Reconstruction of the microbiota-metabolite interaction network and investigation of metabolites and biological pathways of microbiota in colorectal cancer

SHAHRAKI GHADIMI, HOSSEIN; Abdolmaleki, Parviz; Arab, Seyed Shahriar

Reconstruction of the microbiota-metabolite interaction network and investigation of metabolites and biological pathways of microbiota in colorectal cancer

Document Type : Original Research

Authors

HOSSEIN SHAHRAKI GHADIMI ¹

Parviz Abdolmaleki ²

Seyed Shahriar Arab ³

¹ 1. Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran

² Department of Biophysics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran

³ Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA

Abstract

The recent developments in scientific advancements notably enhanced the understanding of the complex relationship between cancer and the microbiome.Various experimental studies demonstrated that the interaction between the host and microbiota plays a crucial role in the health or disease of the human body. The human microbiome has various benefits, including regulating fundamental processes such as signal transmission, immunity, and metabolism, which contribute to the proper functioning of the host. The imbalance of intestinal microbiota or dysbiosis is associated with the onset and progression of complex diseases such as colorectal cancer(CRC). Motivated by these, in this research, by utilizing metagenomic and metabolomic data and functional analyses of the colon microbiome, we have identified bacteria, metabolites, and important bacterial pathways in colorectal cancer compared to the healthy control group. Also, we investigated the role of different bacteria in pathways with significant abundance. Ultimately, by analyzing the network of bacteria-metabolite interaction in both healthy and cancer groups, we identified the differences between these two networks in terms of topological parameters. Our findings introduced potential biomarkers for CRC that could be used in future research orientation. Furthermore, it highlighted that some bacteria, such as Bacteroides fragilis and Bifidobacterium longum, which had increases and decreases in abundance in the cancer group, respectively, also contribute to key bacterial biological pathways in CRC. These findings underscore the potential of the gut microbiome as a promising non-invasive approach for early CRC screening, emphasizing the significance of gut microbiota composition and their metabolites in providing valuable insights into CRC.

