Skip to main content

Advertisement

SpringerLink
Log in

Characterization of the fecal microbiota in gastrointestinal cancer patients and healthy people

  • Research Article
  • Published:
Clinical and Translational Oncology Aims and scope Submit manuscript

Abstract

Background

The incidence and mortality of gastrointestinal (GI) tumors are high in China. Some studies suggest that the gut microbiota is related to the occurrence and development of tumors. At present, there are no prospective studies based on the correlation between gastrointestinal tumors and gut microbiota in the Chinese population. The objective of this report is to characterize the fecal microbiota in healthy control participants and patients with esophageal cancer, gastric cancer, and colorectal cancer.

Methods

Patients with locally advanced or metastatic esophageal, gastric, and colorectal cancer were enrolled, and healthy people were included as controls. 16S rRNA sequencing was used to analyze the characteristics of fecal microbiota. PICRUSt software was used for functional prediction.

Results

Significant differences in the composition and abundance of fecal microbiota were identified between gastrointestinal cancer patients (n = 130) and healthy controls (n = 147). The abundance of Faecalibacterium prausnitzii, Clostridium clostridioforme and Bifidobacterium adolescent in tumor groups were all significantly lower than in the control group (P < 0.05). The levels of Blautia producta and R. faecis in the gastric (n = 46) and colorectal cancer (n = 44) groups were significantly lower than those in the control group (P < 0.05). The level of Butyricicoccus pullicaecorum in the esophageal cancer (n = 40) and gastric cancer groups was significantly lower than that in the control group (P < 0.05). B. fragilis, Akkermansia muciniphila, Clostridium hathewayi and Alistipes finegoldii were overabundant in the different tumor groups compared with the control (P < 0.05). We observed significant differences in functional metabolism and cell biological function between the tumor and control groups (P < 0.05). Optimal microbial markers were identified on a random forest model and achieved an area under the curve of 85.59% between 130 GI cancer samples and 147 control samples. The respective AUC values were 86.89%, 97.11%, and 79.1% in detecting esophageal cancer, gastric cancer, and colorectal cancer.

Conclusions

Patients with esophageal or gastric cancers had similar features of fecal bacteria as those with colorectal cancer. The metabolic function of fecal bacteria in the gastrointestinal cancer patients and the healthy controls were different. The microbial signatures may potentially be applied to distinguish GI cancer patients from healthy people as a non-invasive diagnostic biomarker.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Availability of data and materials

Please contact author for data requests.

Notes

  1. http://ccb.jhu.edu/software/FLASH/index.shtml/FLASH-1.2.11.tar.gz.

  2. http://www.drive5.com/usearch.

  3. http://greengenes.secondgenome.com.

  4. https://download.csdn.net/download/weixin_43585681/11530367.

  5. (https://github.com/picrust/picrust).

  6. (https://www.r-project.org).

  7. (http://www.onlinedown.net/soft/577760.htm?t=1492483499557).

Abbreviations

GI:

Gastrointestinal

EC:

Esophageal cancer

GC:

Gastric cancer

CRC:

Colorectal cancer

rRNA:

Ribosomal RNA

PD-L1:

Anti-programmed cell death ligand-1

PD-1:

Anti-programmed cell death receptor-1

PUMCH:

Peking Union Medical College Hospital

ESR:

Erythrocyte sedimentation rate

hsCRP:

Hypersensitive C-reactive protein

ANA:

Antinuclear antibody

OTU:

Operational taxonomic units

PCoA:

Principal coordinate analysis

ANOSIM:

Analysis of similarity

LDA:

Linear discriminant analysis

LEfSe:

Linear discriminant analysis effect size

PICRUSt:

Phylogenetic Investigation of Communities by Reconstruction of Unobserved States

KEGG:

Kyoto Encyclopedia of Genes and Genomes

COG:

Clusters of Orthologous Groups of proteins

ANOVA:

Analysis of variance

FDR:

False discovery rate

RF:

Random forest

ROC:

Receiver operating characteristic

NK:

Natural killer cell

NF-kB:

Nuclear factor kappa beta

STAT3:

Signal transducer and activator of transcription 3

TNF-α:

Tumor necrosis factor-α

COX-2:

Cyclooxygenase-2

SCFA:

Short-chain fatty acids

Treg:

Regulated T cells

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30.

