Please wait a minute...
Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2019, Vol. 13 Issue (4) : 461-470    https://doi.org/10.1007/s11684-019-0695-7
RESEARCH ARTICLE
Altered intestinal microbiota associated with colorectal cancer
Hong Zhang1, Ying Chang2, Qingqing Zheng2, Rong Zhang1, Cheng Hu1(), Weiping Jia1
1. Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
2. Digestive Endoscopic Center, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China
 Download: PDF(692 KB)   HTML
 Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks
Abstract

The gut microbiota plays an important role in the development and progression of colorectal cancer (CRC). To learn more about the dysbiosis of carcinogenesis, we assessed alterations in gut microbiota in patients with CRC. A total of 23 subjects were enrolled in this study: 9 had CRC (CRC group) and 14 had normal colons (normal group). The microbiome of the mucosal--luminal interface of each subject was sampled and analyzed using 16S rRNA gene amplicon sequencing. We also used Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) to predict microbial functional profiles. The microbial composition of the mucosal lumen differed between the groups, and the presence of specific bacteria may serve as a potential biomarker for colorectal carcinogenesis. We identified a significant reduction in Eubacterium, which is a butyrate-producing genera of bacteria, and a significant increase in Devosia in the gut microbiota of CRC patients. Different levels of gut microflora in healthy and CRC samples were identified. The observed abundance of bacterial species belonging to Eubacterium and Devosia may serve as a promising biomarker for the early detection of CRC.

Keywords colorectal cancer (CRC)      gut microbiota      intestinal      Eubacterium      Devosia     
Corresponding Author(s): Cheng Hu   
Just Accepted Date: 28 May 2019   Online First Date: 01 July 2019    Issue Date: 02 August 2019
 Cite this article:   
Hong Zhang,Ying Chang,Qingqing Zheng, et al. Altered intestinal microbiota associated with colorectal cancer[J]. Front. Med., 2019, 13(4): 461-470.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-019-0695-7
https://academic.hep.com.cn/fmd/EN/Y2019/V13/I4/461
  NG (n = 14) CG (n = 9) P value
Male/female 7/7 6/3 0.6693
Age (year), mean±SD 44.1±15 62.6±8.9 0.0041
BMI (kg/m2), mean±SD 22.03±2.68 22.37±2.17 0.7527
Family history of CRC, % 0 22.2 0.0001
Tab.1  Summary of population information
Fig.1  Quality control of the sequencing data. (A) Sequence number, (B) Chao richness estimator, and (C) Shannon index of the 16S rRNA sequencing data for the normal (NG) and CRC (CG) groups.
Fig.2  Bacterial taxonomic groups discriminating between NG and CG. Relative abundances of dominant bacterial taxonomic groups discriminating between NG and CG. (A) Phylum level, (B) class level, (C) order level, and (D) family level.
