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Open Access 01-12-2024 | Colorectal Cancer | Research

Gut microbial and metabolomics profiles reveal the potential mechanism of fecal microbiota transplantation in modulating the progression of colitis-associated colorectal cancer in mice

Authors: Qishi Song, Yongchao Gao, Kun Liu, Yukai Tang, Yichun Man, Haijun Wu

Published in: Journal of Translational Medicine | Issue 1/2024

Abstract

Purpose

Intestinal flora promotes the pathogenesis of colorectal cancer (CRC) through microorganisms and their metabolites. This study aimed to investigate the composition of intestinal flora in different stages of CRC progression and the effect of fecal microbiota transplantation (FMT) on CRC mice.

Methods

The fecal microbiome from healthy volunteers (HC), colorectal adenoma (CRA), inflammatory bowel disease (IBD), and CRC patients were analyzed by 16s rRNA gene sequencing. In an azoxymethane (AOM)/dextran-sulfate-sodium (DSS)-induced CRC mouse, the effect of FMT from HC, CRA, CRC, and IBD patients on CRC mice was assessed by histological analysis. Expression of inflammation- EMT-associated proteins and Wnt/β-catenin pathway were assessed using qRT-PCR and western blot. The ratio of the fecal microorganisms and metabolomics alteration after FMT were also assessed.

Result

Prevotella, Faecalibacterium, Phascolarctobacterium, Veillonella, Alistipes, Fusobacterium, Oscillibacter, Blautia, and Ruminococcus abundance was different among HC, IBD, CRC, and CRA patients. HC-FMT alleviated disease progression and inflammatory response in CRC mice, inhibited splenic T help (Th)1 and Th17 cell numbers, and suppressed the EMT and Wnt/β-catenin pathways in tumor tissues of CRC mice. IBD-FMT, CRA-FMT, and CRC-FMT played deleterious roles; the CRC-FMT mice exhibited the most malignant phenotype. Compared with the non-FMT CRC mice, Muribaculaceae abundance was lower after FMT, especially lowest in the IBD-FMT group; while Lactobacillus abundance was higher after FMT and especially high in HC-FMT. Akkermansia and Ileibacterium abundance increased after FMT-HC compared to other groups. Metabolite correlation analysis revealed that Muribaculaceae abundance was significantly correlated with metabolites such as Betaine, LysoPC, and Soyasaponin III. Lactobacillus abundance was positively correlated with Taurocholic acid 3-sulfate, and Ileibacterium abundance was positively correlated with Linoleoyl ethanolamide.

Conclusion

The different intestinal microbiota communities of HC, IBD, CRA, and CRC patients may be attributed to the different modulation effects of FMT on CRC mice. CRC-FMT promoted, while HC-FMT inhibited the progress of CRC. Increased linoleoyl ethanolamide levels and abundance of Muribaculaceae, Akkermansia, and Ileibacterium and reduced Fusobacterium might participate in inhibiting CRC initiation and development. This study demonstrated that FMT intervention could restore the intestinal microbiota and metabolomics of CRC mice, suggesting FMT as a potential strategy for CRC therapy.

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Xi Y, Xu P. Global colorectal cancer burden in 2020 and projections to 2040. Transl Oncol. 2021;14:101174. https://doi.org/10.1016/j.tranon.2021.101174.CrossRefPubMedPubMedCentral

Wang B, et al. Identification and clinical validation of key genes as the potential biomarkers in colorectal adenoma. BMC Cancer. 2023;23:39. https://doi.org/10.1186/s12885-022-10422-9.CrossRefPubMedPubMedCentral

Hnatyszyn A, et al. Colorectal carcinoma in the course of inflammatory bowel diseases. Hereditary cancer Clin Pract. 2019;17. https://doi.org/10.1186/s13053-019-0118-4.

Quaglio AEV, Grillo TG, De Oliveira ECS, Di Stasi LC, Sassaki LY. Gut microbiota, inflammatory bowel disease and colorectal cancer. World J Gastroenterol. 2022;28:4053–60. https://doi.org/10.3748/wjg.v28.i30.4053.CrossRefPubMedPubMedCentral

Shah SC, Itzkowitz SH. Colorectal Cancer in inflammatory bowel disease: mechanisms and management. Gastroenterology. 2022;162:715–e730713. https://doi.org/10.1053/j.gastro.2021.10.035.CrossRefPubMed

Yang M et al. Bile acid–gut microbiota axis in inflammatory bowel disease: from bench to bedside. 13, 3143 (2021).

