Microbiota modification by probiotic supplementation reduces colitis associated colon cancer in mice
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摘要
AIM To investigate the effect of probiotic supplementation during the development of an experimental model of colitis associated colon cancer(CAC). METHODS C57 BL/6 mice received an intraperitoneal injection of azoxymethane(10 mg/kg), followed by three cycles of sodium dextran sulphate diluted in water(5% w/v). Probiotic group received daily a mixture of Lactobacillus acidophilus, Lactobacil us rhamnosus and Bifidobacterium bifidum. Microbiota composition was assessed by 16 Sr RNA Illumina Hi Seq sequencing. Colon samples were collected for histological analysis. Tumor cytokines was assessed by Real Time-PCR(Polymerase Chain Reaction); and serum cytokines by Multiplex assay. All tests were two-sided. The level of significance was set at P < 0.05. Graphs were generated and statistical analysis performed using the software Graph Pad Prism 5.0. The project was approved by the institutional review board committee. RESULTS At day 60 after azoxymethane injection, the mean number of tumours in the probiotic group was 40% lower than that in the control group, and the probiotic group exhibited tumours of smaller size(< 2 mm)(P < 0.05). There was no difference in richness and diversity between groups. However, there was a significant difference in beta diversity in the multidimensional scaling analysis. The abundance of the genera Lactobacillus, Bifidobacterium, Allobaculum, Clostridium XI and Clostridium XVⅢ increased in the probiotic group(P < 0.05). The microbial change was accompanied by reduced colitis, demonstrated by a 46% reduction in the colon inflammatory index; reduced expression of the serum chemokines RANTES and Eotaxin; decreased p-IKK and TNF-α and increased IL-10 expression in the colon. CONCLUSION Our results suggest a potential chemopreventive effect of probiotic on CAC. Probiotic supplementation changes microbiota structure and regulates the inflammatory response, reducing colitis and preventing CAC.
AIM To investigate the effect of probiotic supplementation during the development of an experimental model of colitis associated colon cancer(CAC). METHODS C57 BL/6 mice received an intraperitoneal injection of azoxymethane(10 mg/kg), followed by three cycles of sodium dextran sulphate diluted in water(5% w/v). Probiotic group received daily a mixture of Lactobacillus acidophilus, Lactobacil us rhamnosus and Bifidobacterium bifidum. Microbiota composition was assessed by 16 Sr RNA Illumina Hi Seq sequencing. Colon samples were collected for histological analysis. Tumor cytokines was assessed by Real Time-PCR(Polymerase Chain Reaction); and serum cytokines by Multiplex assay. All tests were two-sided. The level of significance was set at P < 0.05. Graphs were generated and statistical analysis performed using the software Graph Pad Prism 5.0. The project was approved by the institutional review board committee. RESULTS At day 60 after azoxymethane injection, the mean number of tumours in the probiotic group was 40% lower than that in the control group, and the probiotic group exhibited tumours of smaller size(< 2 mm)(P < 0.05). There was no difference in richness and diversity between groups. However, there was a significant difference in beta diversity in the multidimensional scaling analysis. The abundance of the genera Lactobacillus, Bifidobacterium, Allobaculum, Clostridium XI and Clostridium XVⅢ increased in the probiotic group(P < 0.05). The microbial change was accompanied by reduced colitis, demonstrated by a 46% reduction in the colon inflammatory index; reduced expression of the serum chemokines RANTES and Eotaxin; decreased p-IKK and TNF-α and increased IL-10 expression in the colon. CONCLUSION Our results suggest a potential chemopreventive effect of probiotic on CAC. Probiotic supplementation changes microbiota structure and regulates the inflammatory response, reducing colitis and preventing CAC.
