Metabolomic analysis of gut metabolites in patients with colorectal cancer: Association with disease development and outcome

Xie,Zhufu; Zhu,Rui; Huang,Xiaoying; Yao,Fei; Jin,Shu; Huang,Qiyou; Wang,Dequan; Li,Huan; Wang,Qiang; Long,Hui; Wu,Qingming

doi:10.3892/ol.2023.13944

Metabolomic analysis of gut metabolites in patients with colorectal cancer: Association with disease development and outcome

Authors:
- Zhufu Xie
- Rui Zhu
- Xiaoying Huang
- Fei Yao
- Shu Jin
- Qiyou Huang
- Dequan Wang
- Huan Li
- Qiang Wang
- Hui Long
- Qingming Wu
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Affiliations: Institute of Infection, Immunology and Tumor Microenvironment, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, Hubei 430065, P.R. China, Department of Gastroenterology, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, Hubei 430064, P.R. China, Department of Public Health, The First Hospital of Wuhan, Wuhan, Hubei 430000, P.R. China, College of Medical Science, China Three Gorges University, Yichang, Hubei 443002, P.R. China, Department of Gastroenterology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
Published online on: July 4, 2023 https://doi.org/10.3892/ol.2023.13944
Article Number: 358
Copyright: © Xie et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Colorectal cancer (CRC) is one of the leading global malignancies with low 5‑year survival and high mortality rates. Despite extensive research, the precise role of gut metabolites in CRC development and clinical outcomes remains unclear, while its elucidation may aid the development of improved clinical diagnosis and treatment options. In the present study, targeted metabolomic analysis was conducted on fecal samples from 35 patients with CRC, 37 patients with colorectal adenoma and 30 healthy controls (HC) to identify metabolite biomarkers. Using orthogonal partial least squares discriminant analysis, metabolomic features distinguishing the three groups were identified. Receiver operating characteristic (ROC) curve analysis was used to assess diagnostic utility for distinguishing CRC from HC. The association of gut metabolites with survival in patients with CRC was also analyzed by comparing short‑term survivors (STS) and long‑term survivors (LTS), and the prognostic ability of metabolites was predicted using Cox regression and Kaplan‑Meier analysis. The results of the current study showed that the enriched pathways in CRC included ‘caffeine metabolism’, ‘thiamine metabolism’, ‘phenylalanine, tyrosine and tryptophan biosynthesis’ and ‘phenylalanine metabolism’. ROC analysis found that 9,10‑dihydroxy‑12‑octadecenoic acid, cholesterol ester (18:2) and lipoxinA4 distinguished CRC from HC. Joint quantification of these three metabolites resulted in an area under the ROC curve of 0.969 in the diagnosis of CRC. The analysis of the current study also showed that the expression of metabolites involved in ‘sphingolipid metabolism’ was mainly dysregulated in LTS and STS, while N‑acetylmannosamine and 2,5‑dihydroxybenzaldehyde were associated with better overall survival. In conclusion, the present study provided preliminary insight into the metabolic changes associated with CRC and may have important implications for the development of future diagnostic and treatment strategies.