Guo XY, Liu XJ, Hao JY. Gut microbiota in ulcerative colitis: insights on pathogenesis and treatment. J Dig Dis. 2020;21:147–59. https://doi.org/10.1111/1751-2980.12849.CrossRefPubMed

Antushevich H. Fecal microbiota transplantation in disease therapy. Clin Chim Acta. 2020;503:90–8. https://doi.org/10.1016/j.cca.2019.12.010.CrossRefPubMed

Chen D, Wu J, Jin D, Wang B, Cao H. Fecal microbiota transplantation in cancer management: current status and perspectives. Int J Cancer. 2019;145:2021–31. https://doi.org/10.1002/ijc.32003.CrossRefPubMed

10.

Wong SH et al. Gavage of Fecal Samples From Patients With Colorectal Cancer Promotes Intestinal Carcinogenesis in Germ-Free and Conventional Mice. Gastroenterology 153, 1621–1633.e1626, https://doi.org/10.1053/j.gastro.2017.08.022 (2017).

11.

Yu H, et al. Fecal microbiota transplantation inhibits colorectal cancer progression: reversing intestinal microbial dysbiosis to enhance anti-cancer immune responses. Front Microbiol. 2023;14:1126808. https://doi.org/10.3389/fmicb.2023.1126808.CrossRefPubMedPubMedCentral

12.

Bokoliya SC, Dorsett Y, Panier H, Zhou Y. Procedures for fecal microbiota transplantation in murine Microbiome studies. Front Cell Infect Microbiol. 2021;11:711055. https://doi.org/10.3389/fcimb.2021.711055.CrossRefPubMedPubMedCentral

13.

Sadeghipour A, Babaheidarian P. Making formalin-fixed, paraffin embedded blocks. Biobanking: Methods Protocols, 253–68 (2019).

14.

Chen J, et al. Bone marrow stromal cell-derived exosomal circular RNA improves diabetic foot ulcer wound healing by activating the nuclear factor erythroid 2-related factor 2 pathway and inhibiting ferroptosis. Diabet Medicine: J Br Diabet Association. 2023;40:e15031. https://doi.org/10.1111/dme.15031.CrossRef

15.

Yang L, Wu G, Wu Q, Peng L, Yuan L. METTL3 overexpression aggravates LPS-induced cellular inflammation in mouse intestinal epithelial cells and DSS-induced IBD in mice. Cell Death Discovery. 2022;8:62. https://doi.org/10.1038/s41420-022-00849-1.CrossRefPubMedPubMedCentral

16.

Wishart DS, et al. HMDB: the human metabolome database. Nucleic Acids Res. 2007;35:D521–6.CrossRefPubMedPubMedCentral

17.

Smith CA, et al. METLIN: a metabolite mass spectral database. Ther Drug Monit. 2005;27:747–51.CrossRefPubMed

18.

Martín R, et al. Faecalibacterium: a bacterial genus with promising human health applications. FEMS Microbiol Rev. 2023;47. https://doi.org/10.1093/femsre/fuad039.

19.

Flint HJ, Scott KP, Duncan SH, Louis P, Forano E. Microbial degradation of complex carbohydrates in the gut. Gut Microbes. 2012;3:289–306. https://doi.org/10.4161/gmic.19897.CrossRefPubMedPubMedCentral

20.

Rashid ZA, Bardaweel SK. Novel matrix Metalloproteinase-9 (MMP-9) inhibitors in Cancer Treatment. Int J Mol Sci. 2023;24. https://doi.org/10.3390/ijms241512133.

21.

Pastushenko I, Blanpain C. EMT Transition States during Tumor Progression and Metastasis. Trends Cell Biol. 2019;29:212–26. https://doi.org/10.1016/j.tcb.2018.12.001.CrossRefPubMed

22.

Tewari D et al. Targeting the crosstalk between canonical Wnt/β-catenin and inflammatory signaling cascades: a novel strategy for cancer prevention and therapy. 227, 107876 (2021).

23.

Wong SH, Yu J. Gut microbiota in colorectal cancer: mechanisms of action and clinical applications. Nat Reviews Gastroenterol Hepatol. 2019;16:690–704.CrossRef

24.

Mohebali N, et al. Faecalibacterium prausnitzii, Bacteroides faecis and Roseburia intestinalis attenuate clinical symptoms of experimental colitis by regulating Treg/Th17 cell balance and intestinal barrier integrity. Biomed Pharmacother. 2023;167:115568. https://doi.org/10.1016/j.biopha.2023.115568.CrossRefPubMed

25.

Dikeocha IJ, Al-Kabsi AM, Chiu H-T, Alshawsh MA. Faecalibacterium prausnitzii Ameliorates Colorectal Tumorigenesis and Suppresses Proliferation of HCT116 Colorectal Cancer Cells. Biomedicines 10, https://doi.org/10.3390/biomedicines10051128 (2022).

