| Objective:To investigate the effects of curcumin on Azoxymethane(AOM)/ Dextran sodium sulfate(DSS)induced colorectal tumorigenesis in mice,and the role of curcumin on regulating intestinal microbiota and metabolites.Methods:Forty male C57BL/6JGpt mice aged 6-8 weeks were randomly divided into four groups with 10 mice in each group: negative control(Control)group,curcumin(Cur)group,colorectal cancer model(CRC)group and model-curcumin treatment(CRC-Cur)group.The mice in CRC group were induced by AOM/DSS and simultaneously received an oral gavage of PBS.The mice in curcumin group were treated with oral gavage of PBS.The mice in CRC-Cur group were administrated with AOM/DSS and received an oral gavage of curcumin(150 mg/kg/day).Throughout the experimental period,the mice were weighed every two days.At the end of the experiment,the mice were sacrificed.The length of colorectal tissues and the number of tumors were recorded.Hematoxylin-eosin(HE)staining were used to study the effect of curcumin on colorectal tumorigenesis.Additionally,fecal samples were collected.16 Sr RNA sequencing and non-targeted metabolomics analysis were used to observe the changes of intestinal flora and intestinal metabolites.Results:Compared to negative control group,the colon length of the mice in CRC group was significantly shortened(P<0.0001).Notably,tumors were observed in mice of the CRC group.Compared to the CRC group,the colon length of mice in CRC-Cur group was increased,and the number of colon tumors was significantly decreased(P<0.05).HE staining showed that high-grade intraepithelial neoplasia was observed in the mice of CRC group,characterized by crypt destruction,inflammatory cell infiltration,and tumor formation.Normal goblet cells and colic glands were observed in the mice of CRC-Cur group,although polymorphonuclear cells were infiltrated and lymphocytes were accumulated in the submucosa.The 16 Sr RNA sequencing analysis indicated that the diversity and richness of core and total species of intestinal microflora in mice of CRC group was significantly lower than that in negative control group.However,the diversity and richness of core and total species of intestinal microorganisms were significantly increased in the CRC-Cur group compared to CRC group.Furthermore,the abundance of Desulfovibrio and Lleibacterium(P< 0.05)in Cur group were significantly lower than that in control group,while the abundance of Bifidobacterium(P<0.05)and Clostridium-UCG-041(P<0.01)in Cur group were significantly higher than that in control group.Notably,an increased abundance of Clostridium-UCG-041(P<0.01)and Lactobacillus(P<0.001),and a decreased abundance of Lleibacterium(P< 0.05)in CRC-Cur group compared with the CRC group.The results of LC-MS mass spectrometry showed that several intestinal metabolites,such as,Xanthine,Ethosuximide and 17-beta-estradiol 3-sulfate-17-(beta-D-glucuronide)were significantly up-regulated in CRC group compared to the control group.Additionally,several metabolites,such as,Glutamylleucine,GammaGlu-leu,Ubenimex,7,8-Dihydropteroic acid,Libenzapril,Xenognosin A,7,4’-Dihydroxy-8-methylflavan and 7,8-Dihydropteroic acid were significantly reduced in CRC group compared to the control group.Interestingly,curcumin significantly reduced the expression of Xanthine,Ethosuximide and 17-beta-estradiol 3-sulfate-17-(beta-D-glucuronide)which highly expressed in CRC group,while increased the expression of Liquiritin,Ubenimex,7,8-Dihydropteroic acid,5’-Deoxy-5’-fluorouridine,Glutamylleucine and Gamma-Glu-leu which is low expressed in CRC group.Conclusion:Curcumin inhibits the development of AOM/DSS induced colorectal cancer.The gut microbiota homeostasis was disrupted in the AOM/DSS induced colon cancer mice,while curcumin could restore intestinal microflora.The intestinal metabolites changed in the AOM/DSS induced colon cancer mice,but curcumin could regulate intestinal metabolites in mice.Curcumin may alleviate the development of AOM/DSS induced colorectal cancer in mice by regulating intestinal flora homeostasis and intestinal metabolites. |
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