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1	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI
2	Li N, Lu B, Luo C, Cai J, Lu M, Zhang Y, Chen H and Dai M: Incidence, mortality, survival, risk factor and screening of colorectal cancer: A comparison among China, Europe, and northern America. Cancer Lett. 522:255–268. 2021. View Article : Google Scholar : PubMed/NCBI
3	Lynch JP and Hoops TC: The genetic pathogenesis of colorectal cancer. Hematol Oncol Clin North Am. 16:775–810. 2002. View Article : Google Scholar : PubMed/NCBI
4	Biller LH and Schrag D: Diagnosis and treatment of metastatic colorectal cancer: A review. JAMA. 325:669–685. 2021. View Article : Google Scholar : PubMed/NCBI
5	Keum N and Giovannucci E: Global burden of colorectal cancer: Emerging trends, risk factors and prevention strategies. Nat Rev Gastroenterol Hepatol. 16:713–732. 2019. View Article : Google Scholar : PubMed/NCBI
6	Patel SG, Karlitz JJ, Yen T, Lieu CH and Boland CR: The rising tide of early-onset colorectal cancer: A comprehensive review of epidemiology, clinical features, biology, risk factors, prevention, and early detection. Lancet Gastroenterol Hepatol. 7:262–274. 2022. View Article : Google Scholar : PubMed/NCBI
7	Jakobsson HE, Rodríguez-Piñeiro AM, Schütte A, Ermund A, Boysen P, Bemark M, Sommer F, Bäckhed F, Hansson GC and Johansson ME: The composition of the gut microbiota shapes the colon mucus barrier. EMBO Rep. 16:164–177. 2015. View Article : Google Scholar : PubMed/NCBI
8	Yang J, Wei H, Zhou Y, Szeto CH, Li C, Lin Y, Coker OO, Lau HCH, Chan AWH, Sung JJY and Yu J: High-fat diet promotes colorectal tumorigenesis through modulating gut microbiota and metabolites. Gastroenterology. 162:135–149.e2. 2022. View Article : Google Scholar : PubMed/NCBI
9	Liu W, Zhang R, Shu R, Yu J, Li H, Long H, Jin S, Li S, Hu Q, Yao F, et al: Study of the relationship between microbiome and colorectal cancer susceptibility using 16SrRNA sequencing. Biomed Res Int. 2020:78283922020.PubMed/NCBI
10	Vacante M, Ciuni R, Basile F and Biondi A: Gut microbiota and colorectal cancer development: A closer look to the adenoma-carcinoma sequence. Biomedicines. 8:4892020. View Article : Google Scholar : PubMed/NCBI
11	Mima K, Nishihara R, Qian ZR, Cao Y, Sukawa Y, Nowak JA, Yang J, Dou R, Masugi Y, Song M, et al: Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis. Gut. 65:1973–1980. 2016. View Article : Google Scholar : PubMed/NCBI
12	Lucas C, Barnich N and Nguyen HTT: Microbiota, inflammation and colorectal cancer. Int J Mol Sci. 18:13102017. View Article : Google Scholar : PubMed/NCBI
13	Hanus M, Parada-Venegas D, Landskron G, Wielandt AM, Hurtado C, Alvarez K, Hermoso MA, López-Köstner F and De la Fuente M: Immune system, microbiota, and microbial metabolites: The unresolved triad in colorectal cancer microenvironment. Front Immunol. 12:6128262021. View Article : Google Scholar : PubMed/NCBI
14	Dalal N, Jalandra R, Bayal N, Yadav AK, Harshulika, Sharma M, Makharia GK, Kumar P, Singh R, Solanki PR and Kumar A: Gut microbiota-derived metabolites in CRC progression and causation. J Cancer Res Clin Oncol. 147:3141–3155. 2021. View Article : Google Scholar : PubMed/NCBI
15	Alhinai EA, Walton GE and Commane DM: The role of the gut microbiota in colorectal cancer causation. Int J Mol Sci. 20:52952019. View Article : Google Scholar : PubMed/NCBI
16	Yachida S, Mizutani S, Shiroma H, Shiba S, Nakajima T, Sakamoto T, Watanabe H, Masuda K, Nishimoto Y, Kubo M, et al: Metagenomic and metabolomic analyses reveal distinct stage-specific phenotypes of the gut microbiota in colorectal cancer. Nat Med. 25:968–976. 2019. View Article : Google Scholar : PubMed/NCBI
