Background: Intestinal fibrosis is a late complication of pelvic radiotherapy. Epithelial-to-mesenchymal transition (EMT) plays an important role in tissue fibrosis. The aim of this study was to examine the effect of soluble dietary fiber on radiation-induced intestinal EMT and fibrosis in a mouse model. Materials and Methods: Apple pectin (4% wt/wt in drinking water) was administered to wild-type and pVillin-Cre-EGFP transgenic mice with intestinal fibrosis induced by a single dose of abdominal irradiation of 10 Gy. The effects of pectin on intestinal EMT and fibrosis, gut microbiota, and short-chain fatty acid (SCFA) concentration were evaluated. Results: Intestinal fibrosis in late radiation enteropathy showed increased submucosal thickness and subepithelial collagen deposition. Enhanced green fluorescent protein (EGFP)+/vimentin+ and EGFP+/α–smooth muscle actin (SMA)+ coexpressing cells were most clearly observed at 2 weeks after irradiation and gradually decreased at 4 and 12 weeks. Pectin significantly attenuated the thickness of submucosa and collagen deposition at 12 weeks (24.3 vs 27.6 µm in the pectin + radiation-treated group compared with radiation-alone group, respectively, P < .05; 69.0% vs 57.1%, P < .001) and ameliorated EMT at 2 and 4 weeks. Pectin also modulated the intestinal microbiota composition and increased the luminal SCFA concentration. Conclusion: The soluble dietary fiber pectin protected the terminal ileum against radiation-induced fibrosis. This effect might be mediated by altered SCFA concentration in the intestinal lumen and reduced EMT in the ileal epithelium.
YangJDingCZhangTet alClinical features, outcome and risk factors in cervical cancer patients after surgery for chronic radiation enteropathy. Radiation Oncol. 2015;10:128.
3.
LefevreJHAmiotAJolyFBretagnolFPanisY. Risk of recurrence after surgery for chronic radiation enteritis. Br J Surg. 2011;98(12):1792-1797.
4.
HamamaSDelanianSMonceauVVozeninMC. Therapeutic management of intestinal fibrosis induced by radiation therapy: from molecular profiling to new intervention strategies et vice et versa. Fibrogenesis Tissue Repair. 2012;5(suppl 1):S13.
5.
YarnoldJBrotonsMC. Pathogenetic mechanisms in radiation fibrosis. Radiother Oncol. 2010;97(1):149-161.
6.
KalluriRNeilsonEG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest. 2003;112(12):1776-1784.
7.
BatailleFRohrmeierCBatesRet alEvidence for a role of epithelial mesenchymal transition during pathogenesis of fistulae in Crohn’s disease. Inflamm Bowel Dis. 2008;14(11):1514-1527.
8.
FlierSNTanjoreHKokkotouEGSugimotoHZeisbergMKalluriR. Identification of epithelial to mesenchymal transition as a novel source of fibroblasts in intestinal fibrosis. J Biol Chem. 2010;285(26):20202-20212.
9.
StaceyRGreenJT. Radiation-induced small bowel disease: latest developments and clinical guidance. Ther Adv Chronic Dis. 2014;5(1):15-29.
10.
Valérie HaydontM-CV-B. Maintenance of radiation-induced intestinal fibrosis: cellular and molecular features. World J Gastroenterol. 2007;13(19):2675-2683.
11.
KimMHKangSGParkJHYanagisawaMKimCH. Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology. 2013;145(2):396-406.e1-10.
12.
TrompetteAGollwitzerESYadavaKet alGut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nat Med. 2014;20(2):159-166.
13.
FerreiraMRMulsADearnaleyDPAndreyevHJN. Microbiota and radiation-induced bowel toxicity: lessons from inflammatory bowel disease for the radiation oncologist. Lancet Oncol. 2014;15(3):e139-e147.
14.
VinoloMARodriguesHGNachbarRTCuriR. Regulation of inflammation by short chain fatty acids. Nutrients. 2011;3(10):858-876.
15.
CananiRBCostanzoMDLeoneLPedataMMeliRCalignanoA. Potential beneficial effects of butyrate in intestinal and extraintestinal diseases. World J Gastroenterol. 2011;17(12):1519-1528.
16.
PachecoRGEspositoCCMullerLCet alUse of butyrate or glutamine in enema solution reduces inflammation and fibrosis in experimental diversion colitis. World J Gastroenterol. 2012;18(32):4278-4287.
17.
AdamCLWilliamsPAGardenKEThomsonLMRossAW. Dose-dependent effects of a soluble dietary fibre (pectin) on food intake, adiposity, gut hypertrophy and gut satiety hormone secretion in rats. PLoS One. 2015;10(1):e0115438.
BernardHDesseynJLBartkeNet alDietary pectin-derived acidic oligosaccharides improve the pulmonary bacterial clearance of Pseudomonas aeruginosa lung infection in mice by modulating intestinal microbiota and immunity. J Infect Dis. 2015;211(1):156-165.
20.
JiangTGaoXWuCet alApple-derived pectin modulates gut microbiota, improves gut barrier function, and attenuates metabolic endotoxemia in rats with diet-induced obesity. Nutrients. 2016;8(3):126.
21.
MuzumdarMDTasicBMiyamichiKLiLLuoL. A global double-fluorescent Cre reporter mouse. Genesis. 2007;45(9):593-605.
22.