Keywords

Microbiome

Microbiota

Dysbiosis

Colorectal cancer

Metagenomics

Subjects

Molecular biotechnology

1. Kamal, N., Ilowefah, M.A., Hilles, A.R., Anua, N.A., Awin, T., Alshwyeh, H.A., Aldosary, S.K., Jambocus, N.G.S., Alosaimi, A.A., Rahman, A. and Mahmood, S., 2022. Genesis and mechanism of some cancer types and an overview on the role of diet and nutrition in cancer prevention. Molecules, 27(6), p.1794.
2. Mbemi, A., Khanna, S., Njiki, S., Yedjou, C.G. and Tchounwou, P.B., 2020. Impact of gene–environment interactions on cancer development. International journal of environmental research and public health, 17(21), p.8089.
3. Mardis, E.R., 2019. The impact of next-generation sequencing on cancer genomics: from discovery to clinic. Cold Spring Harbor Perspectives in Medicine, 9(9), p.a036269.
4. Raza, M.H., Gul, K., Arshad, A., Riaz, N., Waheed, U., Rauf, A., Aldakheel, F., Alduraywish, S., Rehman, M.U., Abdullah, M. and Arshad, M., 2019. Microbiota in cancer development and treatment. Journal of cancer research and clinical oncology, 145, pp.49-63.
5. Dekker, E., Tanis, P.J., Vleugels, J., Kasi, P.M. and Wallace, M., 2019. Pure-amc. Lancet, 394, pp.1467-80.
6. Marcellinaro, R., Spoletini, D., Grieco, M., Avella, P., Cappuccio, M., Troiano, R., Lisi, G., Garbarino, G.M. and Carlini, M., 2023. Colorectal cancer: current updates and future perspectives. Journal of Clinical Medicine, 13(1), p.40.
7. Sninsky, J.A., Shore, B.M., Lupu, G.V. and Crockett, S.D., 2022. Risk factors for colorectal polyps and cancer. Gastrointestinal Endoscopy Clinics of North America, 32(2), pp.195-213.
8. Rajilić-Stojanović M, de Vos WM. The first 1000 cultured species of the human gastrointestinal microbiota. FEMS Microbiol Rev. 2014 Sep;38(5):996-1047. doi: 10.1111/1574-6976.12075. Epub 2014 Jun 27. PMID: 24861948; PMCID: PMC4262072.
9. Qin, J., Li, R., Raes, J., Arumugam, M., Burgdorf, K.S., Manichanh, C., Nielsen, T., Pons, N., Levenez, F., Yamada, T. and Mende, D.R., 2010. A human gut microbial gene catalogue established by metagenomic sequencing. nature, 464(7285), pp.59-65.
10. Fucarino, A., Burgio, S., Paladino, L., Caruso Bavisotto, C., Pitruzzella, A., Bucchieri, F. and Cappello, F., 2022. The Microbiota Is Not an Organ: Introducing the Muco-Microbiotic Layer as a Novel Morphofunctional Structure. Anatomia, 1(2), pp.186-203.
11. Afzaal, M., Saeed, F., Shah, Y.A., Hussain, M., Rabail, R., Socol, C.T., Hassoun, A., Pateiro, M., Lorenzo, J.M., Rusu, A.V. and Aadil, R.M., 2022. Human gut microbiota in health and disease: Unveiling the relationship. Frontiers in microbiology, 13, p.999001.
12. Murphy, N., Moreno, V., Hughes, D.J., Vodicka, L., Vodicka, P., Aglago, E.K., Gunter, M.J. and Jenab, M., 2019. Lifestyle and dietary environmental factors in colorectal cancer susceptibility. Molecular aspects of medicine, 69, pp.2-9.
13. Tjalsma, H., Boleij, A., Marchesi, J.R. and Dutilh, B.E., 2012. A bacterial driver–passenger model for colorectal cancer: beyond the usual suspects. Nature Reviews Microbiology, 10(8), pp.575-582.
14. Villéger, R., Lopès, A., Veziant, J., Gagnière, J., Barnich, N., Billard, E., Boucher, D. and Bonnet, M., 2018. Microbial markers in colorectal cancer detection and/or prognosis. World journal of gastroenterology, 24(22), p.2327.
15. Hendler, R. and Zhang, Y., 2018. Probiotics in the treatment of colorectal cancer. Medicines, 5(3), p.101.