26.

Ferreira-Halder CV, Faria AVS, Andrade SS. Action and function of Faecalibacterium prausnitzii in health and disease. Best Pract Res Clin Gastroenterol. 2017;31:643–8. https://doi.org/10.1016/j.bpg.2017.09.011.CrossRefPubMed

27.

Sokol H, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A. 2008;105:16731–6. https://doi.org/10.1073/pnas.0804812105.CrossRefPubMedPubMedCentral

28.

Conde-Pérez K, et al. The multispecies microbial cluster of Fusobacterium, Parvimonas, Bacteroides and Faecalibacterium as a precision biomarker for colorectal cancer diagnosis. Mol Oncol. 2024;18:1093–122. https://doi.org/10.1002/1878-0261.13604.CrossRefPubMedPubMedCentral

29.

Mangifesta M, et al. Mucosal microbiota of intestinal polyps reveals putative biomarkers of colorectal cancer. Sci Rep. 2018;8:13974. https://doi.org/10.1038/s41598-018-32413-2.CrossRefPubMedPubMedCentral

30.

Cao LL, et al. Iron chelation inhibits cancer cell growth and modulates global histone methylation status in colorectal cancer. Biometals: Int J role Metal ions Biology Biochem Med. 2018;31:797–805. https://doi.org/10.1007/s10534-018-0123-5.CrossRef

31.

Thapa P, et al. The role of Peroxiredoxins in Cancer Development. Biology. 2023;12:666.CrossRefPubMedPubMedCentral

32.

Sun LQ, Li YX, Guillou L, Mirimanoff RO, Coucke PA. Antitumor and radiosensitizing effects of (E)-2’-deoxy-2’-(fluoromethylene) cytidine, a novel inhibitor of ribonucleoside diphosphate reductase, on human colon carcinoma xenografts in nude mice. Cancer Res. 1997;57:4023–8.PubMed

33.

Zhan Y, et al. Inhibiting RRM2 to enhance the anticancer activity of chemotherapy. Biomed Pharmacother. 2021;133:110996. https://doi.org/10.1016/j.biopha.2020.110996.CrossRefPubMed

34.

Wang S, et al. The role of intestinal flora on tumorigenesis, progression, and the efficacy of PD-1/PD-L1 antibodies in colorectal cancer. Cancer Biology Med. 2023;21:65–82. https://doi.org/10.20892/j.issn.2095-3941.2023.0376.CrossRef

35.

Wang Z, et al. Protective role of fecal microbiota transplantation on Colitis and Colitis-Associated Colon cancer in mice is Associated with Treg cells. Front Microbiol. 2019;10:2498. https://doi.org/10.3389/fmicb.2019.02498.CrossRefPubMedPubMedCentral

36.

Crost EH, Coletto E, Bell A, Juge N. Ruminococcus gnavus: friend or foe for human health. FEMS Microbiol Rev. 2023;47. https://doi.org/10.1093/femsre/fuad014.

37.

Sobhani I, et al. Colorectal cancer-associated microbiota contributes to oncogenic epigenetic signatures. Proc Natl Acad Sci U S A. 2019;116:24285–95. https://doi.org/10.1073/pnas.1912129116.CrossRefPubMedPubMedCentral

38.

Li L, et al. Gut microbiota from colorectal cancer patients enhances the progression of intestinal adenoma in apc(min/+) mice. EBioMedicine. 2019;48:301–15. https://doi.org/10.1016/j.ebiom.2019.09.021.CrossRefPubMedPubMedCentral

39.

Eberhart CE, et al. Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology. 1994;107:1183–8. https://doi.org/10.1016/0016-5085(94)90246-1.CrossRefPubMed

40.

Ogino S, et al. Cyclooxygenase-2 expression is an independent predictor of poor prognosis in colon cancer. Clin cancer Research: Official J Am Association Cancer Res. 2008;14:8221–7. https://doi.org/10.1158/1078-0432.Ccr-08-1841.CrossRef

41.

Wang D, Dubois RN. The role of COX-2 in intestinal inflammation and colorectal cancer. Oncogene. 2010;29:781–8. https://doi.org/10.1038/onc.2009.421.CrossRefPubMed

42.

Rashid G, et al. Non-steroidal anti-inflammatory drugs and biomarkers: a new paradigm in colorectal cancer. Front Med (Lausanne). 2023;10:1130710. https://doi.org/10.3389/fmed.2023.1130710.CrossRefPubMed

43.

Zhou H, et al. Monosexual Cercariae of Schistosoma japonicum infection protects against DSS-Induced colitis by shifting the Th1/Th2 balance and modulating the gut microbiota. Front Microbiol. 2020;11:606605. https://doi.org/10.3389/fmicb.2020.606605.CrossRefPubMed

44.