    Article  PubMed  Google Scholar 

  2. Chen W, Zheng R, Baade PD, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32.

    Article  PubMed  Google Scholar 

  3. Song M, Garrett WS, Chan AT. Nutrients, foods, and colorectal cancer prevention. Gastroenterology. 2015;148(6):1244-1260.e16.

    Article  CAS  PubMed  Google Scholar 

  4. Sender R, Fuchs S, Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol. 2016;14(8):e1002533.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Jandhyala SM, Talukdar R, Subramanyam C, et al. Role of the normal gut microbiota. World J Gastroenterol. 2015;21(29):8787–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Garrett WS. Cancer and the microbiota. Science. 2015;348(6230):80–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Nougayrède JP, Homburg S, Taieb F, et al. Escherichia coli induces DNA double-strand breaks in eukaryotic cells. Science. 2006;313(5788):848–51.

    Article  PubMed  CAS  Google Scholar 

  8. Wang T, Cai G, Qiu Y, et al. Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers. ISME J. 2012;6(2):320–9.

    Article  CAS  PubMed  Google Scholar 

  9. Wu S, Rhee KJ, Albesiano E, et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med. 2009;15(9):1016–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Meng C, Bai C, Brown TD, et al. Human gut microbiota and gastrointestinal cancer. Genomics Proteom Bioinform. 2018;16(1):33–49.

    Article  Google Scholar 

  11. Ren Z, Li A, Jiang J, et al. Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma. Gut. 2019;68(6):1014–23.

    Article  CAS  PubMed  Google Scholar 

  12. Akshintala VS, Talukdar R, Singh VK, et al. The gut microbiome in pancreatic disease. Clin Gastroenterol Hepatol. 2019;17(2):290–5.

    Article  CAS  PubMed  Google Scholar 

  13. Geller LT, Barzily-Rokni M, Danino T, et al. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science. 2017;357(6356):1156–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Iida N, Dzutsev A, Stewart CA, et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science. 2013;342(6161):967–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sivan A, Corrales L, Hubert N, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015;350(6264):1084–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018;359(6371):97–103.

    Article  CAS  PubMed  Google Scholar 

  17. Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359(6371):91–7.

    Article  CAS  PubMed  Google Scholar 

  18. Kozich JJ, Westcott SL, Baxter NT, et al. Development of a dual-index sequencing strategy and curation pipeline for analyzing amplicon sequence data on the MiSeq Illumina sequencing platform. Appl Environ Microbiol. 2013;79(17):5112–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Magoč T, Salzberg SL. FLASH: fast length adjustment of short reads to improve genome assemblies. Bioinformatics. 2011;27(21):2957–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Edgar RC. Search and clustering orders of magnitude faster than BLAST. Bioinformatics. 2010;26(19):2460–1.

    Article  CAS  PubMed  Google Scholar 

  21. Shannon CE. The mathematical theory of communication 1963. MD Comput. 1997;14(4):306–17.

    CAS  PubMed  Google Scholar 

  22. Lozupone C, Lladser ME, Knights D, et al. UniFrac: an effective distance metric for microbial community comparison. ISME J. 2011;5(2):169–72.

    Article  PubMed  Google Scholar 

  23. Segata N, Izard J, Waldron L, et al. Metagenomic biomarker discovery and explanation. Genome Biol. 2011;12(6):R60.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Langille MG, Zaneveld J, Caporaso JG, et al. Predictive functional profifiling of microbial communities using 16S rRNA marker gene sequences. Nat Biotechnol. 2013;31(9):814–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sommer F, Bäckhed F. The gut microbiota-masters of host development and physiology. Nat Rev Microbiol. 2013;11(4):227–38.

