结直肠癌不同原发部位肠道微生物组的宏基因组学荟萃分析

doi:10.3870/j.issn.1672-8009.2026.05.004

摘要/Abstract

摘要： 目的肠道微生物与结直肠癌（colorectal cancer,CRC）的原发部位有关,为探讨结直肠癌不同原发部位肠道微生物组的差异特征,本研究整合宏基因组数据进行荟萃分析。方法从3项研究中收集了宏基因组数据,根据右半结肠癌（right-sided colon cancer,RCC）、左半结肠癌（left-sided colon cancer,LCC）与直肠癌（rectal cancer,RC）这三个部位进行分组,首先通过双因素方差分析及菌群多样性比较识别混杂因素。随后构建微生物共现网络。采用随机森林算法构建原发肿瘤位置的预测模型。最后,将肿瘤位置与混杂因素纳入Maaslin2（microbiome multivariable associations with linear models）模型中,同时使用线性判别分析（linear discriminant analysis,LDA）以识别出差异性物种。结果研究来源和 BMI是主要混杂因素。肠道微生物的α/β多样性在不同肿瘤部位无显著差异。放线菌门、厚壁菌门和变形菌门在三个微生物网络中均发挥关键链接作用,拟杆菌门在 RCC 的微生物网络中更为显著。三个网络中既存在共同的关键菌群,也有各自的特有关键菌群。随机森林分类模型在预测RC时表现良好,但在区分 RCC 和 LCC 时表现较差。通过对比CC与RC,以及对比RCC与LCC,Maaslin2和 LDA鉴定出的部分差异性菌群曾被报道与 CRC 位置相关的分子及免疫特征有关。结论本研究阐明了肠道微生物组与 CRC 原发部位之间的关系,并证实 RCC、LCC 和 RC 在肠道微生物富集模式上存在差异。

关键词: 宏基因组学, 微生物组, 结直肠癌, 肿瘤位置, 荟萃分析

Abstract: Objective The intestinal microbiota is related to the primary site of colorectal cancer （CRC）. To explore the differences in the intestinal microbiome among different primary sites of colorectal cancer, this study conducted a meta-analysis using comprehensive genomic data. Methods Genomic data were collected from three studies and grouped according to three sites： right-sided colon cancer （RCC）, left-sided colon cancer （LCC）, and rectal cancer （RC）. Firstly, confounding factors were identified through two-factor variance analysis and comparison of microbial diversity. Subsequently, a microbial co-occurrence network was constructed. A random forest algorithm was used to build a prediction model for the location of the primary tumor. Finally, tumor location and confounding factors were incorporated into the Maaslin2 （microbiome multivariable associations with linear models） model and linear discriminant analysis （LDA） was used to identify differentially expressed species. Results The sources of research and BMI are the main confounding factors. There is no significant difference in the α/β diversity of intestinal microbiota among different tumor sites. The Actinobacteria phylum, Firmicutes phylum, and Proteobacteria phylum all play key linking roles in the three microbial networks, and the Bacteroidetes phylum is more significant in the microbial network of RCC. There are both common key bacterial groups and their own unique key bacterial groups in the three networks. The random forest classification model performs well in predicting RC, but performs poorly in distinguishing RCC from LCC. By comparing CC with RC, and comparing RCC with LCC, some of the differential bacterial groups identified by Maaslin2 and LDA have been reported to be related to molecular and immune characteristics of CRC location. Conclusion This study elucidated the relationship between gut microbiome and CRC location and confirmed that RCC, LCC, and RC had different enrich patterns of microbiota.

Key words: metagenomic, microbiome, colorectal cancer, tumor location, meta-analysis

中图分类号:

R735.3

廖之诚, 龙夏薇, 黎倩, 王宗佳, 林有智, 李永强, 廖小莉. 结直肠癌不同原发部位肠道微生物组的宏基因组学荟萃分析[J]. 医学分子生物学杂志, 2026, 23(5): 502-513.

LIAO Zhicheng, LONG Xiawei, LI Qian, WANG Zongjia, LIN Youzhi, LI Yongqiang, LIAO Xiaoli. Metagenomic Meta-Analysis of Gut Microbiome in Different Primary Locations of Colorectal Cancer[J]. Journal of Medical Molecular Biology, 2026, 23(5): 502-513.