16. Yang, Y., Misra, B.B., Liang, L., Bi, D., Weng, W., Wu, W., Cai, S., Qin, H., Goel, A., Li, X. and Ma, Y., 2019. Integrated microbiome and metabolome analysis reveals a novel interplay between commensal bacteria and metabolites in colorectal cancer. Theranostics, 9(14), p.4101.
17. Peng, Y., Nie, Y., Yu, J. and Wong, C.C., 2021. Microbial metabolites in colorectal cancer: basic and clinical implications. Metabolites, 11(3), p.159.
18. Niekamp, P. and Kim, C.H., 2023. Microbial metabolite dysbiosis and colorectal cancer. Gut and Liver, 17(2), p.190.
19. Wang, X.N., Yin, Y.H., Cheng, X., Chen, L., Chen, M.L., Zheng, J.Y., Jin, Y.Y., Liu, J.Q., Liu, L.F. and Xin, G.Z., 2019. Development and validation of a systematic platform for broad-scale profiling of microbial metabolites. Talanta, 200, pp.537-546.
20. Gomes, P.W.P., de Tralia Medeiros, T.C., Maimone, N.M., Leão, T.F., de Moraes, L.A.B. and Bauermeister, A., 2023. Microbial metabolites annotation by mass spectrometry-based metabolomics. In Microbial Natural Products Chemistry: A Metabolomics Approach (pp. 225-248). Cham: Springer International Publishing.
21. Gomes, P.W.P., de Tralia Medeiros, T.C., Maimone, N.M., Leão, T.F., de Moraes, L.A.B. and Bauermeister, A., 2023. Microbial metabolites annotation by mass spectrometry-based metabolomics. In Microbial Natural Products Chemistry: A Metabolomics Approach (pp. 225-248). Cham: Springer International Publishing.
22. Nugent, J.L., McCoy, A.N., Addamo, C.J., Jia, W., Sandler, R.S. and Keku, T.O., 2014. Altered tissue metabolites correlate with microbial dysbiosis in colorectal adenomas. Journal of proteome research, 13(4), pp.1921-1929.
23. Proal, A.D., Lindseth, I.A. and Marshall, T.G., 2017. Microbe-microbe and host-microbe interactions drive microbiome dysbiosis and inflammatory processes. Discovery medicine, 23(124), pp.51-60.
24. Andrighetti, T., Bohar, B., Lemke, N., Sudhakar, P. and Korcsmaros, T., 2020. MicrobioLink: an integrated computational pipeline to infer functional effects of microbiome–host interactions. Cells, 9(5), p.1278.
25. Pavlopoulos, G.A., Secrier, M., Moschopoulos, C.N., Soldatos, T.G., Kossida, S., Aerts, J., Schneider, R. and Bagos, P.G., 2011. Using graph theory to analyze biological networks. BioData mining, 4, pp.1-27.
26. Bauer, E. and Thiele, I., 2018. From network analysis to functional metabolic modeling of the human gut microbiota. MSystems, 3(3), pp.10-1128.
27. Zackular, J.P., Rogers, M.A., Ruffin IV, M.T. and Schloss, P.D., 2014. The human gut microbiome as a screening tool for colorectal cancer. Cancer prevention research, 7(11), pp.1112-1121.
28. Dulal, S. and Keku, T.O., 2014. Gut microbiome and colorectal adenomas. The Cancer Journal, 20(3), pp.225-231.
29. - Feng, Q., Liang, S., Jia, H., Stadlmayr, A., Tang, L., Lan, Z., Zhang, D., Xia, H., Xu, X., Jie, Z. and Su, L., 2015. Gut microbiome development along the colorectal adenoma–carcinoma sequence. Nature communications, 6(1), p.6528.
30. Haghi, F., Goli, E., Mirzaei, B. and Zeighami, H., 2019. The association between fecal enterotoxigenic B. fragilis with colorectal cancer. BMC cancer, 19, pp.1-4.
31. Peterson, J., Garges, S., Giovanni, M., McInnes, P., Wang, L., Schloss, J.A., Bonazzi, V., McEwen, J.E., Wetterstrand, K.A., Deal, C. and Baker, C.C., 2009. The NIH human microbiome project. Genome research, 19(12), pp.2317-2323.
32. Emmert, D.B., Stoehr, P.J., Stoesser, G. and Cameron, G.N., 1994. The European bioinformatics institute (EBI) databases. Nucleic Acids Research, 22(17), pp.3445-3449.