AIM To investigate the effect of probiotic supplementation during the development of an experimental model of colitis associated colon cancer(CAC). METHODS C57 BL/6 mice received an intraperitoneal injection of azoxymethane(10 mg/kg), followed by three cycles of sodium dextran sulphate diluted in water(5% w/v). Probiotic group received daily a mixture of Lactobacillus acidophilus, Lactobacil us rhamnosus and Bifidobacterium bifidum. Microbiota composition was assessed by 16 Sr RNA Illumina Hi Seq sequencing. Colon samples were collected for histological analysis. Tumor cytokines was assessed by Real Time-PCR(Polymerase Chain Reaction); and serum cytokines by Multiplex assay. All tests were two-sided. The level of significance was set at P < 0.05. Graphs were generated and statistical analysis performed using the software Graph Pad Prism 5.0. The project was approved by the institutional review board committee. RESULTS At day 60 after azoxymethane injection, the mean number of tumours in the probiotic group was 40% lower than that in the control group, and the probiotic group exhibited tumours of smaller size(< 2 mm)(P < 0.05). There was no difference in richness and diversity between groups. However, there was a significant difference in beta diversity in the multidimensional scaling analysis. The abundance of the genera Lactobacillus, Bifidobacterium, Allobaculum, Clostridium XI and Clostridium XVⅢ increased in the probiotic group(P < 0.05). The microbial change was accompanied by reduced colitis, demonstrated by a 46% reduction in the colon inflammatory index; reduced expression of the serum chemokines RANTES and Eotaxin; decreased p-IKK and TNF-α and increased IL-10 expression in the colon. CONCLUSION Our results suggest a potential chemopreventive effect of probiotic on CAC. Probiotic supplementation changes microbiota structure and regulates the inflammatory response, reducing colitis and preventing CAC.
引文
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2 Grivennikov SI,Greten FR,Karin M.Immunity,inflammation,and cancer.Cell 2010;140:883-899[PMID:20303878 DOI:10.1016/j.cell.2010.01.025]
3 Hanahan D,Weinberg RA.Hallmarks of cancer:the next generation.Cell 2011;144:646-674[PMID:21376230 DOI:10.1016/j.cell.2011.02.013]
4 Hooper LV,Littman DR,Macpherson AJ.Interactions between the microbiota and the immune system.Science 2012;336:1268-1273[PMID:22674334 DOI:10.1126/science.1223490]
5 Zhu Q,Gao R,Wu W,Qin H.The role of gut microbiota in the pathogenesis of colorectal cancer.Tumour Biol 2013;34:1285-1300[PMID:23397545 DOI:10.1007/s13277-013-0684-4]
6 O’Keefe SJ.Diet,microorganisms and their metabolites,and colon cancer.Nat Rev Gastroenterol Hepatol 2016;13:691-706[PMID:27848961 DOI:10.1038/nrgastro.2016.165]
7 Tennyson CA,Friedman G.Microecology,obesity,and probiotics.Curr Opin Endocrinol Diabetes Obes 2008;15:422-427[PMID:18769213 DOI:10.1097/MED.0b013e328308dbfb]
8 Tamburini S,Shen N,Wu HC,Clemente JC.The microbiome in early life:implications for health outcomes.Nat Med 2016;22:713-722[PMID:27387886 DOI:10.1038/nm.4142]
9 Brennan CA,Garrett WS.Gut Microbiota,Inflammation,and Colorectal Cancer.Annu Rev Microbiol 2016;70:395-411[PMID:27607555 DOI:10.1146/annurev-micro-102215-095513]
10 Hill C,Guarner F,Reid G,Gibson GR,Merenstein DJ,Pot B,Morelli L,Canani RB,Flint HJ,Salminen S,Calder PC,Sanders ME.Expert consensus document.The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic.Nat Rev Gastroenterol Hepatol 2014;11:506-514[PMID:24912386 DOI:10.1038/nrgastro.2014.66]