参考文献

[1] WU S, ZHANG Y, LIN Z, et al.Global burden of colorectal cancer in 2022 and projections to 2050: incidence and mortality estimates from GLOBOCAN[J]. BMC Cancer, 2025, 25: 1770.
[2] BUFILL J A.Colorectal cancer: Evidence for distinct genetic categories based on proximal or distal tumor location[J]. Ann Intern Med,1990,113(10):779-788.
[3] TRAN B,KOPETZ S,TIE J,et al.Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer[J]. Cancer,2011,117(20):4623-4632.
[4] Glebov OK, Rodriguez LM, Nakahara K, Jenkins J, Cliatt J, Humbyrd CJ, DeNobile J, Soballe P, Simon R, Wright G et al: Distinguishing right from left colon by the pattern of gene expression. Cancer Epidemiol Biomarkers Prev 2003, 12(8):755-762.
[5] WONG S H,YU J.Gut microbiota in colorectal cancer: Mechanisms of action and clinical applications[J]. Nat Rev Gastroenterol Hepatol,2019,16(11):690-704.
[6] OLOVO C V,HUANG X,ZHENG X,et al.Faecal microbial biomarkers in early diagnosis of colorectal cancer[J]. J Cell Mol Med,2021,25(23):10783-10797.
[7] DE SOUZA J B,BRELAZ-DE-CASTRO M C A,CAVALCANTI I M F. Strategies for the treatment of colorectal cancer caused by gut microbiota[J]. Life Sci,2022,290:120202.
[8] ZHANG Y,HOFFMEISTER M,WECK M N,et al.Helicobacter pylori infection and colorectal cancer risk: Evidence from a large population-based case-control study in Germany[J]. Am J Epidemiol,2012,175(5):441-450.
[9] KOHOUTOVA D,SMAJS D,MORAVKOVA P,et al.Escherichia coli strains of phylogenetic group B2 and D and bacteriocin production are associated with advanced colorectal neoplasia[J]. BMC Infect Dis,2014,14:733.
[10] GAO Z,GUO B,GAO R,et al.Microbiota disbiosis is associated with colorectal cancer[J]. Front Microbiol,2015,6:20.
[11] MIYAKE T,MORI H,YASUKAWA D,et al.The comparison of fecal microbiota in left-side and right-side human colorectal cancer[J]. Eur Surg Res,2021,62(4):248-254.
[12] LAUDADIO I,FULCI V,PALONE F,et al.Quantitative assessment of shotgun metagenomics and 16S rDNA amplicon sequencing in the study of human gut microbiome[J]. OMICS,2018,22(4):248-254.
[13] IMPERIAL R,AHMED Z,TOOR O M,et al.Comparative proteogenomic analysis of right-sided colon cancer,left-sided colon cancer and rectal cancer reveals distinct mutational profiles[J]. Mol Cancer,2018,17(1):177.
[14] BAI J,BARANDOUZI Z A,ROWCLIFFE C,et al.Gut microbiome and its associations with acute and chronic gastrointestinal toxicities in cancer patients with pelvic radiation therapy: A systematic review[J]. Front Oncol,2021,11:745262.
[15] OH B,EADE T,LAMOURY G,et al.The gut microbiome and gastrointestinal toxicities in pelvic radiation therapy: A clinical review[J]. Cancers,2021,13(10):2353.
[16] GUPTA A,DHAKAN D B,MAJI A,et al.Association of Flavonifractor plautii,a flavonoid-degrading bacterium,with the gut microbiome of colorectal cancer patients in India[J]. mSystems,2019,4(6):e00438-e00419.
[17] YACHIDA S,MIZUTANI S,SHIROMA H,et al.Metagenomic and metabolomic analyses reveal distinct stage-specific phenotypes of the gut microbiota in colorectal cancer[J]. Nat Med,2019,25(6):968-976.
[18] YU J,FENG Q,WONG S H,et al.Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer[J]. Gut,2017,66(1):70-78.
[19] CHONG J,LIU P,ZHOU G,et al.Using MicrobiomeAnalyst for comprehensive statistical,functional,and meta-analysis of microbiome data[J]. Nat Protoc,2020,15(3):799-821.
[20] MCMURDIE P J,HOLMES S.Phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data[J]. PLoS One,2013,8(4):e61217.
[21] KURTZ Z D,MÜLLER C L,MIRALDI E R,et al. Sparse and compositionally robust inference of microbial ecological networks[J]. PLoS Comput Biol,2015,11(5):e1004226.
[22] MALLICK H,RAHNAVARD A,MCIVER L J,et al.Multivariable association discovery in population-scale meta-omics studies[J]. PLoS Comput Biol,2021,17(11):e1009442.
[23] LUO W,GUO S,ZHOU Y,et al.Hepatocellular carcinoma: How the gut microbiota contributes to pathogenesis,diagnosis,and therapy[J]. Front Microbiol,2022,13:873160.
[24] LAI Y,DHINGRA R,ZHANG Z,et al.Toward elucidating the human gut microbiota-brain axis: Molecules,biochemistry,and implications for health and diseases[J]. Biochemistry,2022,61(24):2806-2821.