33. Beghini, F., McIver, L.J., Blanco-Míguez, A., Dubois, L., Asnicar, F., Maharjan, S., Mailyan, A., Manghi, P., Scholz, M., Thomas, A.M. and Valles-Colomer, M., 2021. Integrating taxonomic, functional, and strain-level profiling of diverse microbial communities with bioBakery 3. elife, 10, p.e65088.
34. Varet, H., Brillet-Guéguen, L., Coppée, J.Y. and Dillies, M.A., 2016. SARTools: a DESeq2-and EdgeR-based R pipeline for comprehensive differential analysis of RNA-Seq data. PloS one, 11(6), p.e0157022.
35. Weiss, S., Xu, Z.Z., Peddada, S., Amir, A., Bittinger, K., Gonzalez, A., Lozupone, C., Zaneveld, J.R., Vázquez-Baeza, Y., Birmingham, A. and Hyde, E.R., 2017. Normalization and microbial differential abundance strategies depend upon data characteristics. Microbiome, 5, pp.1-18.
36. Love, M.I., Huber, W. and Anders, S., 2014. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome biology, 15, pp.1-21.
37. Soofi, A., Taghizadeh, M., Tabatabaei, S.M., Tavirani, M.R., Shakib, H., Namaki, S. and Alighiarloo, N.S., 2020. Centrality analysis of protein-protein interaction networks and molecular docking prioritize potential drug-targets in type 1 diabetes. Iranian Journal of Pharmaceutical Research: IJPR, 19(4), p.121.
38. Winterbach, W., Mieghem, P.V., Reinders, M., Wang, H. and Ridder, D.D., 2013. Topology of molecular interaction networks. BMC systems biology, 7, pp.1-15.
39. Goenawan, I.H., Bryan, K. and Lynn, D.J., 2016. DyNet: visualization and analysis of dynamic molecular interaction networks. Bioinformatics, 32(17), pp.2713-2715.
40. Kohl, M., Wiese, S. and Warscheid, B., 2011. Cytoscape: software for visualization and analysis of biological networks. Data mining in proteomics: from standards to applications, pp.291-303.
41. Yu, J., Feng, Q., Wong, S.H., Zhang, D., yi Liang, Q., Qin, Y., Tang, L., Zhao, H., Stenvang, J., Li, Y. and Wang, X., 2017. Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer. Gut, 66(1), pp.70-78.
42. Dai, Z., Coker, O.O., Nakatsu, G., Wu, W.K., Zhao, L., Chen, Z., Chan, F.K., Kristiansen, K., Sung, J.J., Wong, S.H. and Yu, J., 2018. Multi-cohort analysis of colorectal cancer metagenome identified altered bacteria across populations and universal bacterial markers. Microbiome, 6, pp.1-12.
43. Martin-Gallausiaux, C., Marinelli, L., Blottière, H.M., Larraufie, P. and Lapaque, N., 2021. SCFA: mechanisms and functional importance in the gut. Proceedings of the Nutrition Society, 80(1), pp.37-49.
44. Farriol, M., Segovia-Silvestre, T., Castellanos, J.M., Venereo, Y. and Orta, X., 2001. Role of putrescine in cell proliferation in a colon carcinoma cell line. Nutrition, 17(11-12), pp.934-938.
45. Barreiro-Alonso, E., Castro-Estrada, P., Sanchez, M., Peña-Iglesias, P., Suarez, L. and Cantabrana, B., 2024. Association of Polyamine and Other Dietary Component Intake and Feces Content of N-acetyl Putrescine, and Cadaverine with Patients’ Colorectal Lesions.
46. Chen, C. and Li, H., 2020. The inhibitory effect of gut microbiota and its metabolites on colorectal cancer. Journal of Microbiology and Biotechnology, 30(11), p.1607.
47. Long, J., Guan, P., Hu, X., Yang, L., He, L., Lin, Q., Luo, F., Li, J., He, X., Du, Z. and Li, T., 2021. Natural polyphenols as targeted modulators in colon cancer: molecular mechanisms and applications. Frontiers in Immunology, 12, p.635484.