11 Mantovani A.From phagocyte diversity and activation to probiotics:back to Metchnikoff.Eur J Immunol 2008;38:3269-3273[PMID:19039773 DOI:10.1002/eji.200838918]
12 Didari T,Mozaffari S,Nikfar S,Abdollahi M.Effectiveness of probiotics in irritable bowel syndrome:Updated systematic review with meta-analysis.World J Gastroenterol 2015;21:3072-3084[PMID:25780308 DOI:10.3748/wjg.v21.i10.3072]
13 Kim JY,Kwon JH,Ahn SH,Lee SI,Han YS,Choi YO,Lee SY,Ahn KM,Ji GE.Effect of probiotic mix(Bifidobacterium bifidum,Bifidobacterium lactis,Lactobacillus acidophilus)in the primary prevention of eczema:a double-blind,randomized,placebocontrolled trial.Pediatr Allergy Immunol 2010;21:e386-e393[PMID:19840300 DOI:10.1111/j.1399-3038.2009.00958.x]
14 King S,Glanville J,Sanders ME,Fitzgerald A,Varley D.Effectiveness of probiotics on the duration of illness in healthy children and adults who develop common acute respiratory infectious conditions:a systematic review and meta-analysis.Br J Nutr 2014;112:41-54[PMID:24780623 DOI:10.1017/S0007114514000075]
15 Mennini M,Dahdah L,Artesani MC,Fiocchi A,Martelli A.Probiotics in Asthma and Allergy Prevention.Front Pediatr 2017;5:165[PMID:28824889 DOI:10.3389/fped.2017.00165]
16 Sun J,Buys NJ.Glucose-and glycaemic factor-lowering effects of probiotics on diabetes:a meta-analysis of randomised placebocontrolled trials.Br J Nutr 2016;115:1167-1177[PMID:26899960 DOI:10.1017/S0007114516000076]
17 Schwabe RF,Jobin C.The microbiome and cancer.Nat Rev Cancer2013;13:800-812[PMID:24132111 DOI:10.1038/nrc3610]
18 Bienenstock J,Gibson G,Klaenhammer TR,Walker WA,Neish AS.New insights into probiotic mechanisms:a harvest from functional and metagenomic studies.Gut Microbes 2013;4:94-100[PMID:23249742 DOI:10.4161/gmic.23283]
19 Orlando A,Russo F.Intestinal microbiota,probiotics and human gastrointestinal cancers.J Gastrointest Cancer 2013;44:121-131[PMID:23180023 DOI:10.1007/s12029-012-9459-1]
20 Bron PA,Kleerebezem M,Brummer RJ,Cani PD,Mercenier A,Mac Donald TT,Garcia-Ródenas CL,Wells JM.Can probiotics modulate human disease by impacting intestinal barrier function?Br J Nutr 2017;117:93-107[PMID:28102115 DOI:10.1017/S0007114516004037]
21 Geier MS,Butler RN,Howarth GS.Probiotics,prebiotics and synbiotics:a role in chemoprevention for colorectal cancer?Cancer Biol Ther 2006;5:1265-1269[PMID:16969130 DOI:10.4161/cbt.5.10.3296]
22 Thomas CM,Versalovic J.Probiotics-host communication:Modulation of signaling pathways in the intestine.Gut Microbes2010;1:148-163[PMID:20672012 DOI:10.4161/gmic.1.3.11712]
23 Greten FR,Eckmann L,Greten TF,Park JM,Li ZW,Egan LJ,Kagnoff MF,Karin M.IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer.Cell 2004;118:285-296[PMID:15294155 DOI:10.1016/j.cell.2004.07.013]
24 Edgar RC.UPARSE:highly accurate OTU sequences from microbial amplicon reads.Nat Methods 2013;10:996-998[PMID:23955772 DOI:10.1038/nmeth.2604]
25 Mc Murdie PJ,Holmes S.Waste not,want not:why rarefying microbiome data is inadmissible.PLo S Comput Biol 2014;10:e1003531[PMID:24699258 DOI:10.1371/journal.pcbi.1003531]
26 Cooper HS,Murthy SN,Shah RS,Sedergran DJ.Clinicopathologic study of dextran sulfate sodium experimental murine colitis.Lab Invest 1993;69:238-249[PMID:8350599]
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