[25] LI C,LIANG Y,QIAO Y.Messengers from the gut: Gut microbiota-derived metabolites on host regulation[J]. Front Microbiol,2022,13:863407.
[26] MIRZA A,MAO-DRAAYER Y.The gut microbiome and microbial translocation in multiple sclerosis[J]. Clin Immunol,2017,183:213-224.
[27] OGINO S,GOEL A.Molecular classification and correlates in colorectal cancer[J]. J Mol Diagn,2008,10(1):13-27.
[28] SMITH K J,JOHNSON K A,BRYAN T M,et al.The APC gene product in normal and tumor cells[J]. Proc Natl Acad Sci U S A,1993,90(7):2846-2850.
[29] LYNCH H T,SMYRK T C.Classification of familial adenomatous polyposis: a diagnostic nightmare[J]. Am J Hum Genet,1998,62(6):1288-1289.
[30] LYNCH H T,LYNCH J F,SHAW T G,et al.HNPCC (lynch syndrome): Differential diagnosis,molecular genetics and management-a review[J]. Hered Cancer Clin Pract,2003,1(1):7.
[31] WATANABE T,KOBUNAI T,TODA E,et al.Distal colorectal cancers with microsatellite instability (MSI) display distinct gene expression profiles that are different from proximal MSI cancers[J]. Cancer Res,2006,66(20):9804-9808.
[32] SLATTERY M L,CURTIN K,WOLFF R K,et al.A comparison of colon and rectal somatic DNA alterations[J]. Dis Colon Rectum,2009,52(7):1304-1311.
[33] YANG S Y,CHO M S,KIM N K.Difference between right-sided and left-sided colorectal cancers: From embryology to molecular subtype[J]. Expert Rev Anticancer Ther,2018,18(4):351-358.
[34] PASCHKE S,JAFAROV S,STAIB L,et al.Are colon and rectal cancer two different tumor entities? A proposal to abandon the term colorectal cancer[J]. Int J Mol Sci,2018,19(9):2577.
[35] GUINNEY J,DIENSTMANN R,WANG X,et al.The consensus molecular subtypes of colorectal cancer[J]. Nat Med,2015,21(11):1350-1356.
[36] GALON J,COSTES A,SANCHEZ-CABO F,et al.Type,density,and location of immune cells within human colorectal tumors predict clinical outcome[J]. Science,2006,313(5795):1960-1964.
[37] OGINO S,NOSHO K,IRAHARA N,et al.Lymphocytic reaction to colorectal cancer is associated with longer survival,independent of lymph node count,microsatellite instability,and CpG island methylator phenotype[J]. Clin Cancer Res,2009,15(20):6412-6420.
[38] RIBIC C M,SARGENT D J,MOORE M J,et al.Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer[J]. N Engl J Med,2003,349(3):247-257.
[39] PASSARDI A,CANALE M,VALGIUSTI M,et al.Immune checkpoints as a target for colorectal cancer treatment[J]. Int J Mol Sci,2017,18(6):1324.
[40] SHENG Q,DU H,CHENG X,et al.Characteristics of fecal gut microbiota in patients with colorectal cancer at different stages and different sites[J]. Oncol Lett,2019,18(5):4834-4844.
[41] SUI X,CHEN Y,LIU B,et al.The relationship between KRAS gene mutation and intestinal flora in tumor tissues of colorectal cancer patients[J]. Ann Transl Med,2020,8(17):1085.
[42] PURCELL R V,VISNOVSKA M,BIGGS P J,et al.Distinct gut microbiome patterns associate with consensus molecular subtypes of colorectal cancer[J]. Sci Rep,2017,7(1):11590.
[43] LÖWENMARK T,LI X,LÖFGREN-BURSTRÖM A,et al. Parvimonas micra is associated with tumour immune profiles in molecular subtypes of colorectal cancer[J]. Cancer Immunol Immunother,2022,71(10):2565-2575.
[44] JANG H J,CHOI J Y,KIM K,et al.Relationship of the lung microbiome with PD-L1 expression and immunotherapy response in lung cancer[J]. Respir Res,2021,22(1):322.
[45] LEE P C,WU C J,HUNG Y W,et al.Gut microbiota and metabolites associate with outcomes of immune checkpoint inhibitor-treated unresectable hepatocellular carcinoma[J]. J Immunother Cancer,2022,10(6):e004779.
[46] MILLER P L,CARSON T L.Mechanisms and microbial influences on CTLA-4 and PD-1-based immunotherapy in the treatment of cancer: a narrative review[J]. Gut Pathog,2020,12:43.
[47] YOON Y,KIM G,JEON B N,et al.Bifidobacterium strain-specific enhances the efficacy of cancer therapeutics in tumor-bearing mice[J]. Cancers,2021,13(5):957.
[48] KARPIŃSKI T M,OŻAROWSKI M,STASIEWICZ M. Carcinogenic microbiota and its role in colorectal cancer development[J]. Semin Cancer Biol,2022,86(Pt 3):420-430.
[49] ZHAO L,ZHANG X,ZHOU Y,et al.Parvimonas micra promotes colorectal tumorigenesis and is associated with prognosis of colorectal cancer patients[J]. Oncogene,2022,41(36):4200-4210.