Group enriched Taxonomic rank Bacteria NG (%) CG (%) P value
CG Genus Devosia 0.006 (0.003–0.010) 0.023 (0.009–0.029) 0.008
Family Hyphomicrobiaceae 0.006 (0.003–0.010) 0.023 (0.009–0.029) 0.008
Order Rhizobiales 0.008 (0.003–0.012) 0.027 (0.019–0.034) 0.012
Class Alphaproteobacteria 0.010 (0.006–0.017) 0.031 (0.027–0.039) 0.020
NG Species stercorea 0.063 (0.042–0.138) 0.004 (0–0.035) 0.001
Species copri 0.126 (0.051–0.993) 0.009 (0.004–0.115) 0.006
Family Prevotellaceae 0.225 (0.172–1.310) 0.042 (0.023–0.170) 0.006
Genus Eubacterium 0.025 (0.016–0.123) 0.005 (0–0.017) 0.009
Genus Klebsiella 0.020 (0.010–0.090) 0.008 (0.005-0.012) 0.014
Order Desulfovibrionales 0.127 (0.049–0.441) 0.037 (0.021–0.104) 0.014
Class Deltaproteobacteria 0.127 (0.049–0.446) 0.037 (0.025–0.104) 0.017
Family Desulfovibrionaceae 0.126 (0.045–0.368) 0.037 (0.017–0.104) 0.017
Genus 02d06 0.044 (0.015–0.074) 0.009 (0–0.025) 0.018
Species producta 0.189 (0.033–0.287) 0.014 (0.008–0.059) 0.023
Genus Phascolarctobacterium 0.062 (0.005–0.125) 0.005 (0–0.014) 0.027
Family Clostridiaceae 0.269 (0.164–0.843) 0.122 (0.033–0.182) 0.038
  Genus Leptotrichia 0.028 (0.021–0.132) 0.010 (0.005–0.016) 0.038
Tab.2  Relative abundance of significantly enriched bacterial taxa from different groups
Fig.3  Key contributors of the structural segregation of different groups identified using LEfSe. (A) A cladogram of the phylotypes that differed between the groups displayed according to effect size. Differences are represented by the color of the most abundant class (red= CRC group; green= normal group). Significant bacterial taxonomic groups are labeled, with the genus, family, species, or order in parentheses. (B) LDA scores of enriched bacterial taxa (LDA>2 of LEfSe). Significantly enriched bacterial taxa from different groups are clustered on different sides (NG= right; CG= left) and labeled with different colors. NG= normal group; CG= CRC group; LDA= linear discriminate analysis.
KEGG pathways NG CG P value
Cancers      
Small cell lung cancer 0.10 (0.07–0.18) 0.30 (0.13–0.40) 0.016
Colorectal cancer 0.10 (0.07–0.18) 0.30 (0.13–0.40) 0.017
Bladder cancer 30.26 (11.85–69.91) 42.23 (29.89–109.37) 0.441
Renal cell carcinoma 55.01 (22.16–123.0) 69.56 (37.40–201.82) 0.443
Infectious diseases      
Vibrio cholerae infection 0.90 (0.54–3.02) 0.57 (0.37–0.79) 0.005
Influenza A 0.10 (0.07–0.18) 0.30 (0.13–0.40) 0.016
Toxoplasmosis 0.10 (0.07–0.18) 0.30 (0.13–0.40) 0.016
Pertussis 541.81 (190.97–942.52) 596.60 (481.92–1893.19) 0.256
African trypanosomiasis 37.04 (20.87–72.41) 43.24 (32.99–109.60) 0.400
Chagas disease (American trypanosomiasis) 31.72 (20.66–72.18) 43.15 (32.76–109.52) 0.403
Cardiovascular diseases      
Viral myocarditis 0.10 (0.07–0.18) 0.30 (0.13–0.40) 0.016
Cell growth and death      
p53 signaling pathway 0.10 (0.07–0.18) 0.30 (0.13–0.40) 0.016
Meiosis-yeast 5.88 (2.38–8.91) 1.77 (1.17–5.87) 0.088
Apoptosis 1.79 (1.56–2.06) 2.27 (0.82–6.38) 0.295
Transport and catabolism      
Endocytosis 0 0.04 (0–0.05) 0.044
Lysosome 621.65 (352.94–720.52) 428.15 (241.70–638.47) 0.282
Biosynthesis of other secondary metabolites      
Stilbenoid, diarylheptanoid, and gingerol biosynthesis 3.89 (1.75–5.86) 3.67 (1.58–6.24) 0.085