    Article  CAS  PubMed  Google Scholar 

  26. Wang Q, Garrity GM, Tiedje JM, et al. Naive Bayesian classifer for rapid assignment of rRNA sequences into the new bacterial taxonomy. Appl Environ Microbiol. 2007;73(16):5261–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Badal VD, Vaccariello ED, Murray ER, et al. The Gut Microbiome, Aging, and Longevity: A Systematic Review. Nutrients. 2020;12(12):3759.

    Article  PubMed Central  Google Scholar 

  28. Ahn J, Sinha R, Pei Z, et al. Human gut microbiome and risk for colorectal cancer. J Natl Cancer Inst. 2013;105(24):1907–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lopez-Siles M, Martinez-Medina M, Surís-Valls R, et al. Changes in the abundance of Faecalibacterium prausnitzii Phylogroups I and II in the intestinal mucosa of inflammatory bowel disease and patients with colorectal cancer. Inflamm Bowel Dis. 2016;22(1):28–41.

    Article  PubMed  Google Scholar 

  30. Ohkusa T, Yoshida T, Sato N, et al. Commensal bacteria can enter colonic epithelial cells and induce proinflammatory cytokine secretion: a possible pathogenic mechanism of ulcerative colitis. J Med Microbiol. 2009;58(Pt 5):535–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sinha R, Ahn J, Sampson JN, et al. Fecal microbiota, fecal metabolome, and colorectal cancer interrelations. PLoS ONE. 2016;11(3):e0152126.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Feng Q, Liang S, Jia H, et al. Gut microbiome development along the colorectal adenoma-carcinoma sequence. Nat Commun. 2015;6:6528.

    Article  CAS  PubMed  Google Scholar 

  33. Borges-Canha M, Portela-Cidade JP, Dinis-Ribeiro M, et al. Role of colonic microbiota in colorectal carcinogenesis: a systematic review. Rev Esp Enferm Dig. 2015;107(11):659–71.

    CAS  PubMed  Google Scholar 

  34. Chen W, Liu F, Ling Z, et al. Human intestinal lumen and mucosa-associated microbiota in patients with colorectal cancer. PLoS ONE. 2012;7(6):e39743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Chang S-C, Shen M-H, Liu C-Y, et al. A gut butyrate-producing bacterium Butyricicoccus pullicaecorumregulates short-chain fatty acid transporter and receptor to reduce the progression of 1,2-dimethylhydrazine-associated colorectal cancer. Oncol Lett. 2020;20(6):327.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Osaki T, Matsuki T, Asahara T, et al. Comparative analysis of gastric bacterial microbiota in Mongolian gerbils after long-term infection with Helicobacter pylori. Microb Pathog. 2012;53(1):12–8.

    Article  PubMed  Google Scholar 

  37. Wu N, Yang X, Zhang R, et al. Dysbiosis signature of fecal microbiota in colorectal cancer patients. Microb Ecol. 2013;66(2):462–70.

    Article  CAS  PubMed  Google Scholar 

  38. Wu S, Powell J, Mathioudakis N, et al. Bacteroides fragilis enterotoxin induces intestinal epithelial cell secretion of interleukin-8 through mitogen-activated protein kinases and a tyrosine kinase-regulated nuclear factor-kappaB pathway. Infect Immunity. 2004;72(10):5832–9.

    Article  CAS  Google Scholar 

  39. Wu S, Morin PJ, Maouyo D, et al. Bacteroides fragilis enterotoxin induces c-Myc expression and cellular proliferation. Gastroenterology. 2003;124(2):392–400.

    Article  CAS  PubMed  Google Scholar 

  40. Weir TL, Manter DK, Sheflin AM, et al. Stool microbiome and metabolome differences between colorectal cancer patients and healthy adults. PLoS ONE. 2013;8(8):e70803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Grivennikov SI, Wang K, Mucida D, et al. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature. 2012;491(7423):254–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Blackett KL, Siddhi SS, Cleary S, et al. Oesophageal bacterial biofilm changes in gastro-oesophageal reflux disease, Barrett’s and oesophageal carcinoma: association or causality? Aliment Pharmacol Ther. 2013;37(11):1084–92.