Wang L, et al. A purified membrane protein from Akkermansia muciniphila or the pasteurised bacterium blunts colitis associated tumourigenesis by modulation of CD8(+) T cells in mice. Gut. 2020;69:1988–97. https://doi.org/10.1136/gutjnl-2019-320105.CrossRefPubMed

45.

Fan L, et al. Muciniphila suppresses colorectal tumorigenesis by inducing TLR2/NLRP3-Mediated M1-Like TAMs. Cancer Immunol Res. 2021;9:1111–24. https://doi.org/10.1158/2326-6066.CIR-20-1019.CrossRefPubMed

46.

Cai K et al. Xianlian Jiedu Decoction alleviates colorectal cancer by regulating metabolic profiles, intestinal microbiota and metabolites. 155385 (2024).

47.

Zhou Z, Chen J, Yao H, Hu H. J. F. i. o. Fusobacterium and colorectal cancer. 8, 371 (2018).

48.

Liu J, et al. Gut microbiota profiling variated during colorectal cancer development in mouse. BMC Genomics. 2022;23:848. https://doi.org/10.1186/s12864-022-09008-3.CrossRefPubMedPubMedCentral

49.

de Figueiredo Junior AG, et al. Analysis of the lipid Profile in patients with Colorectal Cancer in Advanced stages. Asian Pac J Cancer Prev. 2018;19:1287–93. https://doi.org/10.22034/apjcp.2018.19.5.1287.CrossRefPubMed

50.

Lv J et al. Gegen Qinlian decoction enhances the effect of PD-1 blockade in colorectal cancer with microsatellite stability by remodelling the gut microbiota and the tumour microenvironment. 10, 415 (2019).

51.

Tovar R, et al. Administration of Linoleoylethanolamide reduced Weight Gain, Dyslipidemia, and inflammation Associated with High-Fat-Diet-Induced obesity. Nutrients. 2023;15. https://doi.org/10.3390/nu15204448.

52.

Ishida T, et al. Linoleoyl ethanolamide reduces lipopolysaccharide-induced inflammation in macrophages and ameliorates 2,4-dinitrofluorobenzene-induced contact dermatitis in mice. Eur J Pharmacol. 2013;699:6–13. https://doi.org/10.1016/j.ejphar.2012.11.030.CrossRefPubMed

53.

Brown DG, et al. Metabolomics and metabolic pathway networks from human colorectal cancers, adjacent mucosa, and stool. Cancer Metab. 2016;4:11. https://doi.org/10.1186/s40170-016-0151-y.CrossRefPubMedPubMedCentral

54.

Jayakrishnan T, et al. Plasma metabolomic differences in early-onset compared to average-onset colorectal cancer. Sci Rep. 2024;14:4294. https://doi.org/10.1038/s41598-024-54560-5.CrossRefPubMedPubMedCentral

55.

Wang G et al. Role of SCFAs in gut microbiome and glycolysis for colorectal cancer therapy. 234, 17023–49 (2019).

56.

Zhang H-L, et al. Targeting regulation of tryptophan metabolism for colorectal cancer therapy: a systematic review. RSC Adv. 2019;9:3072–80. https://doi.org/10.1039/c8ra08520j.CrossRefPubMedPubMedCentral

57.

Wenxuan L, et al. Role of gonadally synthesized steroid hormones in the colorectal cancer microenvironment. Front Oncol. 2023;13:1323826. https://doi.org/10.3389/fonc.2023.1323826.CrossRefPubMedPubMedCentral

58.

Zhou Z, Sun B, Huang S, Yu D, Zhang X. Roles of aminoacyl-tRNA synthetase-interacting multi-functional proteins in physiology and cancer. Cell Death Dis. 2020;11:579. https://doi.org/10.1038/s41419-020-02794-2.CrossRefPubMedPubMedCentral

59.

Yang Y, et al. Fecal microbiota transplantation: no longer cinderella in tumour immunotherapy. EBioMedicine. 2024;100:104967. https://doi.org/10.1016/j.ebiom.2024.104967.CrossRefPubMedPubMedCentral

Title: Gut microbial and metabolomics profiles reveal the potential mechanism of fecal microbiota transplantation in modulating the progression of colitis-associated colorectal cancer in mice
Authors: Qishi Song
Yongchao Gao
Kun Liu
Yukai Tang
Yichun Man
Haijun Wu
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Colorectal Cancer
Colorectal Cancer
Respiratory Microbiota
Chronic Inflammatory Bowel Disease
Published in: Journal of Translational Medicine / Issue 1/2024
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-024-05786-4

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