Betalain biosynthesis 0.06 (0.03–0.14) 0.05 (0.02–0.24) 0.199
Butirosin and neomycin biosynthesis 601.70 (441.17–668.97) 356.68 (328.17–538.20) 0.451
Flavonoid biosynthesis 26.09 (22.30–43.97) 24.90 (10.00–35.72) 0.485
Endocrine system      
GnRH signaling pathway 0 0.04 (0–0.05) 0.043
Melanogenesis 0.01 (0–0.05) 0.03 (0–0.12) 0.061
Proximal tubule bicarbonate reclamation 124.57 (83.98–164.06) 101.69 (95.73–231.88) 0.453
Immune system      
FcγR-mediated phagocytosis 0 0.04 (0–0.05) 0.043
RIG-I-like receptor signaling pathway 30.90 (13.48–42.25) 14.64 (7.41–26.66) 0.065
Tab.3  Selected main microbial pathways grouped into level-3 functional categories determined by PICRUSt
1 D Cunningham, W Atkin, HJ Lenz, HT Lynch, B Minsky, B Nordlinger, N Starling. Colorectal cancer. Lancet 2010; 375(9719): 1030–1047
https://doi.org/10.1016/S0140-6736(10)60353-4 pmid: 20304247
2 J Regula, M Rupinski, E Kraszewska, M Polkowski, J Pachlewski, J Orlowska, MP Nowacki, E Butruk. Colonoscopy in colorectal-cancer screening for detection of advanced neoplasia. N Engl J Med 2006; 355(18): 1863–1872
https://doi.org/10.1056/NEJMoa054967 pmid: 17079760
3 MA Azcárate-Peril, M Sikes, JM Bruno-Bárcena. The intestinal microbiota, gastrointestinal environment and colorectal cancer: a putative role for probiotics in prevention of colorectal cancer? Am J Physiol Gastrointest Liver Physiol 2011; 301(3): G401–G424
https://doi.org/10.1152/ajpgi.00110.2011 pmid: 21700901
4 Y Horiuchi, J Fujisaki, N Ishizuka, M Omae, A Ishiyama, T Yoshio, T Hirasawa, Y Yamamoto, M Nagahama, H Takahashi, T Tsuchida. Study on clinical factors involved in Helicobacter pylori-uninfected, undifferentiated-type early gastric cancer. Digestion 2017; 96(4): 213–219
https://doi.org/10.1159/000481817 pmid: 29050004
5 JK Nicholson, E Holmes, J Kinross, R Burcelin, G Gibson, W Jia, S Pettersson. Host-gut microbiota metabolic interactions. Science 2012; 336(6086): 1262–1267
https://doi.org/10.1126/science.1223813 pmid: 22674330
6 T Yatsunenko, FE Rey, MJ Manary, I Trehan, MG Dominguez-Bello, M Contreras, M Magris, G Hidalgo, RN Baldassano, AP Anokhin, AC Heath, B Warner, J Reeder, J Kuczynski, JG Caporaso, CA Lozupone, C Lauber, JC Clemente, D Knights, R Knight, JI Gordon. Human gut microbiome viewed across age and geography. Nature 2012; 486(7402): 222–227
https://doi.org/10.1038/nature11053 pmid: 22699611
7 DM Parkin. The global health burden of infection-associated cancers in the year 2002. Int J Cancer 2006; 118(12): 3030–3044
https://doi.org/10.1002/ijc.21731 pmid: 16404738
8 EL Amitay, S Werner, M Vital, DH Pieper, D Höfler, IJ Gierse, J Butt, Y Balavarca, K Cuk, H Brenner. Fusobacterium and colorectal cancer: causal factor or passenger? Results from a large colorectal cancer screening study. Carcinogenesis 2017; 38(8): 781–788
https://doi.org/10.1093/carcin/bgx053 pmid: 28582482
9 Y Yamaoka, Y Suehiro, S Hashimoto, T Hoshida, M Fujimoto, M Watanabe, D Imanaga, K Sakai, T Matsumoto, M Nishioka, T Takami, N Suzuki, S Hazama, H Nagano, I Sakaida, T Yamasaki. Fusobacterium nucleatum as a prognostic marker of colorectal cancer in a Japanese population. J Gastroenterol 2018; 53(4): 517–524
pmid: 28823057