48. Yan, L., Spitznagel, E.L. and Bosland, M.C., 2010. Soy consumption and colorectal cancer risk in humans: a meta-analysis. Cancer epidemiology, biomarkers & prevention, 19(1), pp.148-158.
49. Lv, J., Jin, S., Zhang, Y., Zhou, Y., Li, M. and Feng, N., 2024. Equol: a metabolite of gut microbiota with potential antitumor effects. Gut Pathogens, 16.
50. Du, P., Tseng, Y., Liu, P., Zhang, H., Huang, G. and Chen, J., 2024. Role of exhaled hydrogen sulfide in the diagnosis of colorectal cancer. BMJ Open Gastroenterology, 11(1), p.e001229.
51. Thomas, A.M., Jesus, E.C., Lopes, A., Aguiar Jr, S., Begnami, M.D., Rocha, R.M., Carpinetti, P.A., Camargo, A.A., Hoffmann, C., Freitas, H.C. and Silva, I.T., 2016. Tissue-associated bacterial alterations in rectal carcinoma patients revealed by 16S rRNA community profiling. Frontiers in cellular and infection microbiology, 6, p.179.
52. He, T., Cheng, X. and Xing, C., 2021. The gut microbial diversity of colon cancer patients and the clinical significance. Bioengineered, 12(1), pp.7046-7060.
53. Xu, S., Yin, W., Zhang, Y., Lv, Q., Yang, Y. and He, J., 2020. Foes or friends? Bacteria enriched in the tumor microenvironment of colorectal cancer. Cancers, 12(2), p.372.
54. Weir, T.L., Manter, D.K., Sheflin, A.M., Barnett, B.A., Heuberger, A.L. and Ryan, E.P., 2013. Stool microbiome and metabolome differences between colorectal cancer patients and healthy adults. PloS one, 8(8), p.e70803.
55. Purcell, R.V., Pearson, J., Aitchison, A., Dixon, L., Frizelle, F.A. and Keenan, J.I., 2017. Colonization with enterotoxigenic Bacteroides fragilis is associated with early-stage colorectal neoplasia. PloS one, 12(2), p.e0171602.
56. Cheng, W.T., Kantilal, H.K. and Davamani, F., 2020. The mechanism of Bacteroides fragilis toxin contributes to colon cancer formation. The Malaysian journal of medical sciences: MJMS, 27(4), p.9.
57. Derrien, M., Belzer, C. and de Vos, W.M., 2017. Akkermansia muciniphila and its role in regulating host functions. Microbial pathogenesis, 106, pp.171-181.
58. N. Sanapareddy, R.M. Legge, B. Jovov, A. McCoy, L. Burcal, F. Araujo-Perez, T.A. Randall, J. Galanko, A. Benson, R.S. Sandler, J.F. Rawls, Z. Abdo, A.A. Fodor, T.O. Keku Increased rectal microbial richness is associated with the presence of colorectal adenomas in humans ISME J., 6 (10) (2012), pp. 1858-1868
59. Shang, F., Jiang, X., Wang, H., Guo, S., Kang, S., Xu, B., Wang, X., Chen, S., Li, N., Liu, B. and Zhao, Z., 2024. Bifidobacterium longum suppresses colorectal cancer through the modulation of intestinal microbes and immune function. Frontiers in Microbiology, 15, p.1327464.
60. Kostic, A.D., Gevers, D., Pedamallu, C.S., Michaud, M., Duke, F., Earl, A.M., Ojesina, A.I., Jung, J., Bass, A.J., Tabernero, J. and Baselga, J., 2012. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome research, 22(2), pp.292-298.
61. Han, Y.W., 2015. Fusobacterium nucleatum: a commensal-turned pathogen. Current opinion in microbiology, 23, pp.141-147.
62. Rubinstein, M.R., Wang, X., Liu, W., Hao, Y., Cai, G. and Han, Y.W., 2013. Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin. Cell host & microbe, 14(2), pp.195-206.
63. Han, Y.W., 2014. Oral bacteria and colorectal cancer: etiology and mechanism'. AACR Education book, pp.61-64.
64. Rubinstein, M.R., Baik, J.E., Lagana, S.M., Han, R.P., Raab, W.J., Sahoo, D., Dalerba, P., Wang, T.C. and Han, Y.W., 2019. Fusobacterium nucleatum promotes colorectal cancer by inducing Wnt/β‐catenin modulator Annexin A1. EMBO reports, 20(4), p.e47638.