17	Lu S, Han L, Hu X, Sun T, Xu D, Li Y, Chen Q, Yao W, He M, Wang Z, et al: N6-methyladenosine reader IMP2 stabilizes the ZFAS1/OLA1 axis and activates the Warburg effect: Implication in colorectal cancer. J Hematol Oncol. 14:1882021. View Article : Google Scholar : PubMed/NCBI
18	Jonsson AL and Bäckhed F: Role of gut microbiota in atherosclerosis. Nat Rev Cardiol. 14:79–87. 2017. View Article : Google Scholar : PubMed/NCBI
19	Shuwen H, Yinhang W, Xingming Z, Jing Z, Jinxin L, Wei W and Kefeng D: Using whole-genome sequencing (WGS) to plot colorectal cancer-related gut microbiota in a population with varied geography. Gut Pathog. 14:502022. View Article : Google Scholar : PubMed/NCBI
20	Zhang C, Zhou S, Chang H, Zhuang F, Shi Y, Chang L, Ai W, Du J, Liu W, Liu H, et al: Metabolomic profiling identified serum metabolite biomarkers and related metabolic pathways of colorectal cancer. Dis Markers. 2021:68588092021. View Article : Google Scholar : PubMed/NCBI
21	Gu J, Xiao Y, Shu D, Liang X, Hu X, Xie Y, Lin D and Li H: Metabolomics analysis in serum from patients with colorectal polyp and colorectal cancer by ¹H-NMR spectrometry. Dis Markers. 2019:34918522019. View Article : Google Scholar : PubMed/NCBI
22	Luo XJ, Zhao Q, Liu J, Zheng JB, Qiu MZ, Ju HQ and Xu RH: Novel genetic and epigenetic biomarkers of prognostic and predictive significance in stage II/III colorectal cancer. Mol Ther. 29:587–596. 2021. View Article : Google Scholar : PubMed/NCBI
23	Rebersek M: Gut microbiome and its role in colorectal cancer. BMC Cancer. 21:13252021. View Article : Google Scholar : PubMed/NCBI
24	Vymetalkova V, Vodicka P, Vodenkova S, Alonso S and Schneider-Stock R: DNA methylation and chromatin modifiers in colorectal cancer. Mol Aspects Med. 69:73–92. 2019. View Article : Google Scholar : PubMed/NCBI
25	Zhang C, Wang XY, Zhang P, He TC, Han JH, Zhang R, Lin J, Fan J, Lu L, Zhu WW, et al: Cancer-derived exosomal HSPC111 promotes colorectal cancer liver metastasis by reprogramming lipid metabolism in cancer-associated fibroblasts. Cell Death Dis. 13:572022. View Article : Google Scholar : PubMed/NCBI
26	Vernia F, Longo S, Stefanelli G, Viscido A and Latella G: Dietary factors modulating colorectal carcinogenesis. Nutrients. 13:1432021. View Article : Google Scholar : PubMed/NCBI
27	Bian X, Liu R, Meng Y, Xing D, Xu D and Lu Z: Lipid metabolism and cancer. J Exp Med. 218:e202016062021. View Article : Google Scholar : PubMed/NCBI
28	Munir R, Lisec J, Swinnen JV and Zaidi N: Lipid metabolism in cancer cells under metabolic stress. Br J Cancer. 120:1090–1098. 2019. View Article : Google Scholar : PubMed/NCBI
29	Tomonaga N, Manabe Y, Aida K and Sugawara T: Dietary ceramide 2-aminoethylphosphonate, a marine sphingophosphonolipid, improves skin barrier function in hairless mice. Sci Rep. 10:138912020. View Article : Google Scholar : PubMed/NCBI
30	Vučetić M, Cormerais Y, Parks SK and Pouysségur J: The central role of amino acids in cancer redox homeostasis: Vulnerability points of the cancer redox code. Front Oncol. 7:3192017. View Article : Google Scholar : PubMed/NCBI
31	Vettore L, Westbrook RL and Tennant DA: New aspects of amino acid metabolism in cancer. Br J Cancer. 122:150–156. 2020. View Article : Google Scholar : PubMed/NCBI
32	Jiang F, Zhang Z, Zhang Y, Pan X, Yu L and Liu S: L-carnitine ameliorates cancer cachexia in mice partly via the carnitine palmitoyltransferase-associated PPAR-γ signaling pathway. Oncol Res Treat. 38:511–516. 2015. View Article : Google Scholar : PubMed/NCBI