10 J Repass, N Maherali, K, Owen Reproducibility Project: Cancer Biology. Registered report: Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. eLife 2016; 5:e10012
https://doi.org/DOI:10.7554/eLife.10012 pmid: 26882501
11 L Mira-Pascual, R Cabrera-Rubio, S Ocon, P Costales, A Parra, A Suarez, F Moris, L Rodrigo, A Mira, MC Collado. Microbial mucosal colonic shifts associated with the development of colorectal cancer reveal the presence of different bacterial and archaeal biomarkers. J Gastroenterol 2015; 50(2): 167–179
https://doi.org/10.1007/s00535-014-0963-x pmid: 24811328
12 W Mottawea, CK Chiang, M Mühlbauer, AE Starr, J Butcher, T Abujamel, SA Deeke, A Brandel, H Zhou, S Shokralla, M Hajibabaei, R Singleton, EI Benchimol, C Jobin, DR Mack, D Figeys, A Stintzi. Altered intestinal microbiota-host mitochondria crosstalk in new onset Crohn’s disease. Nat Commun 2016; 7(1): 13419
https://doi.org/10.1038/ncomms13419 pmid: 27876802
13 C Quast, E Pruesse, P Yilmaz, J Gerken, T Schweer, P Yarza, J Peplies, FO Glöckner. The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res 2013; 41(Database issue): D590–D596
pmid: 23193283
14 PD Schloss, SL Westcott, T Ryabin, JR Hall, M Hartmann, EB Hollister, RA Lesniewski, BB Oakley, DH Parks, CJ Robinson, JW Sahl, B Stres, GG Thallinger, DJ Van Horn, CF Weber. Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities. Appl Environ Microbiol 2009; 75(23): 7537–7541
https://doi.org/10.1128/AEM.01541-09 pmid: 19801464
15 N Segata, J Izard, L Waldron, D Gevers, L Miropolsky, WS Garrett, C Huttenhower. Metagenomic biomarker discovery and explanation. Genome Biol 2011; 12(6): R60
https://doi.org/10.1186/gb-2011-12-6-r60 pmid: 21702898
16 MG Langille, J Zaneveld, JG Caporaso, D McDonald, D Knights, JA Reyes, JC Clemente, DE Burkepile, RL Vega Thurber, R Knight, RG Beiko, C Huttenhower. Predictive functional profiling of microbial communities using 16S rRNA marker gene sequences. Nat Biotechnol 2013; 31(9): 814–821
https://doi.org/10.1038/nbt.2676 pmid: 23975157
17 RE Ley, DA Peterson, JI Gordon. Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 2006; 124(4): 837–848
https://doi.org/10.1016/j.cell.2006.02.017 pmid: 16497592
18 K Kimura, AL McCartney, MA McConnell, GW Tannock. Analysis of fecal populations of bifidobacteria and lactobacilli and investigation of the immunological responses of their human hosts to the predominant strains. Appl Environ Microbiol 1997; 63(9): 3394–3398
pmid: 9292990
19 CL Sears. A dynamic partnership: celebrating our gut flora. Anaerobe 2005; 11(5): 247–251
https://doi.org/10.1016/j.anaerobe.2005.05.001 pmid: 16701579
20 Q Zhu, Z Jin, W Wu, R Gao, B Guo, Z Gao, Y Yang, H Qin. Analysis of the intestinal lumen microbiota in an animal model of colorectal cancer. PLoS One 2014; 9(6): e90849
https://doi.org/10.1371/journal.pone.0090849 pmid: 24603888
21 T Wang, G Cai, Y Qiu, N Fei, M Zhang, X Pang, W Jia, S Cai, L Zhao. Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers. ISME J 2012; 6(2): 320–329
https://doi.org/10.1038/ismej.2011.109 pmid: 21850056
22 T Tahara, E Yamamoto, H Suzuki, R Maruyama, W Chung, J Garriga, J Jelinek, HO Yamano, T Sugai, B An, I Shureiqi, M Toyota, Y Kondo, MR Estécio, JP Issa. Fusobacterium in colonic flora and molecular features of colorectal carcinoma. Cancer Res 2014; 74(5): 1311–1318