    Article  CAS  PubMed  Google Scholar 

  43. Aviles-Jimenez F, Vazquez-Jimenez F, Medrano-Guzman R, et al. Stomach microbiota composition varies between patients with non-atrophic gastritis and patients with intestinal type of gastric cancer. Sci Rep. 2014;4:4202.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Liang Q, Chiu J, Chen Y, et al. Fecal bacteria act as novel biomarkers for noninvasive diagnosis of colorectal cancer. Clin Cancer Res. 2017;23:2061–70.

    Article  CAS  PubMed  Google Scholar 

  45. Moschen AR, Gerner RR, Wang J, Reider SJ, et al. Lipocalin 2 protects from inflammation and tumorigenesis associated with gut microbiota alterations. Cell Host Microbe. 2016;19:455–69.

    Article  CAS  PubMed  Google Scholar 

  46. Agoff SN, Brentnall TA, Crispin DA, et al. The role of cyclooxygenase 2 in ulcerative colitis-associated neoplasia. Am J pathol. 2000;157(3):737–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. IBD in EPIC Study Investigators, Tjonneland A, Overvad K, et al. Linoleic acid, a dietary n-6 polyunsaturated fatty acid, and the aetiology of ulcerative colitis: a nested case-control study within a European prospective cohort study. Gut. 2009;58(12):1606–11.

    Article  CAS  Google Scholar 

  48. Kasala ER, Bodduluru LN, Barua CC, et al. Antioxidant and antitumor efficacy of Luteolin, a dietary flavone on benzo(a)pyrene-induced experimental lung carcinogenesis. Biomed Pharmacother. 2016;82:568–77.

    Article  CAS  PubMed  Google Scholar 

  49. Laviano A, Cascino A, Muscaritoli M, et al. Tumor-induced changes in host metabolism: a possible role for freetryptophan as a marker of neoplastic disease. Adv Exp Med Biol. 2003;527:363–6.

    Article  CAS  PubMed  Google Scholar 

  50. Zitvogel L, Ayyoub M, Routy B, et al. Microbiome and Anticancer Immunosurveillance. Cell. 2016;165(2):276–87.

    Article  CAS  PubMed  Google Scholar 

  51. Mima K, Sukawa Y, Nishihara R, et al. Fusobacterium nucleatum and T cells in colorectal carcinoma. JAMA Oncol. 2015;1(5):653–61.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Atarshi K, Tanoue T, Shima T, et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science. 2011;331(6015):337–41.

    Article  CAS  Google Scholar 

  53. Hegazy AN, West NR, Stubbington MJT, et al. Circulating and tissue-resident CD4+ T cells with reactivity to intestinal microbiota are abundant in healthy individuals and function is altered during inflammation. Gastroenterology. 2017;153(5):1320–37.

    Article  CAS  PubMed  Google Scholar 

  54. Liang S, Xu L, Zhang D, et al. Effect of probiotics on small intestinal bacterial overgrowth in patients with gastric and colorectal cancer. Turk J Gastroenterol. 2016;27:227–32.

    Article  PubMed  Google Scholar 

Download references

Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 61435001), CAMS Innovation Fund for Medical Sciences (Nos. 2017-I2M-4-003, No.2016-I2M-1-001).

Author information

Authors and Affiliations

  1. Department of Oncology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100730, China

    Ningning Li, Chunmei Bai, Lin Zhao, Yuping Ge & Xiaoyuan Li

Authors
  1. Ningning Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chunmei Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lin Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yuping Ge
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaoyuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

NL designed the study, analyzed the data, and wrote the manuscript. CB, and LZ contributed to the data interpretation and the revision of the manuscript. NL, YG, and XL performed the sample collection. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Chunmei Bai.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

This study was approved by the Ethics Committee of Peking Union Medical College Hospital.

Consent participate

All participants approved to participate, and written informed consent was obtained.

Consent for publication

All of the co-authors consented to publish this manuscript. A copy of the written consent is available for review.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, N., Bai, C., Zhao, L. et al. Characterization of the fecal microbiota in gastrointestinal cancer patients and healthy people. Clin Transl Oncol 24, 1134–1147 (2022). https://doi.org/10.1007/s12094-021-02754-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12094-021-02754-y

Keywords

Search

Navigation