33	Zeller G, Tap J, Voigt AY, Sunagawa S, Kultima JR, Costea PI, Amiot A, Böhm J, Brunetti F, Habermann N, et al: Potential of fecal microbiota for early-stage detection of colorectal cancer. Mol Syst Biol. 10:7662014. View Article : Google Scholar : PubMed/NCBI
34	Weir TL, Manter DK, Sheflin AM, Barnett BA, Heuberger AL and Ryan EP: Stool microbiome and metabolome differences between colorectal cancer patients and healthy adults. PLoS One. 8:e708032013. View Article : Google Scholar : PubMed/NCBI
35	Clos-Garcia M, Garcia K, Alonso C, Iruarrizaga-Lejarreta M, D'Amato M, Crespo A, Iglesias A, Cubiella J, Bujanda L and Falcón-Pérez JM: Integrative analysis of fecal metagenomics and metabolomics in colorectal cancer. Cancers (Basel). 12:11422020.2020. View Article : Google Scholar : PubMed/NCBI
36	Chen F, Dai X, Zhou CC, Li KX, Zhang YJ, Lou XY, Zhu YM, Sun YL, Peng BX and Cui W: Integrated analysis of the faecal metagenome and serum metabolome reveals the role of gut microbiome-associated metabolites in the detection of colorectal cancer and adenoma. Gut. 71:1315–1325. 2022. View Article : Google Scholar : PubMed/NCBI
37	Tanoue T, Morita S, Plichta DR, Skelly AN, Suda W, Sugiura Y, Narushima S, Vlamakis H, Motoo I, Sugita K, et al: A defined commensal consortium elicits CD8 T cells and anti-cancer immunity. Nature. 565:600–605. 2019. View Article : Google Scholar : PubMed/NCBI
38	Zhao S, Gao G, Li W, Li X, Zhao C, Jiang T, Jia Y, He Y, Li A, Su C, et al: Antibiotics are associated with attenuated efficacy of anti-PD-1/PD-L1 therapies in Chinese patients with advanced non-small cell lung cancer. Lung Cancer. 130:10–17. 2019. View Article : Google Scholar : PubMed/NCBI
39	Ogretmen B: Sphingolipid metabolism in cancer signalling and therapy. Nat Rev Cancer. 18:33–50. 2018. View Article : Google Scholar : PubMed/NCBI
40	Govindarajah N, Clifford R, Bowden D, Sutton PA, Parsons JL and Vimalachandran D: Sphingolipids and acid ceramidase as therapeutic targets in cancer therapy. Crit Rev Oncol Hematol. 138:104–111. 2019. View Article : Google Scholar : PubMed/NCBI
41	Hayase E and Jenq RR: Role of the intestinal microbiome and microbial-derived metabolites in immune checkpoint blockade immunotherapy of cancer. Genome Med. 13:1072021. View Article : Google Scholar : PubMed/NCBI
42	Kim S, Covington A and Pamer EG: The intestinal microbiota: Antibiotics, colonization resistance, and enteric pathogens. Immunol Rev. 279:90–105. 2017. View Article : Google Scholar : PubMed/NCBI
43	Lavelle A and Sokol H: Gut microbiota-derived metabolites as key actors in inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 17:223–237. 2020. View Article : Google Scholar : PubMed/NCBI
44	Azuma K, Xiang H, Tagami T, Kasajima R, Kato Y, Karakawa S, Kikuchi S, Imaizumi A, Matsuo N, Ishii H, et al: Clinical significance of plasma-free amino acids and tryptophan metabolites in patients with non-small cell lung cancer receiving PD-1 inhibitor: A pilot cohort study for developing a prognostic multivariate model. J Immunother Cancer. 10:e0044202022. View Article : Google Scholar : PubMed/NCBI
45	Riquelme E, Zhang Y, Zhang L, Montiel M, Zoltan M, Dong W, Quesada P, Sahin I, Chandra V, San Lucas A, et al: Tumor microbiome diversity and composition influence pancreatic cancer outcomes. Cell. 178:795–806.e12. 2019. View Article : Google Scholar : PubMed/NCBI
46	Botticelli A, Vernocchi P, Marini F, Quagliariello A, Cerbelli B, Reddel S, Del Chierico F, Di Pietro F, Giusti R, Tomassini A, et al: Gut metabolomics profiling of non-small cell lung cancer (NSCLC) patients under immunotherapy treatment. J Transl Med. 18:492020. View Article : Google Scholar : PubMed/NCBI