https://doi.org/10.1158/0008-5472.CAN-13-1865 pmid: 24385213
23 AN McCoy, F Araújo-Pérez, A Azcárate-Peril, JJ Yeh, RS Sandler, TO Keku. Fusobacterium is associated with colorectal adenomas. PLoS One 2013; 8(1): e53653
https://doi.org/10.1371/journal.pone.0053653 pmid: 23335968
24 PD Scanlan, F Shanahan, Y Clune, JK Collins, GC O’Sullivan, M O’Riordan, E Holmes, Y Wang, JR Marchesi. Culture-independent analysis of the gut microbiota in colorectal cancer and polyposis. Environ Microbiol 2008; 10(3): 789–798
https://doi.org/10.1111/j.1462-2920.2007.01503.x pmid: 18237311
25 T Sasada, T Hinoi, Y Saito, T Adachi, Y Takakura, Y Kawaguchi, Y Sotomaru, K Sentani, N Oue, W Yasui, H Ohdan. Chlorinated water modulates the development of colorectal tumors with chromosomal instability and gut microbiota in APC-deficient mice. PLoS One 2015; 10(7): e0132435
https://doi.org/10.1371/journal.pone.0132435 pmid: 26186212
26 PJ Turnbaugh, RE Ley, MA Mahowald, V Magrini, ER Mardis, JI Gordon. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006; 444(7122): 1027–1031
https://doi.org/10.1038/nature05414 pmid: 17183312
27 D Scharlau, A Borowicki, N Habermann, T Hofmann, S Klenow, C Miene, U Munjal, K Stein, M Glei. Mechanisms of primary cancer prevention by butyrate and other products formed during gut flora-mediated fermentation of dietary fibre. Mutat Res 2009; 682(1): 39–53
https://doi.org/10.1016/j.mrrev.2009.04.001 pmid: 19383551
28 R Balamurugan, E Rajendiran, S George, GV Samuel, BS Ramakrishna. Real-time polymerase chain reaction quantification of specific butyrate-producing bacteria, Desulfovibrio and Enterococcus faecalis in the feces of patients with colorectal cancer. J Gastroenterol Hepatol 2008; 23(8 Pt 1): 1298–1303
https://doi.org/10.1111/j.1440-1746.2008.05490.x pmid: 18624900
29 RK Le Leu, JM Winter, CT Christophersen, GP Young, KJ Humphreys, Y Hu, SW Gratz, RB Miller, DL Topping, AR Bird, MA Conlon. Butyrylated starch intake can prevent red meat-induced O6-methyl-2-deoxyguanosine adducts in human rectal tissue: a randomised clinical trial. Br J Nutr 2015; 114(2): 220–230
https://doi.org/10.1017/S0007114515001750 pmid: 26084032
30 SH Duncan, A Belenguer, G Holtrop, AM Johnstone, HJ Flint, GE Lobley. Reduced dietary intake of carbohydrates by obese subjects results in decreased concentrations of butyrate and butyrate-producing bacteria in feces. Appl Environ Microbiol 2007; 73(4): 1073–1078
https://doi.org/10.1128/AEM.02340-06 pmid: 17189447
31 S Sengupta, JG Muir, PR Gibson. Does butyrate protect from colorectal cancer? J Gastroenterol Hepatol 2006; 21(1 Pt 2): 209–218
https://doi.org/10.1111/j.1440-1746.2006.04213.x pmid: 16460475
32 I Sato, M Ito, M Ishizaka, Y Ikunaga, Y Sato, S Yoshida, M Koitabashi, S Tsushima. Thirteen novel deoxynivalenol-degrading bacteria are classified within two genera with distinct degradation mechanisms. FEMS Microbiol Lett 2012; 327(2): 110–117
https://doi.org/10.1111/j.1574-6968.2011.02461.x pmid: 22098388
[1] FMD-19004-OF-HC_suppl_1 Download
[1] Joseph JY Sung, Nicholas CH Poon. Artificial intelligence in gastroenterology: where are we heading?[J]. Front. Med., 2020, 14(4): 511-517.
