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Frontiers of Medicine

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
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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 Authors: 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.
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http://journal.hep.com.cn/fmd/EN/10.1007/s11684-019-0695-7
http://journal.hep.com.cn/fmd/EN/Y2019/V13/I4/461
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Hong Zhang
Ying Chang
Qingqing Zheng
Rong Zhang
Cheng Hu
Weiping Jia
  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
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