treatment restored the loss of Notch signaling found in the AOM-DSS control and resulted in the enrichment of Lactobacillus species in the gut microbiota. Taken together, our data suggest that EPA-FFA is an excellent candidate for CRC chemoprevention in CAC.
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy; Center for Applied Biomedical Research (CRBA), S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Piazzi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: D'Argenio
authors.forename: Anna
authors.initials: A
authors.lastname: Prossomariti
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Lembo
authors.forename: Giovanna
authors.initials: G
authors.lastname: Mazzone
authors.forename: Marco
authors.initials: M
authors.lastname: Candela
authors.forename: Elena
authors.initials: E
authors.lastname: Biagi
authors.forename: Patrizia
authors.initials: P
authors.lastname: Brigidi
authors.forename: Paola
authors.initials: P
authors.lastname: Vitaglione
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Fogliano
authors.forename: Leonarda
authors.initials: L
authors.lastname: D'Angelo
authors.forename: Chiara
authors.initials: C
authors.lastname: Fazio
authors.forename: Alessandra
authors.initials: A
authors.lastname: Munarini
authors.forename: Andrea
authors.initials: A
authors.lastname: Belluzzi
authors.forename: Claudio
authors.initials: C
authors.lastname: Ceccarelli
authors.forename: Pasquale
authors.initials: P
authors.lastname: Chieco
authors.forename: Tiziana
authors.initials: T
authors.lastname: Balbi
authors.forename: Paul M
authors.initials: PM
authors.lastname: Loadman
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hull
authors.forename: Marco
authors.initials: M
authors.lastname: Romano
authors.forename: Franco
authors.initials: F
authors.lastname: Bazzoli
authors.forename: Luigi
authors.initials: L
authors.lastname: Ricciardiello
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D003092:Colitis / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D003106:Colon / Q000382:microbiology / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D015118:Eicosapentaenoic Acid / Q000008:administration & dosage*; D005230:Fatty Acids, Nonesterified / Q000008:administration & dosage*; D041981:Gastrointestinal Tract / Q000187:drug effects* / Q000378:metabolism / Q000382:microbiology; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D064307:Microbiota / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D051880:Receptors, Notch / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D005230:Fatty Acids, Nonesterified; D012333:RNA, Messenger; D051880:Receptors, Notch; D015118:Eicosapentaenoic Acid
keywords: Notch; colon cancer; inflammation; microbiota; omega 3