MadisonBBDunbarLQiaoXTBraunsteinKBraunsteinEGumucioDL. Cis elements of the villin gene control expression in restricted domains of the vertical (crypt) and horizontal (duodenum, cecum) axes of the intestine. J Biol Chem. 2002;277(36):33275-33283.
23.
LinardCBilliardFBenderitterM. Intestinal irradiation and fibrosis in a Th1-deficient environment. Int J Radiat Oncol Biol Phys. 2012;84(1):266-273.
FadroshDWMaBGajerPet alAn improved dual-indexing approach for multiplexed 16S rRNA gene sequencing on the Illumina MiSeq platform. Microbiome. 2014;2(1):6.
26.
ZhengXQiuYZhongWet alA targeted metabolomic protocol for short-chain fatty acids and branched-chain amino acids. Metabolomics. 2013;9(4):818-827.
27.
ManichanhCVarelaEMartinezCet alThe gut microbiota predispose to the pathophysiology of acute postradiotherapy diarrhea. Am J Gastroenterol. 2008;103(7):1754-1761.
28.
ShaoZ-YTangZ-SYanCet alEffects of intensity-modulated radiotherapy on human oral microflora. J Radiat Res. 2011;52(6):834-839.
29.
NamYDKimHJSeoJGKangSWBaeJW. Impact of pelvic radiotherapy on gut microbiota of gynecological cancer patients revealed by massive pyrosequencing. PLoS One. 2013;8(12):e82659.
30.
TouchefeuYMontassierENiemanKet alSystematic review: the role of the gut microbiota in chemotherapy- or radiation-induced gastrointestinal mucositis—current evidence and potential clinical applications. Aliment Pharmacol Ther. 2014;40(5):409-421.
31.
SlavinJ. Fiber and prebiotics: mechanisms and health benefits. Nutrients. 2013;5(4):1417-1435.
32.
KeremMBedirliAKarahaciogluEet alEffects of soluble fiber on matrix metalloproteinase-2 activity and healing of colon anastomosis in rats given radiotherapy. Clin Nutr. 2006;25(4):661-670.
33.
HaydontVGilliotORiveraSet alSuccessful mitigation of delayed intestinal radiation injury using pravastatin is not associated with acute injury improvement or tumor protection. Int J Radiat Oncol Biol Phys. 2007;68(5):1471-1482.
34.
RiederFKesslerSSansMFiocchiC. Animal models of intestinal fibrosis: new tools for the understanding of pathogenesis and therapy of human disease. Am J Physiol Gastrointest Liver Physiol. 2012;303(7):G786-G801.
35.
LeeKKJoHJHongJPet alRecombinant human epidermal growth factor accelerates recovery of mouse small intestinal mucosa after radiation damage. Int J Radiat Oncol Biol Phys. 2008;71(4):1230-1235.
36.
YehMHChangYHTsaiYCet alBone marrow derived macrophages fuse with intestine stromal cells and contribute to chronic fibrosis after radiation. Radiother Oncol. 2016;119(2):250-258.
37.
ViswanathanANThomadsenB. American Brachytherapy Society consensus guidelines for locally advanced carcinoma of the cervix. Part I: general principles. Brachytherapy. 2012;11(1):33-46.
38.
AlmeidaCNagarajanDTianJet alThe role of alveolar epithelium in radiation-induced lung injury. PLoS One. 2013;8(1):e53628.
39.
MassziAFanLRosivallLet alIntegrity of cell-cell contacts is a critical regulator of TGF-beta 1-induced epithelial-to-myofibroblast transition: role for beta-catenin. Am J Pathol. 2004;165(6):1955-1967.
40.
LiuDGWangTM. Role of connective tissue growth factor in experimental radiation nephropathy in rats. Chin Med J. 2008;121(19):1925-1931.
41.
ChangPVHaoLOffermannsSMedzhitovR. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc Natl Acad Sci U S A. 2014;111(6):2247-2252.
42.
PangMZhuangS. Histone deacetylase: a potential therapeutic target for fibrotic disorders. J Pharmacol Exp Ther. 2010;335(2):266-272.
43.
KaimoriAPotterJJChotiMDingZMezeyEKoteishAA. Histone deacetylase inhibition suppresses the transforming growth factor beta1-induced epithelial-to-mesenchymal transition in hepatocytes. Hepatology. 2010;52(3):1033-1045.
44.
ChungYLWangAJYaoLF. Antitumor histone deacetylase inhibitors suppress cutaneous radiation syndrome: implications for increasing therapeutic gain in cancer radiotherapy. Mol Cancer Ther. 2004;3(3):317-325.
45.
WangHGHuangXDShenPLiLRXueHTJiGZ. Anticancer effects of sodium butyrate on hepatocellular carcinoma cells in vitro. Int J Mol Med. 2013;31(4):967-974.
46.
GremyOBenderitterMLinardC. Acute and persisting Th2-like immune response after fractionated colorectal gamma-irradiation. World J Gastroenterol. 2008;14(46):7075-7085.
47.
VosAPHaarmanMvan GinkelJWet alDietary supplementation of neutral and acidic oligosaccharides enhances Th1-dependent vaccination responses in mice. Pediatr Allergy Immunol. 2007;18(4):304-312.
48.
WangALingZYangZet alGut microbial dysbiosis may predict diarrhea and fatigue in patients undergoing pelvic cancer radiotherapy: a pilot study. PLoS One. 2015;10(5):e0126312.
49.
KimYSKimJParkSJ. High-throughput 16S rRNA gene sequencing reveals alterations of mouse intestinal microbiota after radiotherapy. Anaerobe. 2015;33:1-7.