[2] Anqi Chen, Suhua Zhang, Jixi Li, Chaoneng Ji, Jinzhong Chen, Chengtao Li. Detecting genetic hypermutability of gastrointestinal tumor by using a forensic STR kit[J]. Front. Med., 2020, 14(1): 101-111.
[3] Chenfei Zhou, Jun Zhang. Immunotherapy-based combination strategies for treatment of gastrointestinal cancers: current status and future prospects[J]. Front. Med., 2019, 13(1): 12-23.
[4] Ruiting Han, Junli Ma, Houkai Li. Mechanistic and therapeutic advances in non-alcoholic fatty liver disease by targeting the gut microbiota[J]. Front. Med., 2018, 12(6): 645-657.
[5] Xiaojiao Zheng, Shouli Wang, Wei Jia. Calorie restriction and its impact on gut microbial composition and global metabolism[J]. Front. Med., 2018, 12(6): 634-644.
[6] Chenyang Wang, Qiurong Li, Jieshou Li. Gut microbiota and its implications in small bowel transplantation[J]. Front. Med., 2018, 12(3): 239-248.
[7] Lei Huang,Aman Xu. Detection of digestive malignancies and post-gastrectomy complications via gastrointestinal fluid examination[J]. Front. Med., 2017, 11(1): 20-31.
[8] Eric C.H. Lai,Kam Man Chung,Stephanie H.Y. Lau,Wan Yee Lau. A ruptured recurrent small bowel gastrointestinal stromal tumour causing hemoperitoneum[J]. Front. Med., 2015, 9(1): 108-111.
[9] Qinggang Hu, Shanglong Liu, Jianwei Jiang, Chen Zhang, Xiaowei Liu, Qichang Zheng. Potential indicators predict progress after surgical resection of gastrointestinal stromal tumors[J]. Front Med, 2012, 6(3): 317-321.
[10] Zhi-Yong ZHANG, Xiao-Ping CHEN, Qi-Ping LU. Effect of salvia miltiorrhiza pretreatment on the CCK and VIP expression in hepatic ischemia-reperfusion-induced digestive tract congestion[J]. Front Med Chin, 2010, 4(3): 317-322.
[11] Li-Guang TIAN MPH, Jia-Xu CHEN PhD, Yu-Chun CAI BM, Jian GUO MPH, Xiao-Mei TONG, Qin LIU DVM, Xiao-Nong ZHOU PhD, Tian-Ping WANG PhD, Xiao-Mei YIN, Wei-Duo WU, Li ZHOU, Feng-Feng WANG, Zhen-Li WANG MSc, Guo-Jin CHENG, Peter STEINMANN PhD, Lan-Hua LI MSc, . Co-infection of HIV and parasites in China: Results from an epidemiological survey in rural areas of Fuyang city, Anhui province, China[J]. Front. Med., 2010, 4(2): 192-198.
[12] WANG Zhiqiang. Analysis of the treatment outcomes of esophageal variceal bleeding patients from multiple centers in China[J]. Front. Med., 2008, 2(2): 171-173.
[13] LIANG Yumei, LI Xianghong, LU Youyong, LV Yali, ZHONG Mei, PU Xiaolu, LI Wenmei. Prognostic significance of clinicopathologic parameters in gastrointestinal stromal tumors: a study of 156 cases[J]. Front. Med., 2008, 2(1): 87-94.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed